Article

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

Prostate cancer is the most common noncutaneous cancer in men, accounting for 29% of all incident cancer cases.¹ Typically, prostate cancer metastasizes to bone and regional lymph nodes.² However, intrathoracic manifestation may occur. This report presents 3 cases of rare intrathoracic manifestations of metastatic prostate cancer with a review of the current literature.

CASE PRESENTATIONS

Case 1

A 71-year-old male who was an active smoker and a long-standing employment as a plumber was diagnosed with rectal cancer in 2022. He completed neoadjuvant capecitabine and radiation therapy followed by a rectosigmoidectomy. Several weeks after surgery, the patient presented to the emergency department (ED) with a dry cough and worsening shortness of breath. Point-of-care ultrasound of the lungs revealed a moderate right pleural effusion with several nodular pleural masses. A chest computed tomography (CT) confirmed these findings (Figure 1). A CT of the abdomen and pelvis revealed prostatomegaly with the medial lobe of the prostate protruding into the bladder; however, no enlarged retroperitoneal, mesenteric or pelvic lymph nodes were noted. The patient underwent a right pleural fluid drainage and pleural mass biopsy. Pleural mass histomorphology as well as immunohistochemical (IHC) stains were consistent with metastatic prostate adenocarcinoma. The pleural fluid cytology also was consistent with metastatic prostate adenocarcinoma.

Immunohistochemistry showed weak positive staining for prostate-specific NK3 homeobox 1 gene (NKX3.1), alpha-methylacyl-CoA racemase gene (AMACR), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), and prosaposin, and negative transcription termination factor (TTF-1), keratin-7 (CK7), keratin-20, and caudal type homeobox 2 gene (CDX2) (Figure 2) 2). The patient's prostate-specific antigen (PSA) was found to be elevated at 33.9 ng/mL (reference range, < 4 ng/mL).

Case 2

A 71-year-old male with a history of alcohol use disorder and a 30-year smoking history presented to the ED with worsening dyspnea on exertion. The patient’s baseline exercise tolerance decreased to walking for only 1 block. He reported unintentional weight loss of about 30 pounds over the prior year, no recent respiratory infections, no prior breathing problems, and no personal or family history of cancer. Chest CT revealed findings of bilateral peribronchial opacities as well as mediastinal and hilar lymphadenopathy (Figure 3). The patient developed hypoxic respiratory failure necessitating intubation, mechanical ventilation, and management in the medical intensive care unit, where he was treated for postobstructive pneumonia. Fiberoptic bronchoscopy revealed endobronchial lesions in the right and left upper lobe that were partially obstructing the airway (Figure 4).

The endobronchial masses were debulked using forceps, and samples were sent for surgical pathology evaluation. Staging was completed using linear endobronchial ultrasound, which revealed an enlarged subcarinal lymph node (S7). The surgical pathology of the endobronchial mass and the subcarinal lymph node cytology were consistent with metastatic adenocarcinoma of the prostate. The tumor cells were positive for AE1/AE3, PSA, and NKX3.1, but were negative for CK7 and TTF-1 (Figure 5). Further imaging revealed an enlarged heterogeneous prostate gland, prominent pelvic nodes, and left retroperitoneal lymphadenopathy, as well as sclerotic foci within the T10 vertebral body and right inferior pubic ramus. PSA was also found to be significantly elevated at 700 ng/mL.

Case 3

An 80-year-old male veteran with a history of prostate cancer and recently diagnosed T2N1M0 head and neck squamous cell carcinoma was referred to the Pulmonary service for evaluation of a pulmonary nodule. His medical history was notable for prostate cancer diagnosed 12 years earlier, with an unknown Gleason score. Initial treatment included prostatectomy followed by whole pelvic radiation therapy a year after, due to elevated PSA in surveillance monitoring. This treatment led to remission. After establishing remission for > 10 years, the patient was started on low-dose testosterone replacement therapy to address complications of radiation therapy, namely hypogonadism.

On evaluation, a chest CT was significant for a large 2-cm right middle lobe nodule (Figure 6). At that time, PSA was noted to be borderline elevated at 4.2 ng/mL, and whole-body imaging did not reveal any lesions elsewhere, specifically no bone metastasis. Biopsies of the right middle lobe lung nodule revealed adenocarcinoma consistent with metastatic prostate cancer. Testosterone therapy was promptly discontinued.

The patient initially refused androgen deprivation therapy owing to the antiandrogenic adverse effects. However, subsequent chest CTs revealed growing lung nodules, which convinced him to proceed with androgen deprivation therapy followed by palliative radiation, and chemotherapy and management of malignant pleural effusion with indwelling small bore pleural catheter for about 10 years. He died from COVID-19 during the pandemic.

DISCUSSION

These cases highlight the importance of including prostate cancer in the differential diagnoses of male patients with intrathoracic abnormalities, even in the absence of metastasis to the more common sites. In a large cohort study of 74,826 patients with metastatic prostate cancer, Gandaglia et al found that the most frequent sites of metastasis were bone (84.0%) and distant lymph nodes (10.6%).2 However, thoracic involvement was observed in 9.1% of cases, with isolated thoracic metastasis being rare. The cases described in this report exemplify exceptionally uncommon occurrences within that 9.1%.

Pleural metastases, as observed in Case 1, are a particularly rare manifestation. In a 10-year retrospective assessment, Vinjamoori et al discovered pleural nodules or masses in only 6 of 82 patients (7.3%) with atypical metastases.³ Adrenal and liver metastases accounted for 15% and 37% of cases with atypical distribution. As such, isolated pleural disease is rare even in atypical presentations.³

As seen in Case 2, endobronchial metastases producing airway obstruction are also rare, with the most common primary cancers associated with endobronchial metastasis being breast, colon, and renal cancer.⁴ The available literature on this presentation is confined to case reports. Hameed et al reported a case of synchronous biopsy-proven endobronchial metastasis from prostate cancer.⁵ These cases highlight the importance of maintaining a high level of clinical awareness when encountering endobronchial lesions in patients with prostate cancer.

Case 3 presents a unique situation of lung metastases without any involvement of the bones. It is well known—and was confirmed by Heidenreich et al—that lung metastases in prostate adenocarcinoma usually coincide with extensive osseous disease.⁶ This instance highlights the importance of watchful monitoring for unusual patterns of cancer recurrence.

Immunohistochemistry stains that are specific to prostate cancer include antibodies against PSA. Prostate-specific membrane antigen is another marker that is far more present in malignant than in benign prostate tissue.

The NKX3.1 gene encodes a homeobox protein, which is a transcription factor and tumor suppressor. In prostate cancer, there is loss of heterozygosity of the gene and stains for the IHC antibody to NKX3.1.⁷

On the other hand, lung cells stain positive for TTF-1, which is produced by surfactant-producing type 2 pneumocytes and club cells in the lung. Antibodies to TTF-1, a common IHC stain, are used to identify adenocarcinoma of lung origin and may carry a prognostic value.⁷

The immunohistochemistry profiles, specifically the presence of prostate-specific markers such as PSA and NKX3.1, played a vital role in making the diagnosis.

In Case 1, weak TTF-1 positivity was noted, an unusual finding in metastatic prostate adenocarcinoma. Marak et al documented a rare case of TTF-1–positive metastatic prostate cancer, illustrating the potential for diagnostic confusion with primary lung malignancies.⁸

The 3 cases described in this report demonstrate the importance of clinical consideration, serial follow-up of PSA levels, using more prostate-specific positron emission tomography tracers (eg, Pylarify) alongside traditional imaging, and tissue biopsy to detect unusual metastases.

CONCLUSIONS

Although thoracic metastases from prostate cancer are rare, these presentations highlight the importance of clinical awareness regarding atypical cases. Pleural disease, endobronchial lesions, and isolated pulmonary nodules might be the first clinical manifestation of metastatic prostate cancer. A high index of suspicion, appropriate imaging, and judicious use of immunohistochemistry are important to ensure accurate diagnosis and optimal patient management.

The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.¹ The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.²

Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.³ Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.^4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.⁶

The incidence of melanoma may be higher in the military population compared with the general population.⁷ Melanoma is the fourth-most common cancer diagnosed in veterans.⁸

Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.⁹ According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.⁸

Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.

Methods

A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.

The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.^4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.^6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P  values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.

Results

The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.

The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.^10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.¹² Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).¹³ Table 5 outlines statistically significant findings.

Agent Orange Subgroup

AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.¹⁴ However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.

Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.

Discussion

Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.⁸

Melanoma is one of the most highly mutated malignancies.¹⁵ Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.

Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.¹⁵TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.¹⁶ The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).

In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.¹⁷

This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.¹⁵ Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).

In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.

Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).¹² Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).¹³

One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.^10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.¹⁸ Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.

Limitations

This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.¹⁹

Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.²⁰ However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.²¹ Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.

The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.²² This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.

On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.²³ In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.

Conclusion

The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.

The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.¹ The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.²

Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.³ Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.^4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.⁶

The incidence of melanoma may be higher in the military population compared with the general population.⁷ Melanoma is the fourth-most common cancer diagnosed in veterans.⁸

Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.⁹ According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.⁸

Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.

Methods

A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.

The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.^4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.^6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P  values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.

Results

The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.

The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.^10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.¹² Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).¹³ Table 5 outlines statistically significant findings.

Agent Orange Subgroup

AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.¹⁴ However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.

Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.

Discussion

Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.⁸

Melanoma is one of the most highly mutated malignancies.¹⁵ Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.

Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.¹⁵TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.¹⁶ The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).

In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.¹⁷

This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.¹⁵ Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).

In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.

Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).¹² Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).¹³

One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.^10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.¹⁸ Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.

Limitations

This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.¹⁹

Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.²⁰ However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.²¹ Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.

The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.²² This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.

On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.²³ In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.

Conclusion

The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.

The veteran population, with its unique and diverse types of exposure and military service experiences, faces distinct health factors compared with the general population. These factors can be categorized into exposures during military service and those occurring postservice. While the latter phase incorporates psychological issues that may arise while transitioning to civilian life, the service period is associated with major physical, chemical, and psychological exposures that can impact veterans’ health. Carcinogenesis related to military exposures is concerning, and different types of malignancies have been associated with military exposures.¹ The 2022 introduction of the Cancer Moonshot initiative served as a breeding ground for multiple projects aimed at investigation of exposure-related carcinogenesis, prompting increased attention and efforts to linking specific exposures to specific malignancies.²

Melanoma is the deadliest skin cancer, accounting for 1.3% of all cancer deaths.³ Although it may only account for 1% to 5% of skin cancer diagnoses, its incidence in the United States’ population has been increasing.^4,5 There were 97,610 estimated new cases of melanoma in 2023, according to the National Cancer Institute.⁶

The incidence of melanoma may be higher in the military population compared with the general population.⁷ Melanoma is the fourth-most common cancer diagnosed in veterans.⁸

Several demographic characteristics of the US military population are associated with higher melanoma incidence and poorer prognosis, including male sex, older age, and White race. Apart from sun exposure—a known risk factor for melanoma development—other factors, such as service branch, seem to contribute to risk, with the highest melanoma rates noted in the Air Force.⁹ According to a study by Chang et al, veterans have a higher risk of stage III (18%) or stage IV (13%) melanoma at initial diagnosis.⁸

Molecular testing of metastatic melanoma is currently the standard of care for guiding the use of US Food and Drug Administration-approved targeted therapies such as BRAF, MEK, and KIT inhibitors. This comparative analysis details the melanoma comprehensive genomic profiles observed at a large US Department of Veterans Affairs (VA) medical center (VAMC) and those reported in reference databases.

Methods

A query to select all metastatic melanomas sent for comprehensive genomic profiling from the Kansas City VAMC (KCVAMC), identified 35 cases from 2019 through 2023 as the study population. The health records of these patients were reviewed to collect demographic information, military service history, melanoma history, other medical, social, and family histories. The comprehensive genomic profiling reports were reviewed to collect the reported pathogenic variants, microsatellite instability (MSI) status, and tumor mutational burden (TMB) for each case.

The Catalogue of Somatic Mutations in Cancer (COSMIC) was used to identify the most commonly mutated genes in melanomas from The Cancer Genome Atlas for the general population.^4,5 The literature was consulted to determine the MSI status and TMB in melanomas from The Cancer Genome Atlas for separate reference populations.^6,7 The frequency of MSI-high (MSI-H) status, TMB ≥ 10 mutations/megabase (mut/Mb), and mutations in each of the 20 most commonly mutated genes was determined and compared between melanomas from The Cancer Genome Atlas and KCVAMC cases. Corresponding P  values were calculated to identify significant differences. Values were calculated for the entire sample as well as a subgroup with Agent Orange (AO) exposure. The study was approved by the KCVAMC Institutional Review Board.

Results

The mean (SD) age of study participants was 72.9 (9.4) years (range, 39-90 years). The mean (SD) duration of military service was 1654 (1421) days (about 4 years, 6 months, and 10 days). Of the 35 patients included, 22 (63%) served during the Vietnam era (November 1, 1965, to April 30, 1975) and 2 (6%) served during the Persian Gulf War era (August 2, 1990, to February 28, 1991). Seventeen veterans (49%) served in the Army, 9 in the Navy (26%), 5 in the Air Force (14%), and 4 in the Marine Corps (11%). Definitive AO exposure was noted in 13 patients (37%) (Table 1).

Of the 35 patients, 24 (69%) had metastatic disease and the primary site of melanoma was unknown in 14 patients (40%). One patient (Patient 32) had an intraocular melanoma. The primary site was the trunk for 11 patients (31%), the face/head for 7 patients (20%) and extremities for 3 patients (9%). Eight patients (23%) were pT3 stage (thickness > 2 mm but < 4 mm), 7 patients (20%) were pT4 stage (thickness > 4 mm), and 5 patients (14%) were pT1 (thickness ≥ 1 mm). One patient had a primary lesion at pT2 stage, and 1 had a Tis stage lesion. Three patients (9%) had a family history of melanoma in a first-degree relative.

The list of genes mutated in melanoma cells in the study population is provided in the eAppendix.^10,11 Twenty-seven patients (77%) had mutations in TERT promoter, 15 (43%) in CDKN2A/B, 13 (37%) in BRAF, 11 (31%) in NF1, 9 (26%) in TP53, and 8 (23%) in NRAS (Table 2). The majority of mutations in TERT promoter were c.- 146C>T (18 of 27 patients [67%]), whereas c.-124C>T was the second-most common (8 of 27 patients [30%]). The 2 observed mutations in the 13 patients with BRAF mutations were V600E and V600K, with almost equal distribution (54% and 46%, respectively). The mean (SD) TMB was 33.2 (39) mut/Mb (range, 1-203 mut/Mb). Ten patients (29%) had a TMB < 10 mut/Mb, whereas 24 (69%) had a TMB > 10 mut/Mb. The TMB could not be determined in 1 case. The frequency of TMB-high tumors in the study population compared with frequency in the reference population is shown in Table 3.¹² Only 3 patients (0.64%) in the reference population had MSI-H tumors, and the microsatellite status could not be determined in those tumors (Table 4).¹³ Table 5 outlines statistically significant findings.

Agent Orange Subgroup

AO was a tactical herbicide used by the US military, named for the orange band around the storage barrels. Possible mutagenic properties of AO have been attributed to its byproduct, dioxin. Among the most common cancers known to be associated with AO exposure are bladder and prostate carcinoma and hematopoietic neoplasms. The association between genetic alterations and AO exposure was studied in veterans with prostate cancer.¹⁴ However, to our knowledge, insufficient information is available to determine whether an association exists between exposure to herbicides used in Vietnam or the contaminant dioxin and melanoma. Because a significant proportion of this study population had a well-documented history of AO exposure (37.1%), we were able to analyze them as a subgroup and to separately compare their mutation frequency with the general population.

Results were notable for different distributions of the most frequently mutated genes in the AO subgroup compared with the whole study population. As such, TERT promoter remained the most frequently mutated gene (92%), followed by CDKN2A/B (46%); however, frequency of mutations in NF1 (46%) outnumbered those of BRAF (31%), the fourth-most common mutation. Moreover, when compared with the general melanoma population, a significantly higher frequency of mutations in the NF1 gene was observed in the AO subgroup—not the entire study population.

Discussion

Given that veterans constitute a distinct population, there is reasonable interest in investigating characteristic health issues related to military service. Skin cancer—melanoma in particular—has been researched recently in a veteran population. The differences in demographics, tumor characteristics, and melanoma- specific survival in veterans compared with the general population have already been assessed. According to Chang et al, compared with the general population, veterans are more likely to present with metastatic disease and have lower 5-year survival rates.⁸

Melanoma is one of the most highly mutated malignancies.¹⁵ Fortunately, the most common mutation in melanoma, BRAF V600E, is now considered therapeutically targetable. However, there are still many mutations that are less often discussed and not well understood. Regardless of therapeutic implications, all mutations observed in melanoma are worth investigating because a tumor’s genomic profile also can provide prognostic and etiologic information. Developing comprehensive descriptions of melanoma mutational profiles in specific populations is critical to advancing etiologic understanding and informing prevention strategies.

Our results demonstrate the high prevalence of TERT promoter mutations with characteristic ultraviolet signature (C>T) in the study population. This aligns with general evidence that TERT promoter mutations are common in cutaneous melanomas: 77% of this study sample and up to 86% of all mutations are TERT promoter mutations, according to Davis et al.¹⁵TERT promoter mutations are positively associated with the initiation, invasion, and metastasis of melanoma. In certain subtypes, there is evidence that the presence of TERT promoter mutations is significantly associated with risk for extranodal metastasis and death.¹⁶ The second-most common mutated gene in the veteran study population was CDKN2A/B (43%), and the third-most mutated gene was BRAF (37%).

In chronically sun-exposed skin NF1, NRAS, and occasionally BRAF V600K mutations tend to predominate. BRAF V600E mutations, on the other hand, are rare in these melanomas.15 In our study population, the most prevalent melanoma site was the trunk (31%), which is considered a location with an intermittent pattern of sun exposure.¹⁷

This study population also had a higher frequency of CDKN2A/B mutations. High frequencies of CDKN2A/B mutations have been reported in familial melanomas, but only 1 patient with CDKN2A/B mutations had a known family history of melanoma.¹⁵ Tumors in the study population showed significantly lower frequency of mutations in ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 (P < .05).

In this study the subgroup of veterans with AO exposure differed from the whole study population. As such, CDKN2A/B mutations were observed with the same frequency as NF1 mutations (46% each); however, BRAF mutations constituted only 31% of the mutations. In addition, the frequency of NF1 mutations was significantly higher in the AO subgroup compared with the general population, but not in the whole study population.

Our sample also differed from the reference population by showing a significantly higher frequency of TMB-high (ie, ≥ 10 mut/Mb) tumors (71% vs 49%; P = .01).¹² Interestingly, no significant difference in the frequency of TMB-high tumors was observed between the AO subgroup and the reference population (69% vs 49%; P = .16). There also was no statistically significant difference between the frequency of MSI-H tumors in our study population and the reference population (P = .64).¹³

One patient in the study population had uveal melanoma. Mutations encountered in this patient’s tumor differed from the general mutational profile of tumors. None of the 21 mutations depicted in Table 2 were present in this sample.^10,11 On the other hand, those mutations frequently observed in intraocular melanomas, BAP1 and GNA11, were present in this patient.¹⁸ Additionally, this particular melanoma possessed mutations in genes RICTOR, RAD21, and PIK3R1.

Limitations

This study population consisted exclusively of male patients, introducing sex as a potential confounder in analyzing differences between the study population and the general population. As noted in a 2020 systematic review, there were no sex-based differences in the frequency of mutations in BRAF, NRAS, and KIT genes.¹⁹

Regarding NF1 mutations, only NF1-mutated acral and mucosal melanomas were more frequently observed in female patients, whereas nonacral NF1-mutated melanomas were more frequently observed in male patients.²⁰ However, there is currently no clear evidence of whether the mutational landscapes of cutaneous melanoma differ by sex.²¹ Among the 11 cases with NF1-mutatation, site of origin was known in 6, 5 of which originated at nonacral sites. Although the AO subgroup also consisted entirely of male patients, this does not explain the observed increased frequency of NF1 mutations relative to the general population. No such difference was observed between the whole study population, which also consisted exclusively of male patients, and the general population. The similar frequencies of nonacral location in the whole study population (3 acral, 18 nonacral, 14 unknown site of origin) and AO subgroup (1 acral, 7 nonacral, 5 unknown site of origin) preclude location as an explanation.

The Cancer Genome Atlas Network proposed a framework for genomic classification of melanoma into 4 subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and triple–wild-type. According to that study, BRAF mutations were indeed associated with younger age, in contrast to the NF1-mutant genomic subtype, which was more prevalent in older individuals with higher TMB.²² This emphasizes the need to interpret the potential association of AO exposure and NF1 mutation in melanoma with caution, although additional studies are required to observe the difference between the veteran population and age-matched general population.

On the other hand, Yu et al reported no significant differences of TMB values between patients aged < 60 and ≥ 60 years with melanoma.²³ In short, the observed differences we report in our limited study warrant additional investigation with larger sample sizes, sex-matched controlling, and age-matched controlling. The study was limited by its small sample size and the single location.

Conclusion

The genomic profile of melanomas in the veteran population appears to be similar to that of the general population with a few possible differences. Melanomas in the veteran study population showed a higher frequency of CDKN2A/B mutations; lower frequency of ROS1, GRIN2A, KDR, KMT2C (MLL3), KMT2D (MLL2), LRP1B, PTPRT, PTCH1, FAT4, and PREX2 mutations; and higher TMB. In addition, melanomas in the AO subgroup showed higher frequencies of NF1 mutations. The significance of such findings remains to be determined by further investigation.

A syringe services program (SSP) is a harm reduction strategy designed to improve the quality of care provided to people who use drugs (PWUD). SSPs not only provide sterile syringes but establish a connection to medical services and resources for the safe disposal of syringes. By engaging with an SSP, patients may receive naloxone, condoms, fentanyl test strips, opioid use disorder medications, vaccinations, or testing for infectious diseases such as HIV and hepatitis C virus (HCV). Patients may also be connected to housing or social work services.

SSPs do not lead to increased drug use,¹ increased improperly disposed supplies needed for drug use in the community, or increased crime.^2,3 New users of SSPs are 5 times more likely to enter treatment for drug use than those who do not use SSPs.^4-8 Further, SSPs have been found to reduce HIV and HCV transmission and are cost-effective in HIV prevention.^9-11

Syringe Services Program

SSPs were implemented at the US Department of Veterans Affairs (VA) Alaska VA Healthcare System (AVAHCS) and VA Southern Oregon Healthcare System (VASOHCS). AVAHCS provides outpatient care across Alaska, with sites in Anchorage, Fairbanks, Homer, Juneau, Wasilla, and Soldotna. VASOHCS provides outpatient care to Southern Oregon and Northern California, with sites in White City, Grants Pass, and Klamath Falls, Oregon. Both are part of Veterans Integrated Service Network 20

Workgroups at AVAHCS and VASOHCS developed SSPs to reduce risks associated with drug use, promote positive outcomes for PWUD, and increase availability of harm reduction resources. During the July 2023 to June 2024 pharmacy residency cycle, an ambulatory care pharmacy resident from the Veterans Integrated Services Network 20 Clinical Resource Hub—a regional resource for clinical services—joined the workgroups. The workgroups established a goal that SSP resources would be made available to enrolled patients without any exclusions, prioritizing health equity.

SSP implementation needed buy-in from AVAHCS and VASOHCS leadership and key stakeholders who could participate in the workgroups. Following AVAHCS and VASOHCS leadership approval, each facility workgroup drafted standard operating procedures (SOPs). Both facilities planned to implement the program using prepackaged kits (sterile syringes, alcohol pads, cotton swabs, a sharps container, and an educational brochure on safe injection practices) supplied by the VA National Harm Reduction Program.

Each SSP offered patients direct links to additional care options at the time of kit distribution, including information regarding medications/supplies (ie, hepatitis A/B vaccines, HIV preexposure prophylaxis, substance use disorder pharmacotherapy, naloxone, and condoms), laboratory tests for infectious and sexually transmitted diseases, and referrals to substance use disorder treatment, social work, suicide prevention, mental health, and primary care.

The goal was to implement both SSPs during the July 2023 to June 2024 residency year. Other goals included tracking the quantity of supplies distributed, the number of patients reached, the impact of clinician education on the distribution of supplies, and comparing the implementation of the SSPs in the electronic health record (EHR) systems.

Alaska VA Healthcare System

An SOP was approved on December 20, 2023, and national supply kits were stocked in collaboration with the logistics department at the Anchorage AVAHCS campus. Social and behavioral health teams, primary care social workers, primary care clinicians, and nursing staff received training on the resources available through the SSP. A local adaptation of a template was created in the Computerized Patient Records System (CPRS) EHR. The template facilitates SSP kit distribution and patient screening for additional resources. Patients can engage with the SSP through any trained staff member. The staff member then completes the template and helps to distribute the SSP kit, in collaboration with the logistics department. The SSP does not operate in a dedicated physical space. The behavioral health team is most actively engaged in the SSP. The goal of SSP is to have resources available anywhere a patient requests services, including primary care and specialty clinics and to empower staff to meet patients’ needs. One patient has utilized the SSP as of June 2025.

Southern Oregon Healthcare System

Kits were ordered and stocked as pharmacy items in preparation for dispensing while awaiting medical center policy approval. Education began with the primary care mental health integration team. After initial education, an interdisciplinary presentation was given to VASOHCS clinicians to increase knowledge of the SSP. To enable documentation of SSP engagement, a local template was developed in the Cerner EHR to be shared among care team members at the facility. Similar to AVAHCS, the SSP does not have a physical space. All trained facility staff may engage in the SSP and distribute SSP kits. The workgroup that implemented this program remains available to support staff. Five patients have accessed the SSP since November 2024 and 7 SSP kits have been distributed as of June 2025.

Discussion

The SSP workgroups sought to expand the program through additional education. A number of factors should be considered when implementing an SSP. Across facilities, program implementation can be time-consuming and the timeline for administrative processes may be long. The workgroups met weekly or monthly depending on the status of the program and the administrative processes. Materials developed included SOP and MCP documents, a 1-page educational handout on SSP offerings, and a PowerPoint presentation for initial clinician education. Involving a pharmacy resident supported professional development and accelerated implementation timelines.

The facilities differed in implementation. AVAHCS collaborated with the logistics department to distribute kits, while VASOHCS worked with the Pharmacy service. A benefit of collaborating with logistics is that patients can receive a kit at the point of contact with the health care system, receiving it directly from the clinic the patient is visiting while eliminating the need to make an additional stop at the pharmacy. Conversely, partnering with the Pharmacy service allowed supply kits to be distributed by mail, enabling patients direct access to kits without having to present in-person. This is particularly valuable considering the large geographical area and remote care services available at VASOHCS.

Implementation varied significantly because AVAHCS operated on CPRS while VASOHCS used Cerner, a newer EHR. AVAHCS adapted a national template produced for CPRS sites, while VASOHCS had to prepare a local template (auto-text) for SSP documentation. Future plans at AVAHCS may include adding fentanyl test strips as an orderable item in the EHR given that AVAHCS has a local instance of CPRS; however, VASOHCS cannot order fentanyl test strips through the Pharmacy service due to legal restrictions. While Oregon permits fentanyl test strip use, the Cerner instance used by VA is a national program, and therefore the addition of fentanyl test strips as an orderable item in the EHR would carry national implications, including for VA health care systems in states where fentanyl test strip legality is variable. Despite the challenges, efforts to include fentanyl test strips in both SSPs are ongoing.

No significant EHR changes were needed to make the national supply kits available in the Cerner EHR through the VASOHCS Pharmacy service. To have national supply kits available through the AVAHCS Pharmacy service, the EHR would need to be manipulated by adding a local drug file in CPRS. Differences between the EHRs often facilitated the need for adaptation from existing models of SSPs within VA, which were all based in CPRS.

Conclusions

The implementation of SSPs at AVAHCS and VASOHCS enable clinicians to provide quality harm reduction services to PWUD. Despite variations in EHR systems, AVAHCS and VASOHCS implemented SSP within 1 year. Tracking of program engagement via the number of patients interacting with the program and the number of SSP kits distributed will continue. SSP implementation in states where it is permitted may help provide optimal patient care for PWUD.

A syringe services program (SSP) is a harm reduction strategy designed to improve the quality of care provided to people who use drugs (PWUD). SSPs not only provide sterile syringes but establish a connection to medical services and resources for the safe disposal of syringes. By engaging with an SSP, patients may receive naloxone, condoms, fentanyl test strips, opioid use disorder medications, vaccinations, or testing for infectious diseases such as HIV and hepatitis C virus (HCV). Patients may also be connected to housing or social work services.

SSPs do not lead to increased drug use,¹ increased improperly disposed supplies needed for drug use in the community, or increased crime.^2,3 New users of SSPs are 5 times more likely to enter treatment for drug use than those who do not use SSPs.^4-8 Further, SSPs have been found to reduce HIV and HCV transmission and are cost-effective in HIV prevention.^9-11

Syringe Services Program

SSPs were implemented at the US Department of Veterans Affairs (VA) Alaska VA Healthcare System (AVAHCS) and VA Southern Oregon Healthcare System (VASOHCS). AVAHCS provides outpatient care across Alaska, with sites in Anchorage, Fairbanks, Homer, Juneau, Wasilla, and Soldotna. VASOHCS provides outpatient care to Southern Oregon and Northern California, with sites in White City, Grants Pass, and Klamath Falls, Oregon. Both are part of Veterans Integrated Service Network 20

Workgroups at AVAHCS and VASOHCS developed SSPs to reduce risks associated with drug use, promote positive outcomes for PWUD, and increase availability of harm reduction resources. During the July 2023 to June 2024 pharmacy residency cycle, an ambulatory care pharmacy resident from the Veterans Integrated Services Network 20 Clinical Resource Hub—a regional resource for clinical services—joined the workgroups. The workgroups established a goal that SSP resources would be made available to enrolled patients without any exclusions, prioritizing health equity.

SSP implementation needed buy-in from AVAHCS and VASOHCS leadership and key stakeholders who could participate in the workgroups. Following AVAHCS and VASOHCS leadership approval, each facility workgroup drafted standard operating procedures (SOPs). Both facilities planned to implement the program using prepackaged kits (sterile syringes, alcohol pads, cotton swabs, a sharps container, and an educational brochure on safe injection practices) supplied by the VA National Harm Reduction Program.

Each SSP offered patients direct links to additional care options at the time of kit distribution, including information regarding medications/supplies (ie, hepatitis A/B vaccines, HIV preexposure prophylaxis, substance use disorder pharmacotherapy, naloxone, and condoms), laboratory tests for infectious and sexually transmitted diseases, and referrals to substance use disorder treatment, social work, suicide prevention, mental health, and primary care.

The goal was to implement both SSPs during the July 2023 to June 2024 residency year. Other goals included tracking the quantity of supplies distributed, the number of patients reached, the impact of clinician education on the distribution of supplies, and comparing the implementation of the SSPs in the electronic health record (EHR) systems.

Alaska VA Healthcare System

An SOP was approved on December 20, 2023, and national supply kits were stocked in collaboration with the logistics department at the Anchorage AVAHCS campus. Social and behavioral health teams, primary care social workers, primary care clinicians, and nursing staff received training on the resources available through the SSP. A local adaptation of a template was created in the Computerized Patient Records System (CPRS) EHR. The template facilitates SSP kit distribution and patient screening for additional resources. Patients can engage with the SSP through any trained staff member. The staff member then completes the template and helps to distribute the SSP kit, in collaboration with the logistics department. The SSP does not operate in a dedicated physical space. The behavioral health team is most actively engaged in the SSP. The goal of SSP is to have resources available anywhere a patient requests services, including primary care and specialty clinics and to empower staff to meet patients’ needs. One patient has utilized the SSP as of June 2025.

Southern Oregon Healthcare System

Kits were ordered and stocked as pharmacy items in preparation for dispensing while awaiting medical center policy approval. Education began with the primary care mental health integration team. After initial education, an interdisciplinary presentation was given to VASOHCS clinicians to increase knowledge of the SSP. To enable documentation of SSP engagement, a local template was developed in the Cerner EHR to be shared among care team members at the facility. Similar to AVAHCS, the SSP does not have a physical space. All trained facility staff may engage in the SSP and distribute SSP kits. The workgroup that implemented this program remains available to support staff. Five patients have accessed the SSP since November 2024 and 7 SSP kits have been distributed as of June 2025.

Discussion

The SSP workgroups sought to expand the program through additional education. A number of factors should be considered when implementing an SSP. Across facilities, program implementation can be time-consuming and the timeline for administrative processes may be long. The workgroups met weekly or monthly depending on the status of the program and the administrative processes. Materials developed included SOP and MCP documents, a 1-page educational handout on SSP offerings, and a PowerPoint presentation for initial clinician education. Involving a pharmacy resident supported professional development and accelerated implementation timelines.

The facilities differed in implementation. AVAHCS collaborated with the logistics department to distribute kits, while VASOHCS worked with the Pharmacy service. A benefit of collaborating with logistics is that patients can receive a kit at the point of contact with the health care system, receiving it directly from the clinic the patient is visiting while eliminating the need to make an additional stop at the pharmacy. Conversely, partnering with the Pharmacy service allowed supply kits to be distributed by mail, enabling patients direct access to kits without having to present in-person. This is particularly valuable considering the large geographical area and remote care services available at VASOHCS.

Implementation varied significantly because AVAHCS operated on CPRS while VASOHCS used Cerner, a newer EHR. AVAHCS adapted a national template produced for CPRS sites, while VASOHCS had to prepare a local template (auto-text) for SSP documentation. Future plans at AVAHCS may include adding fentanyl test strips as an orderable item in the EHR given that AVAHCS has a local instance of CPRS; however, VASOHCS cannot order fentanyl test strips through the Pharmacy service due to legal restrictions. While Oregon permits fentanyl test strip use, the Cerner instance used by VA is a national program, and therefore the addition of fentanyl test strips as an orderable item in the EHR would carry national implications, including for VA health care systems in states where fentanyl test strip legality is variable. Despite the challenges, efforts to include fentanyl test strips in both SSPs are ongoing.

No significant EHR changes were needed to make the national supply kits available in the Cerner EHR through the VASOHCS Pharmacy service. To have national supply kits available through the AVAHCS Pharmacy service, the EHR would need to be manipulated by adding a local drug file in CPRS. Differences between the EHRs often facilitated the need for adaptation from existing models of SSPs within VA, which were all based in CPRS.

Conclusions

The implementation of SSPs at AVAHCS and VASOHCS enable clinicians to provide quality harm reduction services to PWUD. Despite variations in EHR systems, AVAHCS and VASOHCS implemented SSP within 1 year. Tracking of program engagement via the number of patients interacting with the program and the number of SSP kits distributed will continue. SSP implementation in states where it is permitted may help provide optimal patient care for PWUD.

A syringe services program (SSP) is a harm reduction strategy designed to improve the quality of care provided to people who use drugs (PWUD). SSPs not only provide sterile syringes but establish a connection to medical services and resources for the safe disposal of syringes. By engaging with an SSP, patients may receive naloxone, condoms, fentanyl test strips, opioid use disorder medications, vaccinations, or testing for infectious diseases such as HIV and hepatitis C virus (HCV). Patients may also be connected to housing or social work services.

SSPs do not lead to increased drug use,¹ increased improperly disposed supplies needed for drug use in the community, or increased crime.^2,3 New users of SSPs are 5 times more likely to enter treatment for drug use than those who do not use SSPs.^4-8 Further, SSPs have been found to reduce HIV and HCV transmission and are cost-effective in HIV prevention.^9-11

Syringe Services Program

SSPs were implemented at the US Department of Veterans Affairs (VA) Alaska VA Healthcare System (AVAHCS) and VA Southern Oregon Healthcare System (VASOHCS). AVAHCS provides outpatient care across Alaska, with sites in Anchorage, Fairbanks, Homer, Juneau, Wasilla, and Soldotna. VASOHCS provides outpatient care to Southern Oregon and Northern California, with sites in White City, Grants Pass, and Klamath Falls, Oregon. Both are part of Veterans Integrated Service Network 20

Workgroups at AVAHCS and VASOHCS developed SSPs to reduce risks associated with drug use, promote positive outcomes for PWUD, and increase availability of harm reduction resources. During the July 2023 to June 2024 pharmacy residency cycle, an ambulatory care pharmacy resident from the Veterans Integrated Services Network 20 Clinical Resource Hub—a regional resource for clinical services—joined the workgroups. The workgroups established a goal that SSP resources would be made available to enrolled patients without any exclusions, prioritizing health equity.

SSP implementation needed buy-in from AVAHCS and VASOHCS leadership and key stakeholders who could participate in the workgroups. Following AVAHCS and VASOHCS leadership approval, each facility workgroup drafted standard operating procedures (SOPs). Both facilities planned to implement the program using prepackaged kits (sterile syringes, alcohol pads, cotton swabs, a sharps container, and an educational brochure on safe injection practices) supplied by the VA National Harm Reduction Program.

Each SSP offered patients direct links to additional care options at the time of kit distribution, including information regarding medications/supplies (ie, hepatitis A/B vaccines, HIV preexposure prophylaxis, substance use disorder pharmacotherapy, naloxone, and condoms), laboratory tests for infectious and sexually transmitted diseases, and referrals to substance use disorder treatment, social work, suicide prevention, mental health, and primary care.

The goal was to implement both SSPs during the July 2023 to June 2024 residency year. Other goals included tracking the quantity of supplies distributed, the number of patients reached, the impact of clinician education on the distribution of supplies, and comparing the implementation of the SSPs in the electronic health record (EHR) systems.

Alaska VA Healthcare System

An SOP was approved on December 20, 2023, and national supply kits were stocked in collaboration with the logistics department at the Anchorage AVAHCS campus. Social and behavioral health teams, primary care social workers, primary care clinicians, and nursing staff received training on the resources available through the SSP. A local adaptation of a template was created in the Computerized Patient Records System (CPRS) EHR. The template facilitates SSP kit distribution and patient screening for additional resources. Patients can engage with the SSP through any trained staff member. The staff member then completes the template and helps to distribute the SSP kit, in collaboration with the logistics department. The SSP does not operate in a dedicated physical space. The behavioral health team is most actively engaged in the SSP. The goal of SSP is to have resources available anywhere a patient requests services, including primary care and specialty clinics and to empower staff to meet patients’ needs. One patient has utilized the SSP as of June 2025.

Southern Oregon Healthcare System

Kits were ordered and stocked as pharmacy items in preparation for dispensing while awaiting medical center policy approval. Education began with the primary care mental health integration team. After initial education, an interdisciplinary presentation was given to VASOHCS clinicians to increase knowledge of the SSP. To enable documentation of SSP engagement, a local template was developed in the Cerner EHR to be shared among care team members at the facility. Similar to AVAHCS, the SSP does not have a physical space. All trained facility staff may engage in the SSP and distribute SSP kits. The workgroup that implemented this program remains available to support staff. Five patients have accessed the SSP since November 2024 and 7 SSP kits have been distributed as of June 2025.

Discussion

The SSP workgroups sought to expand the program through additional education. A number of factors should be considered when implementing an SSP. Across facilities, program implementation can be time-consuming and the timeline for administrative processes may be long. The workgroups met weekly or monthly depending on the status of the program and the administrative processes. Materials developed included SOP and MCP documents, a 1-page educational handout on SSP offerings, and a PowerPoint presentation for initial clinician education. Involving a pharmacy resident supported professional development and accelerated implementation timelines.

The facilities differed in implementation. AVAHCS collaborated with the logistics department to distribute kits, while VASOHCS worked with the Pharmacy service. A benefit of collaborating with logistics is that patients can receive a kit at the point of contact with the health care system, receiving it directly from the clinic the patient is visiting while eliminating the need to make an additional stop at the pharmacy. Conversely, partnering with the Pharmacy service allowed supply kits to be distributed by mail, enabling patients direct access to kits without having to present in-person. This is particularly valuable considering the large geographical area and remote care services available at VASOHCS.

Implementation varied significantly because AVAHCS operated on CPRS while VASOHCS used Cerner, a newer EHR. AVAHCS adapted a national template produced for CPRS sites, while VASOHCS had to prepare a local template (auto-text) for SSP documentation. Future plans at AVAHCS may include adding fentanyl test strips as an orderable item in the EHR given that AVAHCS has a local instance of CPRS; however, VASOHCS cannot order fentanyl test strips through the Pharmacy service due to legal restrictions. While Oregon permits fentanyl test strip use, the Cerner instance used by VA is a national program, and therefore the addition of fentanyl test strips as an orderable item in the EHR would carry national implications, including for VA health care systems in states where fentanyl test strip legality is variable. Despite the challenges, efforts to include fentanyl test strips in both SSPs are ongoing.

No significant EHR changes were needed to make the national supply kits available in the Cerner EHR through the VASOHCS Pharmacy service. To have national supply kits available through the AVAHCS Pharmacy service, the EHR would need to be manipulated by adding a local drug file in CPRS. Differences between the EHRs often facilitated the need for adaptation from existing models of SSPs within VA, which were all based in CPRS.

Conclusions

The implementation of SSPs at AVAHCS and VASOHCS enable clinicians to provide quality harm reduction services to PWUD. Despite variations in EHR systems, AVAHCS and VASOHCS implemented SSP within 1 year. Tracking of program engagement via the number of patients interacting with the program and the number of SSP kits distributed will continue. SSP implementation in states where it is permitted may help provide optimal patient care for PWUD.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States, with an estimated 52,550 deaths in 2023.¹ However, the disease burden varies among different segments of the population.² While both CRC incidence and mortality have been decreasing due to screening and advances in treatment, there are disparities in incidence and mortality across the sociodemographic spectrum including race, ethnicity, education, and income.^1-4 While CRC incidence is decreasing for older adults, it is increasing among those aged < 55 years.⁵ The incidence of CRC in adults aged 40 to 54 years has increased by 0.5% to 1.3% annually since the mid-1990s.⁶ The US Preventive Services Task Force now recommends starting CRC screening at age 45 years for asymptomatic adults with average risk.⁷

Disparities also exist across geographical boundaries and living environment. Rural Americans faces additional challenges in health and lifestyle that can affect CRC outcomes. Compared to their urban counterparts, rural residents are more likely to be older, have lower levels of education, higher levels of poverty, lack health insurance, and less access to health care practitioners (HCPs).^8-10 Geographic proximity, defined as travel time or physical distance to a health facility, has been recognized as a predictor of inferior outcomes.¹¹ These aspects of rural living may pose challenges for accessing care for CRC screening and treatment.^11-13 National and local studies have shown disparities in CRC screening rates, incidence, and mortality between rural and urban populations.^14-16

It is unclear whether rural/urban disparities persist under the Veterans Health Administration (VHA) health care delivery model. This study examined differences in baseline characteristics and mortality between rural and urban veterans newly diagnosed with CRC. We also focused on a subpopulation aged ≤ 45 years.

Methods

This study extracted national data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) hosted in the VA Informatics and Computing Infrastructure (VINCI) environment. VINCI is an initiative to improve access to VA data and facilitate the analysis of these data while ensuring veterans’ privacy and data security.¹⁷ CDW is the VHA business intelligence information repository, which extracts data from clinical and nonclinical sources following prescribed and validated protocols. Data extracted included demographics, diagnosis, and procedure codes for both inpatient and outpatient encounters, vital signs, and vital status. This study used data previously extracted from a national cohort of veterans that encompassed all patients who received a group of commonly prescribed medications, such as statins, proton pump inhibitors, histamine-2 blockers, acetaminophen-containing products, and hydrocortisone-containing skin applications. This cohort encompassed 8,648,754 veterans, from whom 2,460,727 had encounters during fiscal years (FY) 2016 to 2021 (study period). The cohort was used to ensure that subjects were VHA patients, allowing them to adequately capture their clinical profiles.

Patients were identified as rural or urban based on their residence address at the date of their first diagnosis of CRC. The Geospatial Service Support Center (GSSC) aggregates and updates veterans’ residence address records for all enrolled veterans from the National Change of Address database. The data contain 1 record per enrollee. GSSC Geocoded Enrollee File contains enrollee addresses and their rurality indicators, categorized as urban, rural, or highly rural.¹⁸ Rurality is defined by the Rural Urban Commuting Area (RUCA) categories developed by the Department of Agriculture and the Health Resources and Services Administration of the US Department of Health and Human Services.¹⁹ Urban areas had RUCA codes of 1.0 to 1.1, and highly rural areas had RUCA scores of 10.0. All other areas were classified as rural. Since the proportion of veterans from highly rural areas was small, we included residents from highly rural areas in the rural residents’ group.

Inclusion and Exclusion Criteria

All veterans newly diagnosed with CRC from FY 2016 to 2021 were included. We used the ninth and tenth clinical modification revisions of the International Classification of Diseases (ICD-9-CM and ICD-10-CM) to define CRC diagnosis (Supplemental materials).^4,20 To ensure that patients were newly diagnosed with CRC, this study excluded patients with a previous ICD-9-CM code for CRC diagnosis since FY 2003.

Comorbidities were identified using diagnosis and procedure codes from inpatient and outpatient encounters, which were used to calculate the Charlson Comorbidity Index (CCI) at the time of CRC diagnosis using the weighted method described by Schneeweiss et al.²¹ We defined CRC high-risk conditions and CRC screening tests, including flexible sigmoidoscopy and stool tests, as described in previous studies (Supplemental materials).²⁰

The main outcome was total mortality. The date of death was extracted from the VHA Death Ascertainment File, which contains mortality data from the Master Person Index file in CDW and the Social Security Administration Death Master File. We used the date of death from any cause, as cause of death was not available.

A propensity score (PS) was created to match rural (including highly rural) and urban residents at a ratio of 1:1. Using a standard procedure described in prior publications, multivariable logistic regression used all baseline characteristics to estimate the PS and perform nearest-number matching without replacement.^22,23 A caliper of 0.01 maximized the matched cohort size and achieved balance (Supplemental materials). We then examined the balance of baseline characteristics between PS-matched groups.

Analyses

Cox proportional hazards regression analysis estimated the hazard ratio (HR) of death in rural residents compared to urban residents in the PS-matched cohort. The outcome event was the date of death during the study’s follow-up period (defined as period from first CRC diagnosis to death or study end), with censoring at the study’s end date (September 30, 2021). The proportional hazards assumption was assessed by inspecting the Kaplan-Meier curves. Multiple analyses examined the HR of total mortality in the PS-matched cohort, stratified by sex, race, and ethnicity. We also examined the HR of total mortality stratified by duration of follow-up.

Another PS-matching analysis among veterans aged ≤ 45 years was performed using the same techniques described earlier in this article. We performed a Cox proportional hazards regression analysis to compare mortality in PS-matched urban and rural veterans aged ≤ 45 years. The HR of death in all veterans aged ≤ 45 years (before PS-matching) was estimated using Cox proportional hazard regression analysis, adjusting for PS.

Dichotomous variables were compared using X² tests and continuous variables were compared using t tests. Baseline characteristics with missing values were converted into categorical variables and the proportion of subjects with missing values was equalized between treatment groups after PS-matching. For subgroup analysis, we examined the HR of total mortality in each subgroup using separate Cox proportional hazards regression models similar to the primary analysis but adjusted for PS. Due to multiple comparisons in the subgroup analysis, the findings should be considered exploratory. Statistical tests were 2-tailed, and significance was defined as P < .05. Data management and statistical analyses were conducted from June 2022 to January 2023 using STATA, Version 17. The VA Orlando Healthcare System Institutional Review Board approved the study and waived requirements for informed consent because only deidentified data were used.

Results

After excluding 49 patients (Supplemental materials, available at doi:10.12788/fp.0560), we identified 30,219 veterans with newly diagnosed CRC between FY 2016 to 2021 (Table 1). Of these, 19,422 (64.3%) resided in urban areas and 10,797 (35.7%) resided in rural areas (Table 2). The mean (SD) duration from the first CRC diagnosis to death or study end was 832 (640) days, and the median (IQR) was 723 (246–1330) days. Overall, incident CRC diagnoses were numerically highest in FY 2016 and lowest in FY 2020 (Figure 1). Patients with CRC in rural areas vs urban areas were significantly older (mean, 71.2 years vs 70.8 years, respectively; P < .001), more likely to be male (96.7% vs 95.7%, respectively; P < .001), more likely to be White (83.6% vs 67.8%, respectively; P < .001) and more likely to be non-Hispanic (92.2% vs 87.5%, respectively; P < .001). In terms of general health, rural veterans with CRC were more likely to be overweight or obese (81.5% rural vs 78.5% urban; P < .001) but had fewer mean comorbidities as measured by CCI (5.66 rural vs 5.90 urban; P < .001). A higher proportion of rural veterans with CRC had received stool-based (fecal occult blood test or fecal immunochemical test) CRC screening tests (61.6% rural vs 57.2% urban; P < .001). Fewer rural patients presented with systemic symptoms or signs within 1 year of CRC diagnosis (54.4% rural vs 57.5% urban, P < .001). Among urban patients with CRC, 6959 (35.8%) deaths were observed, compared with 3766 (34.9%) among rural patients (P = .10).

There were 21,568 PS-matched veterans: 10,784 in each group. In the PS-matched cohort, baseline characteristics were similar between veterans in urban and rural communities, including age, sex, race/ethnicity, body mass index, and comorbidities. Among rural patients with CRC, 3763 deaths (34.9%) were observed compared with 3702 (34.3%) among urban veterans. There was no significant difference in the HR of mortality between rural and urban CRC residents (HR, 1.01; 95% CI, 0.97-1.06; P = .53) (Figure 2).

Among veterans aged ≤ 45 years, 551 were diagnosed with CRC (391 urban and 160 rural). We PS-matched 142 pairs of urban and rural veterans without residual differences in baseline characteristics (eAppendix 1). There was no significant difference in the HR of mortality between rural and urban veterans aged ≤ 45 years (HR, 0.97; 95% CI, 0.57-1.63; P = .90) (Figure 2). Similarly, no difference in mortality was observed adjusting for PS between all rural and urban veterans aged ≤ 45 years (HR, 1.03; 95% CI, 0.67-1.59; P = .88).

There was no difference in total mortality between rural and urban veterans in any subgroup except for American Indian or Alaska Native veterans (HR, 2.41; 95% CI, 1.29-4.50; P = .006) (eAppendix 2).

Discussion

This study examined characteristics of patients with CRC between urban and rural areas among veterans who were VHA patients. Similar to other studies, rural veterans with CRC were older, more likely to be White, and were obese, but exhibited fewer comorbidities (lower CCI and lower incidence of congestive heart failure, dementia, hemiplegia, kidney diseases, liver diseases and AIDS, but higher incidence of chronic obstructive lung disease).^8,16 The incidence of CRC in this study population was lowest in FY 2020, which was reported by the Centers for Disease Control and Prevention and is attributed to COVID-19 pandemic disruption of health services.²⁴ The overall mortality in this study was similar to rates reported in other studies from the VA Central Cancer Registry.⁴ In the PS-matched cohort, where baseline characteristics were similar between urban and rural patients with CRC, we found no disparities in CRC-specific mortality between veterans in rural and urban areas. Additionally, when analysis was restricted to veterans aged ≤ 45 years, the results remained consistent.

Subgroup analyses showed no significant difference in mortality between rural and urban areas by sex, race or ethnicity, except rural American Indian or Alaska Native veterans who had double the mortality of their urban counterparts (HR, 2.41; 95% CI, 1.29-4.50; P = .006). This finding is difficult to interpret due to the small number of events and the wide CI. While with a Bonferroni correction the adjusted P value was .08, which is not statistically significant, a previous study found that although CRC incidence was lower overall in American Indian or Alaska Native populations compared to non-Hispanic White populations, CRC incidence was higher among American Indian or Alaska Native individuals in some areas such as Alaska and the Northern Plains.^25,26 Studies have noted that rural American Indian/Alaska Native populations experience greater poverty, less access to broadband internet, and limited access to care, contributing to poorer cancer outcomes and lower survival.²⁷ Thus, the finding of disparity in mortality between rural and urban American Indian or Alaska Native veterans warrants further study.

Other studies have raised concerns that CRC disproportionately affects adults in rural areas with higher mortality rates.^14-16 These disparities arise from sociodemographic factors and modifiable risk factors, including physical activity, dietary patterns, access to cancer screening, and gaps in quality treatment resources.^16,28 These factors operate at multiple levels: from individual, local health system, to community and policy.^2,27 For example, a South Carolina study (1996–2016) found that residents in rural areas were more likely to be diagnosed with advanced CRC, possibly indicating lower rates of CRC screening in rural areas. They also had higher likelihood of death from CRC.¹⁵ However, the study did not include any clinical parameters, such as comorbidities or obesity. A statewide, population-based study in Utah showed that rural men experienced a lower CRC survival in their unadjusted analysis.¹⁶ However, the study was small, with only 3948 urban and 712 rural residents. Additionally, there was no difference in total mortality in the whole cohort (HR, 0.96; 95% CI, 0.86-1.07) or in CRC-specific death (HR, 0.93; 95% CI, 0.81-1.08). A nationwide study also showed that CRC mortality rates were 8% higher in nonmetropolitan or rural areas than in the most urbanized areas containing large metropolitan counties.²⁹ However, this study did not include descriptions of clinical confounders, such as comorbidities, making it difficult to ascertain whether the difference in CRC mortality was due to rurality or differences in baseline risk characteristics.

In this study, the lack of CRC-specific mortality disparities may be attributed to the structures and practices of VHA health care. Recent studies have noted that mortality of several chronic medical conditions treated at the VHA was lower than at non-VHA hospitals.^30,31 One study that measured the quality of nonmetastatic CRC care based on National Comprehensive Cancer Network guidelines showed that > 72% of VHA patients received guideline-concordant care for each diagnostic and therapeutic measure, except for follow-up colonoscopy timing, which appear to be similar or superior to that of the private sector.^30,32,33 Some of the VA initiative for CRC screening may bypass the urban-rurality divide such as the mailed fecal immunochemical test program for CRC. This program was implemented at the onset of the COVID-19 pandemic to avoid disruptions of medical care.³⁴ Rural patients are more likely to undergo fecal immunochemical testing when compared to urban patients in this data. Beyond clinical care, the VHA uses processes to tackle social determinants of health such as housing, food security, and transportation, promoting equal access to health care, and promoting cultural competency among HCPs.^35-37

The results suggest that solutions to CRC disparities between rural and urban areas need to consider known barriers to rural health care, including transportation, diminished rural health care workforce, and other social determinants of health.^9,10,27,38 VHA makes considerable efforts to provide equitable care to all enrolled veterans, including specific programs for rural veterans, including ongoing outreach.³⁹ This study demonstrated lack of disparity in CRC-specific mortality in veterans receiving VHA care, highlighting the importance of these efforts.

Strengths and Limitations

This study used the VHA cohort to compare patient characteristics and mortality between patients with CRC residing in rural and urban areas. The study provides nationwide perspectives on CRC across the geographical spectrum and used a longitudinal cohort with prolonged follow-up to account for comorbidities.

However, the study compared a cohort of rural and urban veterans enrolled in the VHA; hence, the results may not reflect CRC outcomes in veterans without access to VHA care. Rurality has been independently associated with decreased likelihood of meeting CRC screening guidelines among veterans and military service members.³⁸ This study lacked sufficient information to compare CRC staging or treatment modalities among veterans. Although the data cannot identify CRC stage, the proportions of patients with metastatic CRC at diagnosis and CRC location were similar between groups. The study did not have information on their care outside of VHA setting.

This study could not ascertain whether disparities existed in CRC treatment modality since rural residence may result in referral to community-based CRC care, which did not appear in the data. To address these limitations, we used death from any cause as the primary outcome, since death is a hard outcome and is not subject to ascertainment bias. The relatively short follow-up time is another limitation, though subgroup analysis by follow-up did not show significant differences. Despite PS matching, residual unmeasured confounding may exist between urban and rural groups. The predominantly White, male VHA population with high CCI may limit the generalizability of the results.

Conclusions

Rural VHA enrollees had similar survival rates after CRC diagnosis compared to their urban counterparts in a PS-matched analysis. The VHA models of care—including mailed CRC screening tools, several socioeconomic determinants of health (housing, food security, and transportation), and promoting equal access to health care, as well as cultural competency among HCPs—HCPs—may help alleviate disparities across the rural-urban spectrum. The VHA should continue efforts to enroll veterans and provide comprehensive coordinated care in community partnerships.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States, with an estimated 52,550 deaths in 2023.¹ However, the disease burden varies among different segments of the population.² While both CRC incidence and mortality have been decreasing due to screening and advances in treatment, there are disparities in incidence and mortality across the sociodemographic spectrum including race, ethnicity, education, and income.^1-4 While CRC incidence is decreasing for older adults, it is increasing among those aged < 55 years.⁵ The incidence of CRC in adults aged 40 to 54 years has increased by 0.5% to 1.3% annually since the mid-1990s.⁶ The US Preventive Services Task Force now recommends starting CRC screening at age 45 years for asymptomatic adults with average risk.⁷

Disparities also exist across geographical boundaries and living environment. Rural Americans faces additional challenges in health and lifestyle that can affect CRC outcomes. Compared to their urban counterparts, rural residents are more likely to be older, have lower levels of education, higher levels of poverty, lack health insurance, and less access to health care practitioners (HCPs).^8-10 Geographic proximity, defined as travel time or physical distance to a health facility, has been recognized as a predictor of inferior outcomes.¹¹ These aspects of rural living may pose challenges for accessing care for CRC screening and treatment.^11-13 National and local studies have shown disparities in CRC screening rates, incidence, and mortality between rural and urban populations.^14-16

It is unclear whether rural/urban disparities persist under the Veterans Health Administration (VHA) health care delivery model. This study examined differences in baseline characteristics and mortality between rural and urban veterans newly diagnosed with CRC. We also focused on a subpopulation aged ≤ 45 years.

Methods

This study extracted national data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) hosted in the VA Informatics and Computing Infrastructure (VINCI) environment. VINCI is an initiative to improve access to VA data and facilitate the analysis of these data while ensuring veterans’ privacy and data security.¹⁷ CDW is the VHA business intelligence information repository, which extracts data from clinical and nonclinical sources following prescribed and validated protocols. Data extracted included demographics, diagnosis, and procedure codes for both inpatient and outpatient encounters, vital signs, and vital status. This study used data previously extracted from a national cohort of veterans that encompassed all patients who received a group of commonly prescribed medications, such as statins, proton pump inhibitors, histamine-2 blockers, acetaminophen-containing products, and hydrocortisone-containing skin applications. This cohort encompassed 8,648,754 veterans, from whom 2,460,727 had encounters during fiscal years (FY) 2016 to 2021 (study period). The cohort was used to ensure that subjects were VHA patients, allowing them to adequately capture their clinical profiles.

Patients were identified as rural or urban based on their residence address at the date of their first diagnosis of CRC. The Geospatial Service Support Center (GSSC) aggregates and updates veterans’ residence address records for all enrolled veterans from the National Change of Address database. The data contain 1 record per enrollee. GSSC Geocoded Enrollee File contains enrollee addresses and their rurality indicators, categorized as urban, rural, or highly rural.¹⁸ Rurality is defined by the Rural Urban Commuting Area (RUCA) categories developed by the Department of Agriculture and the Health Resources and Services Administration of the US Department of Health and Human Services.¹⁹ Urban areas had RUCA codes of 1.0 to 1.1, and highly rural areas had RUCA scores of 10.0. All other areas were classified as rural. Since the proportion of veterans from highly rural areas was small, we included residents from highly rural areas in the rural residents’ group.

Inclusion and Exclusion Criteria

All veterans newly diagnosed with CRC from FY 2016 to 2021 were included. We used the ninth and tenth clinical modification revisions of the International Classification of Diseases (ICD-9-CM and ICD-10-CM) to define CRC diagnosis (Supplemental materials).^4,20 To ensure that patients were newly diagnosed with CRC, this study excluded patients with a previous ICD-9-CM code for CRC diagnosis since FY 2003.

Comorbidities were identified using diagnosis and procedure codes from inpatient and outpatient encounters, which were used to calculate the Charlson Comorbidity Index (CCI) at the time of CRC diagnosis using the weighted method described by Schneeweiss et al.²¹ We defined CRC high-risk conditions and CRC screening tests, including flexible sigmoidoscopy and stool tests, as described in previous studies (Supplemental materials).²⁰

The main outcome was total mortality. The date of death was extracted from the VHA Death Ascertainment File, which contains mortality data from the Master Person Index file in CDW and the Social Security Administration Death Master File. We used the date of death from any cause, as cause of death was not available.

A propensity score (PS) was created to match rural (including highly rural) and urban residents at a ratio of 1:1. Using a standard procedure described in prior publications, multivariable logistic regression used all baseline characteristics to estimate the PS and perform nearest-number matching without replacement.^22,23 A caliper of 0.01 maximized the matched cohort size and achieved balance (Supplemental materials). We then examined the balance of baseline characteristics between PS-matched groups.

Analyses

Cox proportional hazards regression analysis estimated the hazard ratio (HR) of death in rural residents compared to urban residents in the PS-matched cohort. The outcome event was the date of death during the study’s follow-up period (defined as period from first CRC diagnosis to death or study end), with censoring at the study’s end date (September 30, 2021). The proportional hazards assumption was assessed by inspecting the Kaplan-Meier curves. Multiple analyses examined the HR of total mortality in the PS-matched cohort, stratified by sex, race, and ethnicity. We also examined the HR of total mortality stratified by duration of follow-up.

Another PS-matching analysis among veterans aged ≤ 45 years was performed using the same techniques described earlier in this article. We performed a Cox proportional hazards regression analysis to compare mortality in PS-matched urban and rural veterans aged ≤ 45 years. The HR of death in all veterans aged ≤ 45 years (before PS-matching) was estimated using Cox proportional hazard regression analysis, adjusting for PS.

Dichotomous variables were compared using X² tests and continuous variables were compared using t tests. Baseline characteristics with missing values were converted into categorical variables and the proportion of subjects with missing values was equalized between treatment groups after PS-matching. For subgroup analysis, we examined the HR of total mortality in each subgroup using separate Cox proportional hazards regression models similar to the primary analysis but adjusted for PS. Due to multiple comparisons in the subgroup analysis, the findings should be considered exploratory. Statistical tests were 2-tailed, and significance was defined as P < .05. Data management and statistical analyses were conducted from June 2022 to January 2023 using STATA, Version 17. The VA Orlando Healthcare System Institutional Review Board approved the study and waived requirements for informed consent because only deidentified data were used.

Results

After excluding 49 patients (Supplemental materials, available at doi:10.12788/fp.0560), we identified 30,219 veterans with newly diagnosed CRC between FY 2016 to 2021 (Table 1). Of these, 19,422 (64.3%) resided in urban areas and 10,797 (35.7%) resided in rural areas (Table 2). The mean (SD) duration from the first CRC diagnosis to death or study end was 832 (640) days, and the median (IQR) was 723 (246–1330) days. Overall, incident CRC diagnoses were numerically highest in FY 2016 and lowest in FY 2020 (Figure 1). Patients with CRC in rural areas vs urban areas were significantly older (mean, 71.2 years vs 70.8 years, respectively; P < .001), more likely to be male (96.7% vs 95.7%, respectively; P < .001), more likely to be White (83.6% vs 67.8%, respectively; P < .001) and more likely to be non-Hispanic (92.2% vs 87.5%, respectively; P < .001). In terms of general health, rural veterans with CRC were more likely to be overweight or obese (81.5% rural vs 78.5% urban; P < .001) but had fewer mean comorbidities as measured by CCI (5.66 rural vs 5.90 urban; P < .001). A higher proportion of rural veterans with CRC had received stool-based (fecal occult blood test or fecal immunochemical test) CRC screening tests (61.6% rural vs 57.2% urban; P < .001). Fewer rural patients presented with systemic symptoms or signs within 1 year of CRC diagnosis (54.4% rural vs 57.5% urban, P < .001). Among urban patients with CRC, 6959 (35.8%) deaths were observed, compared with 3766 (34.9%) among rural patients (P = .10).

There were 21,568 PS-matched veterans: 10,784 in each group. In the PS-matched cohort, baseline characteristics were similar between veterans in urban and rural communities, including age, sex, race/ethnicity, body mass index, and comorbidities. Among rural patients with CRC, 3763 deaths (34.9%) were observed compared with 3702 (34.3%) among urban veterans. There was no significant difference in the HR of mortality between rural and urban CRC residents (HR, 1.01; 95% CI, 0.97-1.06; P = .53) (Figure 2).

Among veterans aged ≤ 45 years, 551 were diagnosed with CRC (391 urban and 160 rural). We PS-matched 142 pairs of urban and rural veterans without residual differences in baseline characteristics (eAppendix 1). There was no significant difference in the HR of mortality between rural and urban veterans aged ≤ 45 years (HR, 0.97; 95% CI, 0.57-1.63; P = .90) (Figure 2). Similarly, no difference in mortality was observed adjusting for PS between all rural and urban veterans aged ≤ 45 years (HR, 1.03; 95% CI, 0.67-1.59; P = .88).

There was no difference in total mortality between rural and urban veterans in any subgroup except for American Indian or Alaska Native veterans (HR, 2.41; 95% CI, 1.29-4.50; P = .006) (eAppendix 2).

Discussion

This study examined characteristics of patients with CRC between urban and rural areas among veterans who were VHA patients. Similar to other studies, rural veterans with CRC were older, more likely to be White, and were obese, but exhibited fewer comorbidities (lower CCI and lower incidence of congestive heart failure, dementia, hemiplegia, kidney diseases, liver diseases and AIDS, but higher incidence of chronic obstructive lung disease).^8,16 The incidence of CRC in this study population was lowest in FY 2020, which was reported by the Centers for Disease Control and Prevention and is attributed to COVID-19 pandemic disruption of health services.²⁴ The overall mortality in this study was similar to rates reported in other studies from the VA Central Cancer Registry.⁴ In the PS-matched cohort, where baseline characteristics were similar between urban and rural patients with CRC, we found no disparities in CRC-specific mortality between veterans in rural and urban areas. Additionally, when analysis was restricted to veterans aged ≤ 45 years, the results remained consistent.

Subgroup analyses showed no significant difference in mortality between rural and urban areas by sex, race or ethnicity, except rural American Indian or Alaska Native veterans who had double the mortality of their urban counterparts (HR, 2.41; 95% CI, 1.29-4.50; P = .006). This finding is difficult to interpret due to the small number of events and the wide CI. While with a Bonferroni correction the adjusted P value was .08, which is not statistically significant, a previous study found that although CRC incidence was lower overall in American Indian or Alaska Native populations compared to non-Hispanic White populations, CRC incidence was higher among American Indian or Alaska Native individuals in some areas such as Alaska and the Northern Plains.^25,26 Studies have noted that rural American Indian/Alaska Native populations experience greater poverty, less access to broadband internet, and limited access to care, contributing to poorer cancer outcomes and lower survival.²⁷ Thus, the finding of disparity in mortality between rural and urban American Indian or Alaska Native veterans warrants further study.

Other studies have raised concerns that CRC disproportionately affects adults in rural areas with higher mortality rates.^14-16 These disparities arise from sociodemographic factors and modifiable risk factors, including physical activity, dietary patterns, access to cancer screening, and gaps in quality treatment resources.^16,28 These factors operate at multiple levels: from individual, local health system, to community and policy.^2,27 For example, a South Carolina study (1996–2016) found that residents in rural areas were more likely to be diagnosed with advanced CRC, possibly indicating lower rates of CRC screening in rural areas. They also had higher likelihood of death from CRC.¹⁵ However, the study did not include any clinical parameters, such as comorbidities or obesity. A statewide, population-based study in Utah showed that rural men experienced a lower CRC survival in their unadjusted analysis.¹⁶ However, the study was small, with only 3948 urban and 712 rural residents. Additionally, there was no difference in total mortality in the whole cohort (HR, 0.96; 95% CI, 0.86-1.07) or in CRC-specific death (HR, 0.93; 95% CI, 0.81-1.08). A nationwide study also showed that CRC mortality rates were 8% higher in nonmetropolitan or rural areas than in the most urbanized areas containing large metropolitan counties.²⁹ However, this study did not include descriptions of clinical confounders, such as comorbidities, making it difficult to ascertain whether the difference in CRC mortality was due to rurality or differences in baseline risk characteristics.

In this study, the lack of CRC-specific mortality disparities may be attributed to the structures and practices of VHA health care. Recent studies have noted that mortality of several chronic medical conditions treated at the VHA was lower than at non-VHA hospitals.^30,31 One study that measured the quality of nonmetastatic CRC care based on National Comprehensive Cancer Network guidelines showed that > 72% of VHA patients received guideline-concordant care for each diagnostic and therapeutic measure, except for follow-up colonoscopy timing, which appear to be similar or superior to that of the private sector.^30,32,33 Some of the VA initiative for CRC screening may bypass the urban-rurality divide such as the mailed fecal immunochemical test program for CRC. This program was implemented at the onset of the COVID-19 pandemic to avoid disruptions of medical care.³⁴ Rural patients are more likely to undergo fecal immunochemical testing when compared to urban patients in this data. Beyond clinical care, the VHA uses processes to tackle social determinants of health such as housing, food security, and transportation, promoting equal access to health care, and promoting cultural competency among HCPs.^35-37

The results suggest that solutions to CRC disparities between rural and urban areas need to consider known barriers to rural health care, including transportation, diminished rural health care workforce, and other social determinants of health.^9,10,27,38 VHA makes considerable efforts to provide equitable care to all enrolled veterans, including specific programs for rural veterans, including ongoing outreach.³⁹ This study demonstrated lack of disparity in CRC-specific mortality in veterans receiving VHA care, highlighting the importance of these efforts.

Strengths and Limitations

This study used the VHA cohort to compare patient characteristics and mortality between patients with CRC residing in rural and urban areas. The study provides nationwide perspectives on CRC across the geographical spectrum and used a longitudinal cohort with prolonged follow-up to account for comorbidities.

However, the study compared a cohort of rural and urban veterans enrolled in the VHA; hence, the results may not reflect CRC outcomes in veterans without access to VHA care. Rurality has been independently associated with decreased likelihood of meeting CRC screening guidelines among veterans and military service members.³⁸ This study lacked sufficient information to compare CRC staging or treatment modalities among veterans. Although the data cannot identify CRC stage, the proportions of patients with metastatic CRC at diagnosis and CRC location were similar between groups. The study did not have information on their care outside of VHA setting.

This study could not ascertain whether disparities existed in CRC treatment modality since rural residence may result in referral to community-based CRC care, which did not appear in the data. To address these limitations, we used death from any cause as the primary outcome, since death is a hard outcome and is not subject to ascertainment bias. The relatively short follow-up time is another limitation, though subgroup analysis by follow-up did not show significant differences. Despite PS matching, residual unmeasured confounding may exist between urban and rural groups. The predominantly White, male VHA population with high CCI may limit the generalizability of the results.

Conclusions

Rural VHA enrollees had similar survival rates after CRC diagnosis compared to their urban counterparts in a PS-matched analysis. The VHA models of care—including mailed CRC screening tools, several socioeconomic determinants of health (housing, food security, and transportation), and promoting equal access to health care, as well as cultural competency among HCPs—HCPs—may help alleviate disparities across the rural-urban spectrum. The VHA should continue efforts to enroll veterans and provide comprehensive coordinated care in community partnerships.

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States, with an estimated 52,550 deaths in 2023.¹ However, the disease burden varies among different segments of the population.² While both CRC incidence and mortality have been decreasing due to screening and advances in treatment, there are disparities in incidence and mortality across the sociodemographic spectrum including race, ethnicity, education, and income.^1-4 While CRC incidence is decreasing for older adults, it is increasing among those aged < 55 years.⁵ The incidence of CRC in adults aged 40 to 54 years has increased by 0.5% to 1.3% annually since the mid-1990s.⁶ The US Preventive Services Task Force now recommends starting CRC screening at age 45 years for asymptomatic adults with average risk.⁷

Disparities also exist across geographical boundaries and living environment. Rural Americans faces additional challenges in health and lifestyle that can affect CRC outcomes. Compared to their urban counterparts, rural residents are more likely to be older, have lower levels of education, higher levels of poverty, lack health insurance, and less access to health care practitioners (HCPs).^8-10 Geographic proximity, defined as travel time or physical distance to a health facility, has been recognized as a predictor of inferior outcomes.¹¹ These aspects of rural living may pose challenges for accessing care for CRC screening and treatment.^11-13 National and local studies have shown disparities in CRC screening rates, incidence, and mortality between rural and urban populations.^14-16

It is unclear whether rural/urban disparities persist under the Veterans Health Administration (VHA) health care delivery model. This study examined differences in baseline characteristics and mortality between rural and urban veterans newly diagnosed with CRC. We also focused on a subpopulation aged ≤ 45 years.

Methods

This study extracted national data from the US Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) hosted in the VA Informatics and Computing Infrastructure (VINCI) environment. VINCI is an initiative to improve access to VA data and facilitate the analysis of these data while ensuring veterans’ privacy and data security.¹⁷ CDW is the VHA business intelligence information repository, which extracts data from clinical and nonclinical sources following prescribed and validated protocols. Data extracted included demographics, diagnosis, and procedure codes for both inpatient and outpatient encounters, vital signs, and vital status. This study used data previously extracted from a national cohort of veterans that encompassed all patients who received a group of commonly prescribed medications, such as statins, proton pump inhibitors, histamine-2 blockers, acetaminophen-containing products, and hydrocortisone-containing skin applications. This cohort encompassed 8,648,754 veterans, from whom 2,460,727 had encounters during fiscal years (FY) 2016 to 2021 (study period). The cohort was used to ensure that subjects were VHA patients, allowing them to adequately capture their clinical profiles.

Patients were identified as rural or urban based on their residence address at the date of their first diagnosis of CRC. The Geospatial Service Support Center (GSSC) aggregates and updates veterans’ residence address records for all enrolled veterans from the National Change of Address database. The data contain 1 record per enrollee. GSSC Geocoded Enrollee File contains enrollee addresses and their rurality indicators, categorized as urban, rural, or highly rural.¹⁸ Rurality is defined by the Rural Urban Commuting Area (RUCA) categories developed by the Department of Agriculture and the Health Resources and Services Administration of the US Department of Health and Human Services.¹⁹ Urban areas had RUCA codes of 1.0 to 1.1, and highly rural areas had RUCA scores of 10.0. All other areas were classified as rural. Since the proportion of veterans from highly rural areas was small, we included residents from highly rural areas in the rural residents’ group.

Inclusion and Exclusion Criteria

All veterans newly diagnosed with CRC from FY 2016 to 2021 were included. We used the ninth and tenth clinical modification revisions of the International Classification of Diseases (ICD-9-CM and ICD-10-CM) to define CRC diagnosis (Supplemental materials).^4,20 To ensure that patients were newly diagnosed with CRC, this study excluded patients with a previous ICD-9-CM code for CRC diagnosis since FY 2003.

Comorbidities were identified using diagnosis and procedure codes from inpatient and outpatient encounters, which were used to calculate the Charlson Comorbidity Index (CCI) at the time of CRC diagnosis using the weighted method described by Schneeweiss et al.²¹ We defined CRC high-risk conditions and CRC screening tests, including flexible sigmoidoscopy and stool tests, as described in previous studies (Supplemental materials).²⁰

The main outcome was total mortality. The date of death was extracted from the VHA Death Ascertainment File, which contains mortality data from the Master Person Index file in CDW and the Social Security Administration Death Master File. We used the date of death from any cause, as cause of death was not available.

A propensity score (PS) was created to match rural (including highly rural) and urban residents at a ratio of 1:1. Using a standard procedure described in prior publications, multivariable logistic regression used all baseline characteristics to estimate the PS and perform nearest-number matching without replacement.^22,23 A caliper of 0.01 maximized the matched cohort size and achieved balance (Supplemental materials). We then examined the balance of baseline characteristics between PS-matched groups.

Analyses

Cox proportional hazards regression analysis estimated the hazard ratio (HR) of death in rural residents compared to urban residents in the PS-matched cohort. The outcome event was the date of death during the study’s follow-up period (defined as period from first CRC diagnosis to death or study end), with censoring at the study’s end date (September 30, 2021). The proportional hazards assumption was assessed by inspecting the Kaplan-Meier curves. Multiple analyses examined the HR of total mortality in the PS-matched cohort, stratified by sex, race, and ethnicity. We also examined the HR of total mortality stratified by duration of follow-up.

Another PS-matching analysis among veterans aged ≤ 45 years was performed using the same techniques described earlier in this article. We performed a Cox proportional hazards regression analysis to compare mortality in PS-matched urban and rural veterans aged ≤ 45 years. The HR of death in all veterans aged ≤ 45 years (before PS-matching) was estimated using Cox proportional hazard regression analysis, adjusting for PS.

Dichotomous variables were compared using X² tests and continuous variables were compared using t tests. Baseline characteristics with missing values were converted into categorical variables and the proportion of subjects with missing values was equalized between treatment groups after PS-matching. For subgroup analysis, we examined the HR of total mortality in each subgroup using separate Cox proportional hazards regression models similar to the primary analysis but adjusted for PS. Due to multiple comparisons in the subgroup analysis, the findings should be considered exploratory. Statistical tests were 2-tailed, and significance was defined as P < .05. Data management and statistical analyses were conducted from June 2022 to January 2023 using STATA, Version 17. The VA Orlando Healthcare System Institutional Review Board approved the study and waived requirements for informed consent because only deidentified data were used.

Results

After excluding 49 patients (Supplemental materials, available at doi:10.12788/fp.0560), we identified 30,219 veterans with newly diagnosed CRC between FY 2016 to 2021 (Table 1). Of these, 19,422 (64.3%) resided in urban areas and 10,797 (35.7%) resided in rural areas (Table 2). The mean (SD) duration from the first CRC diagnosis to death or study end was 832 (640) days, and the median (IQR) was 723 (246–1330) days. Overall, incident CRC diagnoses were numerically highest in FY 2016 and lowest in FY 2020 (Figure 1). Patients with CRC in rural areas vs urban areas were significantly older (mean, 71.2 years vs 70.8 years, respectively; P < .001), more likely to be male (96.7% vs 95.7%, respectively; P < .001), more likely to be White (83.6% vs 67.8%, respectively; P < .001) and more likely to be non-Hispanic (92.2% vs 87.5%, respectively; P < .001). In terms of general health, rural veterans with CRC were more likely to be overweight or obese (81.5% rural vs 78.5% urban; P < .001) but had fewer mean comorbidities as measured by CCI (5.66 rural vs 5.90 urban; P < .001). A higher proportion of rural veterans with CRC had received stool-based (fecal occult blood test or fecal immunochemical test) CRC screening tests (61.6% rural vs 57.2% urban; P < .001). Fewer rural patients presented with systemic symptoms or signs within 1 year of CRC diagnosis (54.4% rural vs 57.5% urban, P < .001). Among urban patients with CRC, 6959 (35.8%) deaths were observed, compared with 3766 (34.9%) among rural patients (P = .10).

There were 21,568 PS-matched veterans: 10,784 in each group. In the PS-matched cohort, baseline characteristics were similar between veterans in urban and rural communities, including age, sex, race/ethnicity, body mass index, and comorbidities. Among rural patients with CRC, 3763 deaths (34.9%) were observed compared with 3702 (34.3%) among urban veterans. There was no significant difference in the HR of mortality between rural and urban CRC residents (HR, 1.01; 95% CI, 0.97-1.06; P = .53) (Figure 2).

Among veterans aged ≤ 45 years, 551 were diagnosed with CRC (391 urban and 160 rural). We PS-matched 142 pairs of urban and rural veterans without residual differences in baseline characteristics (eAppendix 1). There was no significant difference in the HR of mortality between rural and urban veterans aged ≤ 45 years (HR, 0.97; 95% CI, 0.57-1.63; P = .90) (Figure 2). Similarly, no difference in mortality was observed adjusting for PS between all rural and urban veterans aged ≤ 45 years (HR, 1.03; 95% CI, 0.67-1.59; P = .88).

There was no difference in total mortality between rural and urban veterans in any subgroup except for American Indian or Alaska Native veterans (HR, 2.41; 95% CI, 1.29-4.50; P = .006) (eAppendix 2).

Discussion

This study examined characteristics of patients with CRC between urban and rural areas among veterans who were VHA patients. Similar to other studies, rural veterans with CRC were older, more likely to be White, and were obese, but exhibited fewer comorbidities (lower CCI and lower incidence of congestive heart failure, dementia, hemiplegia, kidney diseases, liver diseases and AIDS, but higher incidence of chronic obstructive lung disease).^8,16 The incidence of CRC in this study population was lowest in FY 2020, which was reported by the Centers for Disease Control and Prevention and is attributed to COVID-19 pandemic disruption of health services.²⁴ The overall mortality in this study was similar to rates reported in other studies from the VA Central Cancer Registry.⁴ In the PS-matched cohort, where baseline characteristics were similar between urban and rural patients with CRC, we found no disparities in CRC-specific mortality between veterans in rural and urban areas. Additionally, when analysis was restricted to veterans aged ≤ 45 years, the results remained consistent.

Subgroup analyses showed no significant difference in mortality between rural and urban areas by sex, race or ethnicity, except rural American Indian or Alaska Native veterans who had double the mortality of their urban counterparts (HR, 2.41; 95% CI, 1.29-4.50; P = .006). This finding is difficult to interpret due to the small number of events and the wide CI. While with a Bonferroni correction the adjusted P value was .08, which is not statistically significant, a previous study found that although CRC incidence was lower overall in American Indian or Alaska Native populations compared to non-Hispanic White populations, CRC incidence was higher among American Indian or Alaska Native individuals in some areas such as Alaska and the Northern Plains.^25,26 Studies have noted that rural American Indian/Alaska Native populations experience greater poverty, less access to broadband internet, and limited access to care, contributing to poorer cancer outcomes and lower survival.²⁷ Thus, the finding of disparity in mortality between rural and urban American Indian or Alaska Native veterans warrants further study.

Other studies have raised concerns that CRC disproportionately affects adults in rural areas with higher mortality rates.^14-16 These disparities arise from sociodemographic factors and modifiable risk factors, including physical activity, dietary patterns, access to cancer screening, and gaps in quality treatment resources.^16,28 These factors operate at multiple levels: from individual, local health system, to community and policy.^2,27 For example, a South Carolina study (1996–2016) found that residents in rural areas were more likely to be diagnosed with advanced CRC, possibly indicating lower rates of CRC screening in rural areas. They also had higher likelihood of death from CRC.¹⁵ However, the study did not include any clinical parameters, such as comorbidities or obesity. A statewide, population-based study in Utah showed that rural men experienced a lower CRC survival in their unadjusted analysis.¹⁶ However, the study was small, with only 3948 urban and 712 rural residents. Additionally, there was no difference in total mortality in the whole cohort (HR, 0.96; 95% CI, 0.86-1.07) or in CRC-specific death (HR, 0.93; 95% CI, 0.81-1.08). A nationwide study also showed that CRC mortality rates were 8% higher in nonmetropolitan or rural areas than in the most urbanized areas containing large metropolitan counties.²⁹ However, this study did not include descriptions of clinical confounders, such as comorbidities, making it difficult to ascertain whether the difference in CRC mortality was due to rurality or differences in baseline risk characteristics.

In this study, the lack of CRC-specific mortality disparities may be attributed to the structures and practices of VHA health care. Recent studies have noted that mortality of several chronic medical conditions treated at the VHA was lower than at non-VHA hospitals.^30,31 One study that measured the quality of nonmetastatic CRC care based on National Comprehensive Cancer Network guidelines showed that > 72% of VHA patients received guideline-concordant care for each diagnostic and therapeutic measure, except for follow-up colonoscopy timing, which appear to be similar or superior to that of the private sector.^30,32,33 Some of the VA initiative for CRC screening may bypass the urban-rurality divide such as the mailed fecal immunochemical test program for CRC. This program was implemented at the onset of the COVID-19 pandemic to avoid disruptions of medical care.³⁴ Rural patients are more likely to undergo fecal immunochemical testing when compared to urban patients in this data. Beyond clinical care, the VHA uses processes to tackle social determinants of health such as housing, food security, and transportation, promoting equal access to health care, and promoting cultural competency among HCPs.^35-37

The results suggest that solutions to CRC disparities between rural and urban areas need to consider known barriers to rural health care, including transportation, diminished rural health care workforce, and other social determinants of health.^9,10,27,38 VHA makes considerable efforts to provide equitable care to all enrolled veterans, including specific programs for rural veterans, including ongoing outreach.³⁹ This study demonstrated lack of disparity in CRC-specific mortality in veterans receiving VHA care, highlighting the importance of these efforts.

Strengths and Limitations

This study used the VHA cohort to compare patient characteristics and mortality between patients with CRC residing in rural and urban areas. The study provides nationwide perspectives on CRC across the geographical spectrum and used a longitudinal cohort with prolonged follow-up to account for comorbidities.

However, the study compared a cohort of rural and urban veterans enrolled in the VHA; hence, the results may not reflect CRC outcomes in veterans without access to VHA care. Rurality has been independently associated with decreased likelihood of meeting CRC screening guidelines among veterans and military service members.³⁸ This study lacked sufficient information to compare CRC staging or treatment modalities among veterans. Although the data cannot identify CRC stage, the proportions of patients with metastatic CRC at diagnosis and CRC location were similar between groups. The study did not have information on their care outside of VHA setting.

This study could not ascertain whether disparities existed in CRC treatment modality since rural residence may result in referral to community-based CRC care, which did not appear in the data. To address these limitations, we used death from any cause as the primary outcome, since death is a hard outcome and is not subject to ascertainment bias. The relatively short follow-up time is another limitation, though subgroup analysis by follow-up did not show significant differences. Despite PS matching, residual unmeasured confounding may exist between urban and rural groups. The predominantly White, male VHA population with high CCI may limit the generalizability of the results.

Conclusions

Rural VHA enrollees had similar survival rates after CRC diagnosis compared to their urban counterparts in a PS-matched analysis. The VHA models of care—including mailed CRC screening tools, several socioeconomic determinants of health (housing, food security, and transportation), and promoting equal access to health care, as well as cultural competency among HCPs—HCPs—may help alleviate disparities across the rural-urban spectrum. The VHA should continue efforts to enroll veterans and provide comprehensive coordinated care in community partnerships.

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

The annual issue of Cancer Data Trends, produced in collaboration with the Association of VA Hematology/Oncology (AVAHO), highlights the latest research in some of the top cancers impacting US veterans. 

In this issue: 

1. Access, Race, and "Colon Age": Improving CRC Screening
2. Lung Cancer: Mortality Trends in Veterans and New Treatments
3. Racial Disparities, Germline Testing, and Improved Overall Survival in Prostate Cancer
4. Breast and Uterine Cancer: Screening Guidelines, Genetic Testing, and Mortality Trends
5. HCC Updates: Quality Care Framework and Risk Stratification Data
6. Rising Kidney Cancer Cases and Emerging Treatments for Veterans
7. Advances in Blood Cancer Care for Veterans
8. AI-Based Risk Stratification for Oropharyngeal Carcinomas: AIROC
9. Brain Cancer: Epidemiology, TBI, and New Treatments

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Pulmonary embolism (PE) is a common cause of morbidity and mortality in the general population.¹ The incidence of PE has been reported to range from 39 to 115 per 100,000 persons per year and has remained stable.² Although mortality rates have declined, they remain high.³ The clinical presentation is nonspecific, making diagnosis and management challenging. A crucial and difficult aspect in the management of patients with PE is weighing the risks vs benefits of treatment, including thrombolytic therapy and other invasive procedures, which carry inherent risks. These factors have led to the development of PE response teams (PERTs) in some hospitals to implement effective multidisciplinary protocols that facilitate prompt diagnosis, management, and follow-up.⁴

CASE PRESENTATIONS

Case 1

New onset seizures and cardiac arrest in the treatment of saddle PE. A 54-year-old male who worked as a draftsman and truck driver with a history of hypertension and nephrolithiasis presented to the emergency department (ED) with progressive shortness of breath for 2 weeks. On the morning of ED presentation the patient experienced an episode of severe shortness of breath, lightheadedness, and chest pressure. He reported no other symptoms such as palpitations, nausea, vomiting, abdominal discomfort, or extremity pain or swelling. He reported no recent travel, immunization, falls, or surgery. Upon evaluation, the patient was found to be in no acute distress, with stable vital signs and laboratory results except for 2 elevated results: > 20 μg/mL D-dimer (reference range, < 0.5 μg/mL) and N-terminal prohormone brain natriuretic peptide (proBNP) level, 3455 pg/mL (reference range, < 125 pg/mL for patients aged < 75 years). Electrocardiogram showed T-wave inversions in leads V2 to V4. Imaging revealed a saddle PE and left popliteal deep venous thrombosis (Figure 1). The patient received an anticoagulation loading dose and was started on heparin drip upon admission to the medical intensive care unit (MICU) for further management and monitoring. The Interventional Radiology Service recommended full anticoagulation with consideration of reperfusion therapies if deterioration developed.

While in the MICU, point-of-care ultrasound findings were confirmed with official echocardiogram by the cardiology service, which demonstrated a preserved ejection fraction of 60% to 65%, a D-shaped left ventricle with septal wall hypokinesis secondary to right heart strain (Figure 2), a markedly elevated right ventricular systolic pressure (RVSP) of 73 mm Hg, and a mean pulmonary artery pressure (mPAP) of 38 mm Hg. The patient’s blood pressure progressively decreased, heart rate increased, and he required increased oxygen supplementation. The case was discussed with the Pharmacy Service, and since the patient had no contraindications to thrombolytic therapy, the appropriate dosage was calculated and 100 mg intravenous (IV) tissue plasminogen activator (tPA) was administered over 2 hours.

About 40 minutes into tPA infusion, the patient suddenly experienced marked shortness of breath, diaphoresis, and anxiety with seizure-like involuntary movements; as a result, the infusion was stopped. He also had episodes of posturing, mental status decline, and briefly going in and out of consciousness, which lasted about 3 minutes before he lost consciousness and pulse. High-quality advanced cardiac life support was initiated, followed by endotracheal intubation. Despite a secured airway and return of spontaneous circulation, the patient remained hypotensive and continued to have seizure-like activity.

The patient was administered a total of 8 mg of lorazepam, sedated with propofol, initiated at 5 μg/kg/min, titrated to stop seizure activity at 15μg/kg/min, and later maintained at 10 μg/kg/min, for a RASS of -1, and started on norepinephrine 0.1 μg/kg/min for acute stabilization. Head computed tomography without contrast showed no acute intracranial pathology as etiology of seizures. Seizure etiology differential at this time was broad; however, hypoxemia due to PE and medication adverse effects were strongly suspected.

The patient’s condition improved, and vasopressor therapy was tapered off the next day. Four days later, the patient was weaned from mechanical ventilation and transferred to the step-down unit. Echocardiogram obtained 48 hours after tPA infusion showed essentially normal left ventricular function (60%-65%), a RVSP of 17 mm Hg and mPAP of 13 mm Hg. The patient’s ProBNP levels markedly decreased to 137 pg/mL. Postextubation, the neurologic examination was at baseline. The Neurology Service recommended temporary treatment with levetiracetam, 1000 mg every 12 hours, and the Hematology Service recommended transitioning to direct oral anticoagulation with follow-up. The patient presented significant clinical and respiratory improvement and was referred for home-based physical rehabilitation as recommended by the physical medicine and rehabilitation service before being discharged.

Case 2

Localized tPA infusion for bilateral PEs via infusion catheters. A 91-year-old male with no history of smoking and a medical history of hypertension, diabetes mellitus, prostate cancer (> 20 years postradiotherapy) and severe osteoarthritis was receiving treatment in the medical ward for medication-induced liver injury secondary to an antibiotic for a urinary tract infection. During the night the patient developed hypotension (86/46 mm Hg), shortness of breath, tachypnea, desaturation, nonradiating retrosternal chest pain, and tachycardia. The hypotension resolved after a 500-mL 0.9 normal saline bolus, and hypoxemia improved with supplemental oxygen via Venturi mask. Chest computed tomography angiography was performed immediately and revealed extensive bilateral acute PE, located most proximally in the right main pulmonary artery (PA) and on the left in the proximal lobar branches, with associated right heart strain. The patient was started on IV heparin with a bolus of 5000 units (80 u/kg) followed by a drip with a partial thromboplastin time goal of 62-103 seconds and transferred to MICU.

Laboratory findings were notable for proBNP that increased from 115 pg/mL to 4470 pg/mL (reference range, < 450 pg/mL for patients aged 75 years) and elevated troponin levels at 218 ng/L to 295 ng/L (reference range, < 22 ng/L), exhibiting chemical evidence of right heart strain. Initial echocardiogram showed mid-right ventricular free wall akinesis with a hypercontractile apex, suggestive of PE (McConnell’s sign) (Figure 3). Interventional Radiology Service was consulted and recommended tPA infusion given that the patient had bilateral PEs and stable blood pressure.

Pulmonary angiogram showed elevated pressures in the right PA of 64/21 mm Hg and the left PA pressures of 63/20 mm Hg. Mechanical disruption of the larger right lower PA thrombus was achieved via a pigtail catheter followed by bilateral catheter bolus infusions of 2 mg tPA (alteplase) and a continuous tPA infusion 0.5 mg/h for 24 hours, in conjunction with a heparin infusion.

After 24 hours of tPA infusion, the catheters were removed, with posttreatment pulmonary angiography demonstrating right and left PA pressures of 42/15 mm Hg and 40/16 mm Hg, respectively. Pre- and postlocalized tPA infusion treatment images are provided for visual comparison (Figure 4). An echocardiogram performed after tPA infusion showed no signs of pulmonary hypertension. The Hematology Service provided recommendations regarding anticoagulation, and after completion of tPA infusion, the patient was transitioned to an unfractioned heparin infusion and subsequently to direct oral anticoagulation prior to transfer back to the medical ward, hemodynamically stable and asymptomatic.

DISCUSSION

PE management can be a straightforward decision when the patient meets criteria for hemodynamic instability, or with small PE burden. In contrast, management can be more challenging in intermediate-risk (submassive) PE when patients remain hemodynamically stable but show signs of cardiopulmonary stress, such as right heart strain, elevated troponins, or increased proBNP levels.² In these situations, case-by- case evaluation is warranted. A PERT can assess the most beneficial treatment approach by considering factors such as right ventricular dysfunction, hemodynamic status, clot burden, and clinical deterioration despite appropriate anticoagulation. The evidence supporting the benefits these organized teams can provide is growing. These case reports emphasize the need for a multidisciplinary and systematic approach in these complex cases, especially in the management of intermediate-risk PE patients.

Currently, the Veterans Affairs Caribbean Healthcare System does not have an organized PERT, although a multidisciplinary approach was applied in the management of these patients. A systematic, structured team could have decreased time to interventions and alleviated the burden of physician decision-making. Having such a team would streamline the diagnostic pathway for patients presenting from a ward or emergency department with suspected PE.

We present 2 cases of patients found to have a high clot burden from PEs. The patients were initially hemodynamically stable (intermediate-risk PE), but later required systemic or localized thrombolysis due to hemodynamic deterioration despite adequate anticoagulation. Despite similar diagnoses and etiologies, these patients were successfully managed using different approaches, yielding positive outcomes. This reflects the complexity and variability in diagnosing and managing intermediate-risk PE in patients with different comorbidities and clot burden effects. In Case 1, our multidisciplinary approach was obtained via consults to selected services such as interventional radiology, cardiology, and direct involvement of pharmacy. An organized PERT conceivably would have allowed quicker discussions among these services, including hematology, to provide recommendations and collaborative support upon the patient’s arrival to the ED. Additionally, with a PERT team, a systematic approach to these patients could have allowed for an earlier official echocardiogram report for evaluation of right heart strain and develop an adequate therapeutic plan in a timely manner.

In Case 2, consultation with the Interventional Radiology Service yielded a better therapeutic plan, utilizing localized tPA infusion for this older adult patient with increased risk of bleeding with systemic tPA infusion. Having a PERT presents an opportunity to optimize PE management through early recognition, diagnosis, and treatment by institutional consensus from an interdisciplinary team.^5,6 These response teams may improve outcomes and prognosis for patients with PE, especially where diagnosis and management is not clear.

The definite etiology of seizure activity in the first case pre- and postcardiac arrest, in the context of no acute intracranial process, remains unknown. Reports have emerged about postreperfusion seizures in acute ischemic stroke, as well as cases of seizures masquerading as PE as the primary presentation. ^7,8 However, there were no reports of patients developing seizures post tPA infusion for the treatment of PE. This report may shed light into possible complications secondary to tPA infusion, raising awareness among physicians and encouraging further investigation into its possible etiologies.

CONCLUSIONS

Management of PE can be challenging in patients that meet criteria for intermediate risk. PERTs are a tool that allow for a multidisciplinary, standardized and systematic approach with a diagnostic and treatment algorithm that conceivably would result in a better consensus and therapeutic approach.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Obesity is a growing worldwide epidemic with significant implications for individual health and public health care costs. It is also associated with several medical conditions, including diabetes, cardiovascular disease, cancer, and mental health disorders.¹ Comprehensive lifestyle intervention is a first-line therapy for obesity consisting of dietary and exercise interventions. Despite initial success, long-term results and durability of weight loss with lifestyle modifications are limited. ² Bariatric surgery, including sleeve gastrectomy and gastric bypass surgery, is a more invasive approach that is highly effective in weight loss. However, these operations are not reversible, and patients may not be eligible for or may not desire surgery. Overall, bariatric surgery is widely underutilized, with < 1% of eligible patients ultimately undergoing surgery.^3,4

Endoscopic bariatric therapies are increasingly popular procedures that address the need for additional treatments for obesity among individuals who have not had success with lifestyle changes and are not surgical candidates. The most common procedure is the endoscopic sleeve gastroplasty (ESG), which applies full-thickness sutures in the stomach to reduce gastric volume, delay gastric emptying, and limit food intake while keeping the fundus intact compared with sleeve gastrectomy. This procedure is typically considered in patients with body mass index (BMI) ≥ 30, who do not qualify for or do not want traditional bariatric surgery. The literature supports robust outcomes after ESG, with studies demonstrating significant and sustained total body weight loss of up to 14% to 16% at 5 years and significant improvement in ≥ 1 metabolic comorbidities in 80% of patients.^5,6 ESG adverse events (AEs) include abdominal pain, nausea, and vomiting that are typically self-limited to 1 week. Rarer but more serious AEs include bleeding, perforation, or infection, and occur in 2% of cases based on large trial data.^5,7

Although the weight loss benefits of ESG are well established, to date, there are limited data on the effects of endoscopic bariatric therapies like ESG on mental health conditions. Here, we describe a case of a veteran with a history of mental health disorders that prevented him from completing bariatric surgery. The patient underwent ESG and had a successful clinical course.

CASE PRESENTATION

A 59-year-old male veteran with a medical history of class III obesity (42.4 BMI), obstructive sleep apnea, hypothyroidism, hypertension, type 2 diabetes mellitus, and a large ventral hernia was referred to the MOVE! (Management of Overweight/ Obese Veterans Everywhere!) multidisciplinary high-intensity weight loss program at the US Department of Veterans Affairs (VA) West Los Angeles VA Medical Center (WLAVAMC). His psychiatric history included generalized anxiety disorder, posttraumatic stress disorder (PTSD), and panic disorder, managed by the Psychiatry Service and treated with sertraline 25 mg daily, lorazepam 0.5 mg twice daily, and hydroxyzine 20 mg nightly. He had previously implemented lifestyle changes and attended MOVE! classes and nutrition coaching for 1 year but was unsuccessful in losing weight. He had also tried liraglutide 3 mg daily for weight loss but was unable to tolerate it and reported worsening medication-related anxiety.

The patient declined further weight loss pharmacotherapy and was referred to bariatric surgery. He was scheduled for a surgical sleeve gastrectomy. However, on the day he arrived at the hospital for surgery, he developed severe anxiety and had a panic attack, and it was canceled. Due to his mental health issues, he was no longer comfortable proceeding with surgery and was left without other options for obesity treatment. The veteran was extremely disappointed because the ventral hernia caused significant quality of life impairment, limited his ability to exercise, and caused him embarrassment in public settings. The hernia could not be surgically repaired until there was significant weight loss.

A bariatric endoscopy program within the Division of Gastroenterology was developed and implemented at the WLAVAMC in February 2023 in conjunction with MOVE! The patient was referred for consideration of an endoscopic weight loss procedure. He was determined to be a suitable candidate for ESG based on his BMI being > 40 and personal preference not to proceed with surgery to lose enough weight to qualify for hernia repair. The veteran underwent an endoscopy, which showed normal anatomy and gastric mucosa. ESG was performed in standard fashion (Figure).⁸ Three vertical lines were made using argon plasma coagulation from the incisura to 2 cm below the gastroesophageal junction along the anterior, posterior, and greater curvature of the stomach to mark the area for endoscopic suture placement. Starting at the incisura, 7 full-thickness sutures were placed to create a volume reduction plication, with preservation of the fundus. The patient did well postprocedure with no immediate or delayed AEs and was discharged home the same day.

Follow-up

The veteran followed a gradual dietary advancement from a clear liquid diet to pureed and soft texture food. The patient’s weight dropped from 359 lbs preprocedure to 304 lbs 6 months postprocedure, a total body weight loss (TWBL) of 15.3%. At 12 months the veteran weighed 299 lbs (16.7% TBWL). He also had notable improvements in metabolic parameters. His systolic blood pressure decreased from ≥ 140 mm Hg to 120 to 130 mm Hg and hemoglobin A_1c dropped from 7.0% to 6.3%. Remarkably, his psychiatrist noted significant improvement in his overall mental health. The veteran reported complete cessation of panic attacks since the ESG, improvements in PTSD and anxiety, and was able to discontinue lorazepam and decrease his dose of sertraline to 12.5 mg daily. He reported feeling more energetic and goal-oriented with increased clarity of thought. Perhaps the most significant outcome was that after the 55-lb weight loss at 6 months, the patient was eligible to undergo ventral hernia surgical repair, which had previously contributed to shame and social isolation. This, in turn, improved his quality of life, allowed him to start walking again, up to 8 miles daily, and to feel comfortable again going out in public settings.

DISCUSSION

Bariatric surgeries are an effective method of achieving weight loss and improving obesity-related comorbidities. However, only a small percentage of individuals with obesity are candidates for bariatric surgery. Given the dramatic increase in the prevalence of obesity, other options are needed. Specifically, within the VA, an estimated 80% of veterans are overweight or obese, but only about 500 bariatric surgeries are performed annually.⁹ With the need for additional weight loss therapies, VA programs are starting to offer endoscopic bariatric procedures as an alternative option. This may be a desirable choice for patients with obesity (BMI > 30), with or without associated metabolic comorbidities, who need more aggressive intervention beyond dietary and lifestyle changes and are either not interested in or not eligible for bariatric surgery or weight loss medications.

Although there is evidence that metabolic comorbidities are associated with obesity, there has been less research on obesity and mental health comorbidities such as depression and anxiety. These psychiatric conditions may even be more common among patients seeking weight loss procedures and more prominent in certain groups such as veterans, which may ultimately exclude these patients from bariatric surgery.¹⁰ Prior studies suggest that bariatric surgery can reduce the severity of depression and, to a lesser extent, anxiety symptoms at 2 years following the initial surgery; however, there is limited literature describing the impact of weight loss procedure on panic disorders.^11-14 We suspect that a weight loss procedure such as ESG may have indirectly improved the veteran’s mood disorder due to the weight loss it induced, increasing the ability to exercise, quality of sleep, and participation in public settings.

This case highlights a veteran who did not tolerate weight loss medication and had severe anxiety and PTSD that prevented him from going through with bariatric surgery. He then underwent an endoscopic weight loss procedure. The ESG helped him successfully achieve significant weight loss, increase his physical activity, reduce his anxiety and panic disorder, and overall, significantly improve his quality of life. More than 1 year after the procedure, the patient has sustained improvements in his psychiatric and emotional health along with durable weight loss, maintaining > 15% of his total weight lost. Additional studies are needed to further understand the prevalence and long-term outcomes of mental health comorbidities, as well as weight loss outcomes in this group of patients who undergo endoscopic bariatric procedures.

CONCLUSIONS

We describe a case of a veteran with severe obesity and significant psychiatric comorbidities that prevented him from undergoing bariatric surgery, who underwent an ESG. This procedure led to significant weight loss, improvement of metabolic parameters, reduction in anxiety and PTSD, and enhancement of his quality of life. This case emphasizes the unique advantages of ESG and supports the expansion of endoscopic bariatric programs in the VA.

Since Lyme disease (LD) was first identified in 1975, there has been uncertainty regarding the proper diagnostic testing for suspected cases.¹ Challenges involved with ordering Lyme serology testing include navigating tests with an array of false negatives and false positives.² Confounding these challenges is the wide variety of ocular manifestations of LD, ranging from nonspecific conjunctivitis, cranial palsies, and anterior and posterior segment inflammation.^2,3 This article provides diagnostic testing guidelines for eye care clinicians who encounter patients with suspected LD.

BACKGROUND

LD is a bacterial infection caused by the spirochete Borrelia burgdorferi sensu lato complex transmitted by the Ixodes tick genus. There are 4 species of Ixodes ticks that can infect humans, and only 2 have been identified as principal vectors in North America: Ixodes scapularis and Ixodes pacificus. The incidence of LD is on the rise due to increasing global temperatures and expanding geographic borders for the organism. Cases in endemic areas range from 10 per 100,000 people to 50 per 100,000 people.⁴

LD occurs in 3 stages: early localized (stage 1), early disseminated (stage 2), and late disseminated (stage 3). In stage 1, patients typically present with erythema migrans (EM) rash (bull’s-eye cutaneous rash) and other nonspecific flu-like symptoms of fever, fatigue, and arthralgia. Stage 2 occurs several weeks to months after the initial infection and the infection has invaded other systemic organs, causing conditions like carditis, meningitis, and arthritis. A small subset of patients may progress to stage 3, which is characterized by chronic arthritis and chronic neurological LD.^2,4,5 Ocular manifestations have been well-documented in all stages of LD but are more prevalent in early disseminated disease (Table).^2,3,6,7

Indications

Recognizing common ocular manifestations associated with LD will allow eye care practitioners to make a timely diagnosis and initiate treatment. The most common ocular findings from LD include conjunctivitis, keratitis, cranial nerve VII palsy, optic neuritis, granulomatous iridocyclitis, and pars planitis.^2,6 While retrospective studies suggest that up to 10% of patients with early localized LD have a nonspecific follicular conjunctivitis, those patients are unlikely to present for ocular evaluation. If a patient does present with an acute conjunctivitis, many clinicians do not consider LD in their differential diagnosis.⁸ In endemic areas, it is important to query patients for additional symptoms that may indicate LD.

Obtaining a complete patient history is vital in aiding a clinician’s decision to order Lyme serology for suspected LD. Epidemiology, history of geography/travel, pet exposure, sexual history (necessary to rule out other conditions [ie, syphilis] to direct appropriate diagnostic testing), and a complete review of systems should be obtained.^2,4 LD may mimic other inflammatory autoimmune conditions or infectious diseases such as syphilis.^2,5 This can lead to obtaining unnecessary Lyme serologies or failing to diagnose LD.^5,7

Diagnostic testing is not indicated when a patient presents with an asymptomatic tick bite (ie, has no fever, malaise, or EM rash) or if a patient does not live in or has not recently traveled to an endemic area because it would be highly unlikely the patient has LD.^9,10 If the patient reports known contact with a tick and has a rash suspicious for EM, the diagnosis may be made without confirmatory testing because EM is pathognomonic for LD.^7,11 Serologic testing is not recommended in these cases, particularly if there is a single EM lesion, since the lesion often presents prior to development of an immune response leading to seronegative results.⁸

Lyme serology is necessary if a patient presents with ocular manifestations known to be associated with LD and resides in, or has recently traveled to, an area where LD is endemic (ie, New England, Minnesota, or Wisconsin).^7,12 These criteria are of particular importance: about 50% of patients do not recall a tick bite and 20% to 40% do not present with an EM.^2,9

Diagnostic Testing

In 2019 the Centers for Disease Control and Prevention (CDC) updated their testing guidelines to the modified 2-tier testing (MTTT) method. The MTTT first recommends a Lyme enzyme immunoassay (EIA), with a second EIA recommended only if the first is positive.^12-14 The MTTT method has better sensitivity in early localized LD compared to standard 2-tier testing.^9,11,12 The CDC advises against the use of any laboratory serology tests not approved by the US Food and Drug Administration.¹³ The CDC also advises that LD serology testing should not be performed as a “test for cure,” because even after successful treatment, an individual may still test positive.^1,9 Follow-up testing in patients treated early in the disease course (ie, in the setting of EM) may never have an antibody response. In these cases, a negative test should not exclude an LD diagnosis. ⁹ For patients with suspected neuroborreliosis, a lumbar puncture may not be needed if a patient already has a positive peripheral serology via the MTTT method.¹² The Figure depicts a flow chart for the process of ordering and interpreting testing.

Most LD testing, if correlated with clinical disease, is positive after 4 to 6 weeks.⁹ If an eye disease is noted and the patient has positive Lyme serology, the patient should still be screened for Lyme neuroborreliosis of the central nervous system (CNS). Examination of the fundus for papilledema, review of symptoms of aseptic meningitis, and a careful neurologic examination should be performed.¹⁵

If CNS disease is suspected, the patient may need additional CNS testing to support treatment decisions. The 2020 Infectious Diseases Society of America Lyme guidelines recommend to: (1) obtain simultaneous samples of cerebrospinal fluid (CSF) and serum for determination of the CSF:serum antibody index; (2) do not obtain CSF serology without measurement of the CSF:serum antibody index; and (3) do not obtain routine polymerase chain reaction or culture of CSF or serum.15 Once an LD diagnosis is confirmed, the CDC recommends a course of 100 mg of oral doxycycline twice daily for 14 to 21 days or an antimicrobial equivalent (eg, amoxicillin) if doxycycline is contraindicated. However, the antimicrobial dosage may vary depending on the stage of LD.¹¹ Patients with confirmed neuroborreliosis should be admitted for 14 days of intravenous ceftriaxone or intravenous penicillin.²

CONCLUSIONS

To ensure timely diagnosis and treatment, eye care clinicians should be familiar with the appropriate diagnostic testing for patients suspected to have ocular manifestations of LD. For patients with suspected LD and a high pretest probability, clinicians should obtain a first-order Lyme EIA.^12-14 If testing confirms LD, refer the patient to an infectious disease specialist for antimicrobial treatment and additional management.¹¹

Since Lyme disease (LD) was first identified in 1975, there has been uncertainty regarding the proper diagnostic testing for suspected cases.¹ Challenges involved with ordering Lyme serology testing include navigating tests with an array of false negatives and false positives.² Confounding these challenges is the wide variety of ocular manifestations of LD, ranging from nonspecific conjunctivitis, cranial palsies, and anterior and posterior segment inflammation.^2,3 This article provides diagnostic testing guidelines for eye care clinicians who encounter patients with suspected LD.

BACKGROUND

LD is a bacterial infection caused by the spirochete Borrelia burgdorferi sensu lato complex transmitted by the Ixodes tick genus. There are 4 species of Ixodes ticks that can infect humans, and only 2 have been identified as principal vectors in North America: Ixodes scapularis and Ixodes pacificus. The incidence of LD is on the rise due to increasing global temperatures and expanding geographic borders for the organism. Cases in endemic areas range from 10 per 100,000 people to 50 per 100,000 people.⁴

LD occurs in 3 stages: early localized (stage 1), early disseminated (stage 2), and late disseminated (stage 3). In stage 1, patients typically present with erythema migrans (EM) rash (bull’s-eye cutaneous rash) and other nonspecific flu-like symptoms of fever, fatigue, and arthralgia. Stage 2 occurs several weeks to months after the initial infection and the infection has invaded other systemic organs, causing conditions like carditis, meningitis, and arthritis. A small subset of patients may progress to stage 3, which is characterized by chronic arthritis and chronic neurological LD.^2,4,5 Ocular manifestations have been well-documented in all stages of LD but are more prevalent in early disseminated disease (Table).^2,3,6,7

Indications

Recognizing common ocular manifestations associated with LD will allow eye care practitioners to make a timely diagnosis and initiate treatment. The most common ocular findings from LD include conjunctivitis, keratitis, cranial nerve VII palsy, optic neuritis, granulomatous iridocyclitis, and pars planitis.^2,6 While retrospective studies suggest that up to 10% of patients with early localized LD have a nonspecific follicular conjunctivitis, those patients are unlikely to present for ocular evaluation. If a patient does present with an acute conjunctivitis, many clinicians do not consider LD in their differential diagnosis.⁸ In endemic areas, it is important to query patients for additional symptoms that may indicate LD.

Obtaining a complete patient history is vital in aiding a clinician’s decision to order Lyme serology for suspected LD. Epidemiology, history of geography/travel, pet exposure, sexual history (necessary to rule out other conditions [ie, syphilis] to direct appropriate diagnostic testing), and a complete review of systems should be obtained.^2,4 LD may mimic other inflammatory autoimmune conditions or infectious diseases such as syphilis.^2,5 This can lead to obtaining unnecessary Lyme serologies or failing to diagnose LD.^5,7

Diagnostic testing is not indicated when a patient presents with an asymptomatic tick bite (ie, has no fever, malaise, or EM rash) or if a patient does not live in or has not recently traveled to an endemic area because it would be highly unlikely the patient has LD.^9,10 If the patient reports known contact with a tick and has a rash suspicious for EM, the diagnosis may be made without confirmatory testing because EM is pathognomonic for LD.^7,11 Serologic testing is not recommended in these cases, particularly if there is a single EM lesion, since the lesion often presents prior to development of an immune response leading to seronegative results.⁸

Lyme serology is necessary if a patient presents with ocular manifestations known to be associated with LD and resides in, or has recently traveled to, an area where LD is endemic (ie, New England, Minnesota, or Wisconsin).^7,12 These criteria are of particular importance: about 50% of patients do not recall a tick bite and 20% to 40% do not present with an EM.^2,9

Diagnostic Testing

In 2019 the Centers for Disease Control and Prevention (CDC) updated their testing guidelines to the modified 2-tier testing (MTTT) method. The MTTT first recommends a Lyme enzyme immunoassay (EIA), with a second EIA recommended only if the first is positive.^12-14 The MTTT method has better sensitivity in early localized LD compared to standard 2-tier testing.^9,11,12 The CDC advises against the use of any laboratory serology tests not approved by the US Food and Drug Administration.¹³ The CDC also advises that LD serology testing should not be performed as a “test for cure,” because even after successful treatment, an individual may still test positive.^1,9 Follow-up testing in patients treated early in the disease course (ie, in the setting of EM) may never have an antibody response. In these cases, a negative test should not exclude an LD diagnosis. ⁹ For patients with suspected neuroborreliosis, a lumbar puncture may not be needed if a patient already has a positive peripheral serology via the MTTT method.¹² The Figure depicts a flow chart for the process of ordering and interpreting testing.

Most LD testing, if correlated with clinical disease, is positive after 4 to 6 weeks.⁹ If an eye disease is noted and the patient has positive Lyme serology, the patient should still be screened for Lyme neuroborreliosis of the central nervous system (CNS). Examination of the fundus for papilledema, review of symptoms of aseptic meningitis, and a careful neurologic examination should be performed.¹⁵

If CNS disease is suspected, the patient may need additional CNS testing to support treatment decisions. The 2020 Infectious Diseases Society of America Lyme guidelines recommend to: (1) obtain simultaneous samples of cerebrospinal fluid (CSF) and serum for determination of the CSF:serum antibody index; (2) do not obtain CSF serology without measurement of the CSF:serum antibody index; and (3) do not obtain routine polymerase chain reaction or culture of CSF or serum.15 Once an LD diagnosis is confirmed, the CDC recommends a course of 100 mg of oral doxycycline twice daily for 14 to 21 days or an antimicrobial equivalent (eg, amoxicillin) if doxycycline is contraindicated. However, the antimicrobial dosage may vary depending on the stage of LD.¹¹ Patients with confirmed neuroborreliosis should be admitted for 14 days of intravenous ceftriaxone or intravenous penicillin.²

CONCLUSIONS

To ensure timely diagnosis and treatment, eye care clinicians should be familiar with the appropriate diagnostic testing for patients suspected to have ocular manifestations of LD. For patients with suspected LD and a high pretest probability, clinicians should obtain a first-order Lyme EIA.^12-14 If testing confirms LD, refer the patient to an infectious disease specialist for antimicrobial treatment and additional management.¹¹

Since Lyme disease (LD) was first identified in 1975, there has been uncertainty regarding the proper diagnostic testing for suspected cases.¹ Challenges involved with ordering Lyme serology testing include navigating tests with an array of false negatives and false positives.² Confounding these challenges is the wide variety of ocular manifestations of LD, ranging from nonspecific conjunctivitis, cranial palsies, and anterior and posterior segment inflammation.^2,3 This article provides diagnostic testing guidelines for eye care clinicians who encounter patients with suspected LD.

BACKGROUND

LD is a bacterial infection caused by the spirochete Borrelia burgdorferi sensu lato complex transmitted by the Ixodes tick genus. There are 4 species of Ixodes ticks that can infect humans, and only 2 have been identified as principal vectors in North America: Ixodes scapularis and Ixodes pacificus. The incidence of LD is on the rise due to increasing global temperatures and expanding geographic borders for the organism. Cases in endemic areas range from 10 per 100,000 people to 50 per 100,000 people.⁴

LD occurs in 3 stages: early localized (stage 1), early disseminated (stage 2), and late disseminated (stage 3). In stage 1, patients typically present with erythema migrans (EM) rash (bull’s-eye cutaneous rash) and other nonspecific flu-like symptoms of fever, fatigue, and arthralgia. Stage 2 occurs several weeks to months after the initial infection and the infection has invaded other systemic organs, causing conditions like carditis, meningitis, and arthritis. A small subset of patients may progress to stage 3, which is characterized by chronic arthritis and chronic neurological LD.^2,4,5 Ocular manifestations have been well-documented in all stages of LD but are more prevalent in early disseminated disease (Table).^2,3,6,7

Indications

Recognizing common ocular manifestations associated with LD will allow eye care practitioners to make a timely diagnosis and initiate treatment. The most common ocular findings from LD include conjunctivitis, keratitis, cranial nerve VII palsy, optic neuritis, granulomatous iridocyclitis, and pars planitis.^2,6 While retrospective studies suggest that up to 10% of patients with early localized LD have a nonspecific follicular conjunctivitis, those patients are unlikely to present for ocular evaluation. If a patient does present with an acute conjunctivitis, many clinicians do not consider LD in their differential diagnosis.⁸ In endemic areas, it is important to query patients for additional symptoms that may indicate LD.

Obtaining a complete patient history is vital in aiding a clinician’s decision to order Lyme serology for suspected LD. Epidemiology, history of geography/travel, pet exposure, sexual history (necessary to rule out other conditions [ie, syphilis] to direct appropriate diagnostic testing), and a complete review of systems should be obtained.^2,4 LD may mimic other inflammatory autoimmune conditions or infectious diseases such as syphilis.^2,5 This can lead to obtaining unnecessary Lyme serologies or failing to diagnose LD.^5,7

Diagnostic testing is not indicated when a patient presents with an asymptomatic tick bite (ie, has no fever, malaise, or EM rash) or if a patient does not live in or has not recently traveled to an endemic area because it would be highly unlikely the patient has LD.^9,10 If the patient reports known contact with a tick and has a rash suspicious for EM, the diagnosis may be made without confirmatory testing because EM is pathognomonic for LD.^7,11 Serologic testing is not recommended in these cases, particularly if there is a single EM lesion, since the lesion often presents prior to development of an immune response leading to seronegative results.⁸

Lyme serology is necessary if a patient presents with ocular manifestations known to be associated with LD and resides in, or has recently traveled to, an area where LD is endemic (ie, New England, Minnesota, or Wisconsin).^7,12 These criteria are of particular importance: about 50% of patients do not recall a tick bite and 20% to 40% do not present with an EM.^2,9

Diagnostic Testing

In 2019 the Centers for Disease Control and Prevention (CDC) updated their testing guidelines to the modified 2-tier testing (MTTT) method. The MTTT first recommends a Lyme enzyme immunoassay (EIA), with a second EIA recommended only if the first is positive.^12-14 The MTTT method has better sensitivity in early localized LD compared to standard 2-tier testing.^9,11,12 The CDC advises against the use of any laboratory serology tests not approved by the US Food and Drug Administration.¹³ The CDC also advises that LD serology testing should not be performed as a “test for cure,” because even after successful treatment, an individual may still test positive.^1,9 Follow-up testing in patients treated early in the disease course (ie, in the setting of EM) may never have an antibody response. In these cases, a negative test should not exclude an LD diagnosis. ⁹ For patients with suspected neuroborreliosis, a lumbar puncture may not be needed if a patient already has a positive peripheral serology via the MTTT method.¹² The Figure depicts a flow chart for the process of ordering and interpreting testing.

Most LD testing, if correlated with clinical disease, is positive after 4 to 6 weeks.⁹ If an eye disease is noted and the patient has positive Lyme serology, the patient should still be screened for Lyme neuroborreliosis of the central nervous system (CNS). Examination of the fundus for papilledema, review of symptoms of aseptic meningitis, and a careful neurologic examination should be performed.¹⁵

If CNS disease is suspected, the patient may need additional CNS testing to support treatment decisions. The 2020 Infectious Diseases Society of America Lyme guidelines recommend to: (1) obtain simultaneous samples of cerebrospinal fluid (CSF) and serum for determination of the CSF:serum antibody index; (2) do not obtain CSF serology without measurement of the CSF:serum antibody index; and (3) do not obtain routine polymerase chain reaction or culture of CSF or serum.15 Once an LD diagnosis is confirmed, the CDC recommends a course of 100 mg of oral doxycycline twice daily for 14 to 21 days or an antimicrobial equivalent (eg, amoxicillin) if doxycycline is contraindicated. However, the antimicrobial dosage may vary depending on the stage of LD.¹¹ Patients with confirmed neuroborreliosis should be admitted for 14 days of intravenous ceftriaxone or intravenous penicillin.²

CONCLUSIONS

To ensure timely diagnosis and treatment, eye care clinicians should be familiar with the appropriate diagnostic testing for patients suspected to have ocular manifestations of LD. For patients with suspected LD and a high pretest probability, clinicians should obtain a first-order Lyme EIA.^12-14 If testing confirms LD, refer the patient to an infectious disease specialist for antimicrobial treatment and additional management.¹¹

ATLANTA —Jacqueline Lee, MD, a reproductive endocrinologist at Emory School of Medicine, frequently treats patients with cancer. Recently, she treated 4 women in their 30s with histories of colon cancer, acute lymphoblastic leukemia, lymphoma, and breast cancer. A young man in his 20s sought her care, to discuss his case of lymphoma.

All these patients sought guidance from Lee because they want to protect their ability to have children. At the annual meeting of the Association of VA Hematology/Oncology, Lee explained that plenty of patients are finding themselves in similar straits due in part to recent trends.

Cancer rates in the US have been rising among people aged 15 to 39 years, who now account for 4.2% of all cancer cases. An estimated 84,100 people in this age group are expected to be diagnosed with cancer this year. Meanwhile, women are having children later in life-birth rates are up among those aged 25 to 49 years-making it more likely that they have histories of cancer.

Although it's difficult to predict how cancer will affect fertility, Lee emphasized that many chemotherapy medications, including cisplatin and carboplatin, are cytotoxic. "It's hard to always predict what someone's arc of care is going to be," she said, "so I really have a low threshold for recommending fertility preservation in patients who have a strong desire to have future childbearing."

For women with cancer, egg preservation isn't the only strategy. Clinicians can also try to protect ovarian tissue from pelvic radiation through surgical reposition of the ovaries, Lee noted. In addition goserelin, a hormone-suppressing therapy, may protect the ovaries from chemotherapy, though its effectiveness in boosting pregnancy rates is still unclear.

"When I mentioned this option, it's usually for patients who can't preserve fertility via egg or embryo preservation, or we don't have the luxury of that kind of time," Lee said. "I say that if helps at all, it might help you resume menses after treatment. But infertility is still very common."

For some patients, freezing eggs is an easy decision. "They don't have a reproductive partner they're ready to make embryos with, so we proceed with egg preservation. It's no longer considered experimental and comes with lower upfront costs since the costs of actually making embryos are deferred until the future."

In addition, she said, freezing eggs also avoids the touchy topic of disposing of embryos. Lee cautions patients that retrieving eggs is a 2-week process that requires any initiation of cancer care to be delayed. However, the retrieval process can be adjusted in patients with special needs due to the type of cancer they have.

For prepubertal girls with cancer, ovarian tissue can be removed and frozen as a fertility preservation option. However, this is not considered standard of care. "We don't do it," she said. "We refer out if needed. Hopefully we'll develop a program in the future."

As for the 5 patients that Lee mentioned, with details changed to protect their privacy, their outcomes were as follows:

• The woman with colon cancer, who had undergone a hemicolectomy, chose to defer fertility preservation.
• The woman with acute lymphoblastic leukemia, who was taking depo-Lupron, had undetectable anti-Müllerian hormone (AMH) levels. Lee discussed the possibility of IVF with a donor egg.
• The woman with breast cancer, who was newly diagnosed, deferred fertility preservation.
• The man with lymphoma (Hodgkin's), who was awaiting chemotherapy, had his sperm frozen.
• The woman with lymphoma (new diagnosis) had 27 eggs frozen.

Lee had no disclosures to report.

ATLANTA —Jacqueline Lee, MD, a reproductive endocrinologist at Emory School of Medicine, frequently treats patients with cancer. Recently, she treated 4 women in their 30s with histories of colon cancer, acute lymphoblastic leukemia, lymphoma, and breast cancer. A young man in his 20s sought her care, to discuss his case of lymphoma.

All these patients sought guidance from Lee because they want to protect their ability to have children. At the annual meeting of the Association of VA Hematology/Oncology, Lee explained that plenty of patients are finding themselves in similar straits due in part to recent trends.

Cancer rates in the US have been rising among people aged 15 to 39 years, who now account for 4.2% of all cancer cases. An estimated 84,100 people in this age group are expected to be diagnosed with cancer this year. Meanwhile, women are having children later in life-birth rates are up among those aged 25 to 49 years-making it more likely that they have histories of cancer.

Although it's difficult to predict how cancer will affect fertility, Lee emphasized that many chemotherapy medications, including cisplatin and carboplatin, are cytotoxic. "It's hard to always predict what someone's arc of care is going to be," she said, "so I really have a low threshold for recommending fertility preservation in patients who have a strong desire to have future childbearing."

For women with cancer, egg preservation isn't the only strategy. Clinicians can also try to protect ovarian tissue from pelvic radiation through surgical reposition of the ovaries, Lee noted. In addition goserelin, a hormone-suppressing therapy, may protect the ovaries from chemotherapy, though its effectiveness in boosting pregnancy rates is still unclear.

"When I mentioned this option, it's usually for patients who can't preserve fertility via egg or embryo preservation, or we don't have the luxury of that kind of time," Lee said. "I say that if helps at all, it might help you resume menses after treatment. But infertility is still very common."

For some patients, freezing eggs is an easy decision. "They don't have a reproductive partner they're ready to make embryos with, so we proceed with egg preservation. It's no longer considered experimental and comes with lower upfront costs since the costs of actually making embryos are deferred until the future."

In addition, she said, freezing eggs also avoids the touchy topic of disposing of embryos. Lee cautions patients that retrieving eggs is a 2-week process that requires any initiation of cancer care to be delayed. However, the retrieval process can be adjusted in patients with special needs due to the type of cancer they have.

For prepubertal girls with cancer, ovarian tissue can be removed and frozen as a fertility preservation option. However, this is not considered standard of care. "We don't do it," she said. "We refer out if needed. Hopefully we'll develop a program in the future."

As for the 5 patients that Lee mentioned, with details changed to protect their privacy, their outcomes were as follows:

• The woman with colon cancer, who had undergone a hemicolectomy, chose to defer fertility preservation.
• The woman with acute lymphoblastic leukemia, who was taking depo-Lupron, had undetectable anti-Müllerian hormone (AMH) levels. Lee discussed the possibility of IVF with a donor egg.
• The woman with breast cancer, who was newly diagnosed, deferred fertility preservation.
• The man with lymphoma (Hodgkin's), who was awaiting chemotherapy, had his sperm frozen.
• The woman with lymphoma (new diagnosis) had 27 eggs frozen.

Lee had no disclosures to report.

ATLANTA —Jacqueline Lee, MD, a reproductive endocrinologist at Emory School of Medicine, frequently treats patients with cancer. Recently, she treated 4 women in their 30s with histories of colon cancer, acute lymphoblastic leukemia, lymphoma, and breast cancer. A young man in his 20s sought her care, to discuss his case of lymphoma.

All these patients sought guidance from Lee because they want to protect their ability to have children. At the annual meeting of the Association of VA Hematology/Oncology, Lee explained that plenty of patients are finding themselves in similar straits due in part to recent trends.

Cancer rates in the US have been rising among people aged 15 to 39 years, who now account for 4.2% of all cancer cases. An estimated 84,100 people in this age group are expected to be diagnosed with cancer this year. Meanwhile, women are having children later in life-birth rates are up among those aged 25 to 49 years-making it more likely that they have histories of cancer.

Although it's difficult to predict how cancer will affect fertility, Lee emphasized that many chemotherapy medications, including cisplatin and carboplatin, are cytotoxic. "It's hard to always predict what someone's arc of care is going to be," she said, "so I really have a low threshold for recommending fertility preservation in patients who have a strong desire to have future childbearing."

For women with cancer, egg preservation isn't the only strategy. Clinicians can also try to protect ovarian tissue from pelvic radiation through surgical reposition of the ovaries, Lee noted. In addition goserelin, a hormone-suppressing therapy, may protect the ovaries from chemotherapy, though its effectiveness in boosting pregnancy rates is still unclear.

"When I mentioned this option, it's usually for patients who can't preserve fertility via egg or embryo preservation, or we don't have the luxury of that kind of time," Lee said. "I say that if helps at all, it might help you resume menses after treatment. But infertility is still very common."

For some patients, freezing eggs is an easy decision. "They don't have a reproductive partner they're ready to make embryos with, so we proceed with egg preservation. It's no longer considered experimental and comes with lower upfront costs since the costs of actually making embryos are deferred until the future."

In addition, she said, freezing eggs also avoids the touchy topic of disposing of embryos. Lee cautions patients that retrieving eggs is a 2-week process that requires any initiation of cancer care to be delayed. However, the retrieval process can be adjusted in patients with special needs due to the type of cancer they have.

For prepubertal girls with cancer, ovarian tissue can be removed and frozen as a fertility preservation option. However, this is not considered standard of care. "We don't do it," she said. "We refer out if needed. Hopefully we'll develop a program in the future."

As for the 5 patients that Lee mentioned, with details changed to protect their privacy, their outcomes were as follows:

• The woman with colon cancer, who had undergone a hemicolectomy, chose to defer fertility preservation.
• The woman with acute lymphoblastic leukemia, who was taking depo-Lupron, had undetectable anti-Müllerian hormone (AMH) levels. Lee discussed the possibility of IVF with a donor egg.
• The woman with breast cancer, who was newly diagnosed, deferred fertility preservation.
• The man with lymphoma (Hodgkin's), who was awaiting chemotherapy, had his sperm frozen.
• The woman with lymphoma (new diagnosis) had 27 eggs frozen.

Lee had no disclosures to report.