ABSTRACT

Reconstructing proximal humeral bone loss in the setting of shoulder arthroplasty can be a daunting task. Proposed techniques include long-stemmed humeral components, allograft-prosthesis composites (APCs), and modular endoprosthetic reconstruction. While unsupported long-stemmed components are at high risk for component loosening, APC reconstruction techniques have been reported with success. However, graft resorption and eventual failure are significant concerns. Modular endoprosthetic systems allow bone deficiencies to be reconstructed with metal, which may allow for a more durable reconstruction.

Continue to: Shoulder arthroplasty is an established procedure...

Shoulder arthroplasty is an established procedure with good results for restoring motion and decreasing pain for a variety of indications, including arthritis, fracture, posttraumatic sequelae, and tumor resection.^1-4 As the population ages, the incidence of these shoulder disorders increases, with the incidence of total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RTSA) increasing at faster rates than that of hemiarthroplasty.^5,6 These expanding indications will, in turn, result in more revisions that would present challenges for surgeons.^1,7,8

The glenoid component is much more commonly revised than the humeral component; however, the humeral component may also require revision or removal to allow exposure of the glenoid component.⁹ Revision of the humeral stem might be required in cases of infection, periprosthetic fracture, dislocation, or aseptic loosening.¹⁰ The survival rate of humeral stems is generally >90% at 10 years and >80% at 20-year follow-up.⁷ Despite these good survival rates, a revision setting the humeral component requires exchange in about half of all cases.¹¹

Humeral bone loss or deficiency is one of the challenges encountered in both primary and revision TSA. The amount of proximal bone loss can be determined by measuring the distance from the top of the prosthesis laterally to the intact lateral cortex.¹² Methods for treating bone loss may involve monoblock revision stems to bypass the deficiency, allografts to rebuild the bone stock, or modular components or endoprostheses to restore the length and stability of the extremity.

Proximal humeral bone loss may make component positioning difficult and may create problems with fixation of the humeral stem. Proper sizing and placement of components are important for improving postoperative function, decreasing component wear and instability, and restoring humeral height and offset. Determining the appropriate center of rotation is important for the function and avoidance of impingement on the acromion, as well as for the restoration of the lever arm of the deltoid without overtensioning. The selection of components with the correct size and the accurate intraoperative placement are important to restore humeral height and offset.^13,14 Components must be positioned <4 mm from the height of the greater tuberosity and <8 mm of offset to avoid compromising motion.¹⁵ De Wilde and Walch¹⁶ described about 3 patients who underwent revision reverse shoulder arthroplasty after failure of the humeral implant because of inadequate proximal humeral bone stock. They concluded that treatment of the bone loss was critical to achieve a successful outcome.

LONG-STEMMED HUMERAL COMPONENTS WITHOUT GRAFTING

There is some evidence indicating that humeral bone loss can be managed without allograft or augmentation. Owens and colleagues¹⁷ evaluated the use of intermediate- or long-stemmed humeral components for primary shoulder arthroplasty in 17 patients with severe proximal humeral bone loss and in 18 patients with large humeral canals. The stems were fully cemented, cemented distally only with proximal allografting, and uncemented. Indications for fully cemented stems were loss of proximal bone that could be filled with a proximal cement mantle to ensure a secure fit. Distal cement fixation was applied when there was significant proximal bone loss and was often supplemented with cancellous or structural allograft and/or cancellous autograft. Intraoperative complications included cortical perforation or cement extrusion in 16% of patients. Excellent or satisfactory results were obtained in 21 (60%) of the 35 shoulders, 14 (78%) of the 18 shoulders with large humeral canals, and 7 (41%) of the 17 shoulders with bone loss. All the 17 components implanted in patients with proximal humeral bone loss were stable with no gross loosening at an average 6-year follow-up.

Continue to: Budge and colleagues...

Budge and colleagues¹² prospectively enrolled 15 patients with substantial proximal humeral bone loss (38.4 mm) who had conversion to RTSA without allografting after a failed TSA. All patients showed improvements in terms of the American Shoulder and Elbow Surgeons (ASES) score, subjective shoulder value, Constant score, and Visual Analog Scale (VAS) pain score, as well as an improved active range of motion (ROM) and good radiographic outcomes at 2-year follow-up. Although the complication rate was high (7 of 15), most of the complications were minor, with only 2 requiring operative intervention. The only component fracture occurred in a patient with a modular prosthesis that was unsupported by bone proximally. Budge and colleagues¹² suggested that concerns about prosthetic fracture can be alleviated using a nonmodular monoblock design. No prosthesis-related complications occurred in their series, leading them to recommend monoblock humeral stems in patients with severe proximal humeral bone loss.

Stephens and colleagues¹⁸ reported revision to RTSA in 32 patients with hemiarthroplasties, half of whom had proximal humeral bone loss (average 36.3 mm). Of these 16 patients, 10 were treated with monoblock stems and 6 with modular components, with cement fixation of all implants. At an average 4-year follow-up, patients with proximal bone loss had improved motion and outcomes, and decreased pain compared to their preoperative condition; however, they had lower functional and pain ratings, as well as less ROM compared to those of patients with intact proximal bone stock. Complications occurred in 5 (31%) of those with bone loss and in 1 (0.6%) of those without bone loss. Three of the 16 patients with bone loss had humeral stem loosening, with 2 of the 3 having subsidence. Only 1 patient required return to the operating room for the treatment of a periprosthetic fracture sustained in a fall. Of the 16 patients with bone loss, 14 patients demonstrated scapular notching, which was severe in 5 of them. Because patients with altered humeral length and/or standard length stems had worse outcomes, the authors recommended longer stems to improve fixation and advocated the use of a long-stemmed monoblock prosthesis over an allograft-prosthesis composite (APC).¹⁸

However, Werner and colleagues¹⁹ reported high rates of loosening and distal migration with the use of long-stemmed humeral implants in 50 patients with revision RTSA. They noted periprosthetic lucency on radiographs in 48% of patients, with more than half of them requiring revision. In 6 patients with subsidence of the humeral shaft, revision was done using custom, modular implants, with the anatomic curve being further stabilized using distal screw and cable fixation to provide rotational stability.

Using a biomechanical model, Cuff and colleagues²⁰ compared 3 RTSA humeral designs, 2 modular designs, and 1 monoblock design in 12 intact models and in 12 models simulating 5 cm of proximal humeral bone loss. They observed that proximal humeral bone loss led to increased humeral component micromotion and rotational instability. The bone loss group had 5 failures compared to 2 in the control group. All failures occurred in those with modular components, whereas those with monoblock implants had no failures.

ALLOGRAFT-PROSTHESIS COMPOSITE

Composite treatment with a humeral stem and a metaphyseal allograft was described by Kassab and colleagues²¹ in 2005 and Levy and colleagues²² in 2007 (Figures 1A-1C) in patients with tumor resections²¹ or failed hemiarthroplasties.²² Allograft was used when there was insufficient metaphyseal bone to support the implant, and a graft was fashioned and fixed with cerclage wire before the component was cemented in place. In the 29 patients reported by Levy and colleagues,²² subjective and objective measurements trended toward better results in those with an APC than in those with RTSA alone, but this difference did not reach statistical significance. Several authors have identified a lack of proximal humeral bone support as 1 of the 4 possible causes of failure, and suggested that the allograft provides structural support, serves as an attachment for subscapularis repair, and maximizes deltoid function by increasing lateral offset and setting the moment arm of the deltoid.^21-23

Continue to: In a prospective study of RTSA...

In a prospective study of RTSA using structural allografts for failed hemiarthroplasty in 25 patients with an average bone loss of 5 cm, 19 patients (76%) reported good or excellent results, 5 reported satisfactory results, and 1 patient reported an unsatisfactory result.¹ Patients had significantly improved forward flexion, abduction, and external rotation and improved outcome scores (ASES and SST). Graft incorporation was good, with 88% and 79% incorporation in the metaphysis and diaphysis, respectively. This technique used a fresh-frozen proximal humeral allograft to fashion a custom proximal block with a lateral step-cut, which was fixed around the stem with cables. A long stem and cement were used. If there was no cement mantle remaining or if the medial portion of the graft was longer than 120 mm, the cement mantle was completely excised. The allograft stump of the subscapularis was used to repair the subscapularis tendon either end-to-end or pants-over-vest. The authors noted that the subscapularis repair provided increased stability; the only dislocation not caused by trauma did not have an identifiable tendon to repair. In this manner, APC reconstruction provided structural and rotational support to the humeral stem as well as bone stock for future revision.^1,20

One significant concern with APC reconstruction is the potential for graft resorption, which can lead to humeral stem loosening, loss of contour of the tuberosity, or weakening to the point of fracture.^24,25 This may be worsened by stress shielding of the allograft by distal stem cement fixation.²⁶ Other concerns include the cost of the allograft, increased risk of de novo infection, donor-to-host infection, increased operative time and complexity, and failure of allograft incorporation.

The use of a proximal femoral allograft has been described when there is a lack of a proximal humeral allograft.^1,27 Kelly and colleagues²⁷ described good results in 2 patients in whom proximal femoral allograft was used along with bone morphogenetic protein, cemented long-stemmed revision implants, and locking plate augmentation.

ENDOPROSTHETIC RECONSTRUCTION

Various forms of prosthetic augmentation have been described to compensate for proximal humeral bone loss, with the majority of reports involving the use of endoprosthetic replacement for tumor procedures.^28-31 Use of endoprostheses has also been described for revision procedures in patients with rheumatoid arthritis with massive bone loss, demonstrating modest improvements compared to severe preoperative functional limitations.³²

Tumor patients, as well as revision arthroplasty patients, may present difficulties with prosthetic fixation due to massive bone loss. Chao and colleagues²⁹ reported about the long-term outcomes after the use of implants with a porous ongrowth surface and extracortical bridging bone graft in multiple anatomic locations, including the proximal humerus, the proximal and distal femur, and the femoral diaphysis. In 3 patients with proximal humeral reconstruction, the measured ongrowth was only 30%. Given the small number of patients with a proximal humerus, no statistical significance was observed in the prosthesis location and the amount of bony ongrowth, but it was far less than that in the lower extremity.

Continue to: Endoprosthetic reconstruction...

Endoprosthetic reconstruction of the proximal humerus is commonly used for tumor resection that resulted in bone loss. Cannon and colleagues²⁸ reported a 97.6% survival rate at a mean follow-up of 30 months in 83 patients with modular and custom reconstruction with a unipolar head. The ROM was limited, but the prosthesis provided adequate stability to allow elbow and hand function. Proximal migration of the prosthetic head was noticed with increasing frequency as the length of follow-up increased.

Use of an endoprosthesis with compressive osteointegration (Zimmer Biomet) has been described in lower extremities and more recently with follow-up on several cases, including 2 proximal humeral replacements for oncology patients to treat severe bone loss. One case was for a primary sarcoma resection, and the other was for the revision of aseptic loosening of a previous endoprosthesis. Follow-up periods for these 2 patients were 54 and 141 months, respectively. Both these patients had complications, but both retained the endoprosthesis. The authors concluded that this is a salvage operation with high risk.³⁰ In another study, Guven and colleagues³¹ reported about reverse endoprosthetic reconstruction for tumor resection with bone loss. The ROM was improved, with a mean active forward elevation of 96° (range, 30°-160°), an abduction of 88° (range, 30-160°), and an external rotation of 13° (range, 0°-20°).

Modular endoprostheses have been evaluated as a method for improving bone fixation and restoring soft-tissue tension, while avoiding the complications associated with traditional endoprostheses or allografts (Figures 2A-2D). These systems allow precise adjustments of length using different trial lengths intraoperatively to obtain proper stability and deltoid tension. Of the 12 patients in a 2 center study, 11 had cementless components inserted using a press-fit technique (unpublished data, J. Feldman). At a minimum 2-year follow-up, the patients had an average improvement in forward elevation from 78° to 97°. Excluding 2 patients with loss of the deltoid tuberosity, the forward elevation averaged 109°. There were significant improvements in internal rotation (from 18° to 38°), as well as in the scores of Quick Disabilities of the Arm, Shoulder and Hand (DASH), forward elevation strength, ASES, and VAS pain. However, the overall complication rate was 41%. Therefore, despite these promising early results, longer-term studies are needed.

CONCLUSION

Proximal humeral bone loss remains a significant challenge for the shoulder arthroplasty surgeon. In the setting of a primary or a revision arthroplasty, the bone stock must be thoroughly evaluated during preoperative planning, and a surgical plan for addressing the deficits should be developed. Because proximal humeral bone loss may contribute to prosthetic failure, every effort should be made to reconstitute the bone stock.¹⁶ If the bone loss is less extensive, impaction grafting may be considered. Options to address massive proximal humeral bone loss include APCs and endoprosthetic reconstruction. The use of an allograft allows subscapularis repair, which may help stabilize the shoulder and restore the natural lever arm, as well as the tension of the deltoid.^1,21-23 In addition, it helps avoid rotational instability and micromotion and provides bone stock for future revisions. However, concern persists regarding allograft resorption over time. More recently, modular endoprosthetic reconstruction systems have been developed to address bone deficiency with metal augmentation. Early clinical results demonstrate a high complication rate in this complex cohort of patients, not unlike those in the series of APCs, but clinical outcomes were improved compared to those in historical series. Nevertheless, longer-term clinical studies are necessary to determine the role of these modular endoprosthetic implant systems.

ABSTRACT

Reconstructing proximal humeral bone loss in the setting of shoulder arthroplasty can be a daunting task. Proposed techniques include long-stemmed humeral components, allograft-prosthesis composites (APCs), and modular endoprosthetic reconstruction. While unsupported long-stemmed components are at high risk for component loosening, APC reconstruction techniques have been reported with success. However, graft resorption and eventual failure are significant concerns. Modular endoprosthetic systems allow bone deficiencies to be reconstructed with metal, which may allow for a more durable reconstruction.

Continue to: Shoulder arthroplasty is an established procedure...

Shoulder arthroplasty is an established procedure with good results for restoring motion and decreasing pain for a variety of indications, including arthritis, fracture, posttraumatic sequelae, and tumor resection.^1-4 As the population ages, the incidence of these shoulder disorders increases, with the incidence of total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RTSA) increasing at faster rates than that of hemiarthroplasty.^5,6 These expanding indications will, in turn, result in more revisions that would present challenges for surgeons.^1,7,8

The glenoid component is much more commonly revised than the humeral component; however, the humeral component may also require revision or removal to allow exposure of the glenoid component.⁹ Revision of the humeral stem might be required in cases of infection, periprosthetic fracture, dislocation, or aseptic loosening.¹⁰ The survival rate of humeral stems is generally >90% at 10 years and >80% at 20-year follow-up.⁷ Despite these good survival rates, a revision setting the humeral component requires exchange in about half of all cases.¹¹

Humeral bone loss or deficiency is one of the challenges encountered in both primary and revision TSA. The amount of proximal bone loss can be determined by measuring the distance from the top of the prosthesis laterally to the intact lateral cortex.¹² Methods for treating bone loss may involve monoblock revision stems to bypass the deficiency, allografts to rebuild the bone stock, or modular components or endoprostheses to restore the length and stability of the extremity.

Proximal humeral bone loss may make component positioning difficult and may create problems with fixation of the humeral stem. Proper sizing and placement of components are important for improving postoperative function, decreasing component wear and instability, and restoring humeral height and offset. Determining the appropriate center of rotation is important for the function and avoidance of impingement on the acromion, as well as for the restoration of the lever arm of the deltoid without overtensioning. The selection of components with the correct size and the accurate intraoperative placement are important to restore humeral height and offset.^13,14 Components must be positioned <4 mm from the height of the greater tuberosity and <8 mm of offset to avoid compromising motion.¹⁵ De Wilde and Walch¹⁶ described about 3 patients who underwent revision reverse shoulder arthroplasty after failure of the humeral implant because of inadequate proximal humeral bone stock. They concluded that treatment of the bone loss was critical to achieve a successful outcome.

LONG-STEMMED HUMERAL COMPONENTS WITHOUT GRAFTING

There is some evidence indicating that humeral bone loss can be managed without allograft or augmentation. Owens and colleagues¹⁷ evaluated the use of intermediate- or long-stemmed humeral components for primary shoulder arthroplasty in 17 patients with severe proximal humeral bone loss and in 18 patients with large humeral canals. The stems were fully cemented, cemented distally only with proximal allografting, and uncemented. Indications for fully cemented stems were loss of proximal bone that could be filled with a proximal cement mantle to ensure a secure fit. Distal cement fixation was applied when there was significant proximal bone loss and was often supplemented with cancellous or structural allograft and/or cancellous autograft. Intraoperative complications included cortical perforation or cement extrusion in 16% of patients. Excellent or satisfactory results were obtained in 21 (60%) of the 35 shoulders, 14 (78%) of the 18 shoulders with large humeral canals, and 7 (41%) of the 17 shoulders with bone loss. All the 17 components implanted in patients with proximal humeral bone loss were stable with no gross loosening at an average 6-year follow-up.

Continue to: Budge and colleagues...

Budge and colleagues¹² prospectively enrolled 15 patients with substantial proximal humeral bone loss (38.4 mm) who had conversion to RTSA without allografting after a failed TSA. All patients showed improvements in terms of the American Shoulder and Elbow Surgeons (ASES) score, subjective shoulder value, Constant score, and Visual Analog Scale (VAS) pain score, as well as an improved active range of motion (ROM) and good radiographic outcomes at 2-year follow-up. Although the complication rate was high (7 of 15), most of the complications were minor, with only 2 requiring operative intervention. The only component fracture occurred in a patient with a modular prosthesis that was unsupported by bone proximally. Budge and colleagues¹² suggested that concerns about prosthetic fracture can be alleviated using a nonmodular monoblock design. No prosthesis-related complications occurred in their series, leading them to recommend monoblock humeral stems in patients with severe proximal humeral bone loss.

Stephens and colleagues¹⁸ reported revision to RTSA in 32 patients with hemiarthroplasties, half of whom had proximal humeral bone loss (average 36.3 mm). Of these 16 patients, 10 were treated with monoblock stems and 6 with modular components, with cement fixation of all implants. At an average 4-year follow-up, patients with proximal bone loss had improved motion and outcomes, and decreased pain compared to their preoperative condition; however, they had lower functional and pain ratings, as well as less ROM compared to those of patients with intact proximal bone stock. Complications occurred in 5 (31%) of those with bone loss and in 1 (0.6%) of those without bone loss. Three of the 16 patients with bone loss had humeral stem loosening, with 2 of the 3 having subsidence. Only 1 patient required return to the operating room for the treatment of a periprosthetic fracture sustained in a fall. Of the 16 patients with bone loss, 14 patients demonstrated scapular notching, which was severe in 5 of them. Because patients with altered humeral length and/or standard length stems had worse outcomes, the authors recommended longer stems to improve fixation and advocated the use of a long-stemmed monoblock prosthesis over an allograft-prosthesis composite (APC).¹⁸

However, Werner and colleagues¹⁹ reported high rates of loosening and distal migration with the use of long-stemmed humeral implants in 50 patients with revision RTSA. They noted periprosthetic lucency on radiographs in 48% of patients, with more than half of them requiring revision. In 6 patients with subsidence of the humeral shaft, revision was done using custom, modular implants, with the anatomic curve being further stabilized using distal screw and cable fixation to provide rotational stability.

Using a biomechanical model, Cuff and colleagues²⁰ compared 3 RTSA humeral designs, 2 modular designs, and 1 monoblock design in 12 intact models and in 12 models simulating 5 cm of proximal humeral bone loss. They observed that proximal humeral bone loss led to increased humeral component micromotion and rotational instability. The bone loss group had 5 failures compared to 2 in the control group. All failures occurred in those with modular components, whereas those with monoblock implants had no failures.

ALLOGRAFT-PROSTHESIS COMPOSITE

Composite treatment with a humeral stem and a metaphyseal allograft was described by Kassab and colleagues²¹ in 2005 and Levy and colleagues²² in 2007 (Figures 1A-1C) in patients with tumor resections²¹ or failed hemiarthroplasties.²² Allograft was used when there was insufficient metaphyseal bone to support the implant, and a graft was fashioned and fixed with cerclage wire before the component was cemented in place. In the 29 patients reported by Levy and colleagues,²² subjective and objective measurements trended toward better results in those with an APC than in those with RTSA alone, but this difference did not reach statistical significance. Several authors have identified a lack of proximal humeral bone support as 1 of the 4 possible causes of failure, and suggested that the allograft provides structural support, serves as an attachment for subscapularis repair, and maximizes deltoid function by increasing lateral offset and setting the moment arm of the deltoid.^21-23

Continue to: In a prospective study of RTSA...

In a prospective study of RTSA using structural allografts for failed hemiarthroplasty in 25 patients with an average bone loss of 5 cm, 19 patients (76%) reported good or excellent results, 5 reported satisfactory results, and 1 patient reported an unsatisfactory result.¹ Patients had significantly improved forward flexion, abduction, and external rotation and improved outcome scores (ASES and SST). Graft incorporation was good, with 88% and 79% incorporation in the metaphysis and diaphysis, respectively. This technique used a fresh-frozen proximal humeral allograft to fashion a custom proximal block with a lateral step-cut, which was fixed around the stem with cables. A long stem and cement were used. If there was no cement mantle remaining or if the medial portion of the graft was longer than 120 mm, the cement mantle was completely excised. The allograft stump of the subscapularis was used to repair the subscapularis tendon either end-to-end or pants-over-vest. The authors noted that the subscapularis repair provided increased stability; the only dislocation not caused by trauma did not have an identifiable tendon to repair. In this manner, APC reconstruction provided structural and rotational support to the humeral stem as well as bone stock for future revision.^1,20

One significant concern with APC reconstruction is the potential for graft resorption, which can lead to humeral stem loosening, loss of contour of the tuberosity, or weakening to the point of fracture.^24,25 This may be worsened by stress shielding of the allograft by distal stem cement fixation.²⁶ Other concerns include the cost of the allograft, increased risk of de novo infection, donor-to-host infection, increased operative time and complexity, and failure of allograft incorporation.

The use of a proximal femoral allograft has been described when there is a lack of a proximal humeral allograft.^1,27 Kelly and colleagues²⁷ described good results in 2 patients in whom proximal femoral allograft was used along with bone morphogenetic protein, cemented long-stemmed revision implants, and locking plate augmentation.

ENDOPROSTHETIC RECONSTRUCTION

Various forms of prosthetic augmentation have been described to compensate for proximal humeral bone loss, with the majority of reports involving the use of endoprosthetic replacement for tumor procedures.^28-31 Use of endoprostheses has also been described for revision procedures in patients with rheumatoid arthritis with massive bone loss, demonstrating modest improvements compared to severe preoperative functional limitations.³²

Tumor patients, as well as revision arthroplasty patients, may present difficulties with prosthetic fixation due to massive bone loss. Chao and colleagues²⁹ reported about the long-term outcomes after the use of implants with a porous ongrowth surface and extracortical bridging bone graft in multiple anatomic locations, including the proximal humerus, the proximal and distal femur, and the femoral diaphysis. In 3 patients with proximal humeral reconstruction, the measured ongrowth was only 30%. Given the small number of patients with a proximal humerus, no statistical significance was observed in the prosthesis location and the amount of bony ongrowth, but it was far less than that in the lower extremity.

Continue to: Endoprosthetic reconstruction...

Endoprosthetic reconstruction of the proximal humerus is commonly used for tumor resection that resulted in bone loss. Cannon and colleagues²⁸ reported a 97.6% survival rate at a mean follow-up of 30 months in 83 patients with modular and custom reconstruction with a unipolar head. The ROM was limited, but the prosthesis provided adequate stability to allow elbow and hand function. Proximal migration of the prosthetic head was noticed with increasing frequency as the length of follow-up increased.

Use of an endoprosthesis with compressive osteointegration (Zimmer Biomet) has been described in lower extremities and more recently with follow-up on several cases, including 2 proximal humeral replacements for oncology patients to treat severe bone loss. One case was for a primary sarcoma resection, and the other was for the revision of aseptic loosening of a previous endoprosthesis. Follow-up periods for these 2 patients were 54 and 141 months, respectively. Both these patients had complications, but both retained the endoprosthesis. The authors concluded that this is a salvage operation with high risk.³⁰ In another study, Guven and colleagues³¹ reported about reverse endoprosthetic reconstruction for tumor resection with bone loss. The ROM was improved, with a mean active forward elevation of 96° (range, 30°-160°), an abduction of 88° (range, 30-160°), and an external rotation of 13° (range, 0°-20°).

Modular endoprostheses have been evaluated as a method for improving bone fixation and restoring soft-tissue tension, while avoiding the complications associated with traditional endoprostheses or allografts (Figures 2A-2D). These systems allow precise adjustments of length using different trial lengths intraoperatively to obtain proper stability and deltoid tension. Of the 12 patients in a 2 center study, 11 had cementless components inserted using a press-fit technique (unpublished data, J. Feldman). At a minimum 2-year follow-up, the patients had an average improvement in forward elevation from 78° to 97°. Excluding 2 patients with loss of the deltoid tuberosity, the forward elevation averaged 109°. There were significant improvements in internal rotation (from 18° to 38°), as well as in the scores of Quick Disabilities of the Arm, Shoulder and Hand (DASH), forward elevation strength, ASES, and VAS pain. However, the overall complication rate was 41%. Therefore, despite these promising early results, longer-term studies are needed.

CONCLUSION

Proximal humeral bone loss remains a significant challenge for the shoulder arthroplasty surgeon. In the setting of a primary or a revision arthroplasty, the bone stock must be thoroughly evaluated during preoperative planning, and a surgical plan for addressing the deficits should be developed. Because proximal humeral bone loss may contribute to prosthetic failure, every effort should be made to reconstitute the bone stock.¹⁶ If the bone loss is less extensive, impaction grafting may be considered. Options to address massive proximal humeral bone loss include APCs and endoprosthetic reconstruction. The use of an allograft allows subscapularis repair, which may help stabilize the shoulder and restore the natural lever arm, as well as the tension of the deltoid.^1,21-23 In addition, it helps avoid rotational instability and micromotion and provides bone stock for future revisions. However, concern persists regarding allograft resorption over time. More recently, modular endoprosthetic reconstruction systems have been developed to address bone deficiency with metal augmentation. Early clinical results demonstrate a high complication rate in this complex cohort of patients, not unlike those in the series of APCs, but clinical outcomes were improved compared to those in historical series. Nevertheless, longer-term clinical studies are necessary to determine the role of these modular endoprosthetic implant systems.

ABSTRACT

Reconstructing proximal humeral bone loss in the setting of shoulder arthroplasty can be a daunting task. Proposed techniques include long-stemmed humeral components, allograft-prosthesis composites (APCs), and modular endoprosthetic reconstruction. While unsupported long-stemmed components are at high risk for component loosening, APC reconstruction techniques have been reported with success. However, graft resorption and eventual failure are significant concerns. Modular endoprosthetic systems allow bone deficiencies to be reconstructed with metal, which may allow for a more durable reconstruction.

Continue to: Shoulder arthroplasty is an established procedure...

Shoulder arthroplasty is an established procedure with good results for restoring motion and decreasing pain for a variety of indications, including arthritis, fracture, posttraumatic sequelae, and tumor resection.^1-4 As the population ages, the incidence of these shoulder disorders increases, with the incidence of total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (RTSA) increasing at faster rates than that of hemiarthroplasty.^5,6 These expanding indications will, in turn, result in more revisions that would present challenges for surgeons.^1,7,8

The glenoid component is much more commonly revised than the humeral component; however, the humeral component may also require revision or removal to allow exposure of the glenoid component.⁹ Revision of the humeral stem might be required in cases of infection, periprosthetic fracture, dislocation, or aseptic loosening.¹⁰ The survival rate of humeral stems is generally >90% at 10 years and >80% at 20-year follow-up.⁷ Despite these good survival rates, a revision setting the humeral component requires exchange in about half of all cases.¹¹

Humeral bone loss or deficiency is one of the challenges encountered in both primary and revision TSA. The amount of proximal bone loss can be determined by measuring the distance from the top of the prosthesis laterally to the intact lateral cortex.¹² Methods for treating bone loss may involve monoblock revision stems to bypass the deficiency, allografts to rebuild the bone stock, or modular components or endoprostheses to restore the length and stability of the extremity.

Proximal humeral bone loss may make component positioning difficult and may create problems with fixation of the humeral stem. Proper sizing and placement of components are important for improving postoperative function, decreasing component wear and instability, and restoring humeral height and offset. Determining the appropriate center of rotation is important for the function and avoidance of impingement on the acromion, as well as for the restoration of the lever arm of the deltoid without overtensioning. The selection of components with the correct size and the accurate intraoperative placement are important to restore humeral height and offset.^13,14 Components must be positioned <4 mm from the height of the greater tuberosity and <8 mm of offset to avoid compromising motion.¹⁵ De Wilde and Walch¹⁶ described about 3 patients who underwent revision reverse shoulder arthroplasty after failure of the humeral implant because of inadequate proximal humeral bone stock. They concluded that treatment of the bone loss was critical to achieve a successful outcome.

LONG-STEMMED HUMERAL COMPONENTS WITHOUT GRAFTING

There is some evidence indicating that humeral bone loss can be managed without allograft or augmentation. Owens and colleagues¹⁷ evaluated the use of intermediate- or long-stemmed humeral components for primary shoulder arthroplasty in 17 patients with severe proximal humeral bone loss and in 18 patients with large humeral canals. The stems were fully cemented, cemented distally only with proximal allografting, and uncemented. Indications for fully cemented stems were loss of proximal bone that could be filled with a proximal cement mantle to ensure a secure fit. Distal cement fixation was applied when there was significant proximal bone loss and was often supplemented with cancellous or structural allograft and/or cancellous autograft. Intraoperative complications included cortical perforation or cement extrusion in 16% of patients. Excellent or satisfactory results were obtained in 21 (60%) of the 35 shoulders, 14 (78%) of the 18 shoulders with large humeral canals, and 7 (41%) of the 17 shoulders with bone loss. All the 17 components implanted in patients with proximal humeral bone loss were stable with no gross loosening at an average 6-year follow-up.

Continue to: Budge and colleagues...

Budge and colleagues¹² prospectively enrolled 15 patients with substantial proximal humeral bone loss (38.4 mm) who had conversion to RTSA without allografting after a failed TSA. All patients showed improvements in terms of the American Shoulder and Elbow Surgeons (ASES) score, subjective shoulder value, Constant score, and Visual Analog Scale (VAS) pain score, as well as an improved active range of motion (ROM) and good radiographic outcomes at 2-year follow-up. Although the complication rate was high (7 of 15), most of the complications were minor, with only 2 requiring operative intervention. The only component fracture occurred in a patient with a modular prosthesis that was unsupported by bone proximally. Budge and colleagues¹² suggested that concerns about prosthetic fracture can be alleviated using a nonmodular monoblock design. No prosthesis-related complications occurred in their series, leading them to recommend monoblock humeral stems in patients with severe proximal humeral bone loss.

Stephens and colleagues¹⁸ reported revision to RTSA in 32 patients with hemiarthroplasties, half of whom had proximal humeral bone loss (average 36.3 mm). Of these 16 patients, 10 were treated with monoblock stems and 6 with modular components, with cement fixation of all implants. At an average 4-year follow-up, patients with proximal bone loss had improved motion and outcomes, and decreased pain compared to their preoperative condition; however, they had lower functional and pain ratings, as well as less ROM compared to those of patients with intact proximal bone stock. Complications occurred in 5 (31%) of those with bone loss and in 1 (0.6%) of those without bone loss. Three of the 16 patients with bone loss had humeral stem loosening, with 2 of the 3 having subsidence. Only 1 patient required return to the operating room for the treatment of a periprosthetic fracture sustained in a fall. Of the 16 patients with bone loss, 14 patients demonstrated scapular notching, which was severe in 5 of them. Because patients with altered humeral length and/or standard length stems had worse outcomes, the authors recommended longer stems to improve fixation and advocated the use of a long-stemmed monoblock prosthesis over an allograft-prosthesis composite (APC).¹⁸

However, Werner and colleagues¹⁹ reported high rates of loosening and distal migration with the use of long-stemmed humeral implants in 50 patients with revision RTSA. They noted periprosthetic lucency on radiographs in 48% of patients, with more than half of them requiring revision. In 6 patients with subsidence of the humeral shaft, revision was done using custom, modular implants, with the anatomic curve being further stabilized using distal screw and cable fixation to provide rotational stability.

Using a biomechanical model, Cuff and colleagues²⁰ compared 3 RTSA humeral designs, 2 modular designs, and 1 monoblock design in 12 intact models and in 12 models simulating 5 cm of proximal humeral bone loss. They observed that proximal humeral bone loss led to increased humeral component micromotion and rotational instability. The bone loss group had 5 failures compared to 2 in the control group. All failures occurred in those with modular components, whereas those with monoblock implants had no failures.

ALLOGRAFT-PROSTHESIS COMPOSITE

Composite treatment with a humeral stem and a metaphyseal allograft was described by Kassab and colleagues²¹ in 2005 and Levy and colleagues²² in 2007 (Figures 1A-1C) in patients with tumor resections²¹ or failed hemiarthroplasties.²² Allograft was used when there was insufficient metaphyseal bone to support the implant, and a graft was fashioned and fixed with cerclage wire before the component was cemented in place. In the 29 patients reported by Levy and colleagues,²² subjective and objective measurements trended toward better results in those with an APC than in those with RTSA alone, but this difference did not reach statistical significance. Several authors have identified a lack of proximal humeral bone support as 1 of the 4 possible causes of failure, and suggested that the allograft provides structural support, serves as an attachment for subscapularis repair, and maximizes deltoid function by increasing lateral offset and setting the moment arm of the deltoid.^21-23

Continue to: In a prospective study of RTSA...

In a prospective study of RTSA using structural allografts for failed hemiarthroplasty in 25 patients with an average bone loss of 5 cm, 19 patients (76%) reported good or excellent results, 5 reported satisfactory results, and 1 patient reported an unsatisfactory result.¹ Patients had significantly improved forward flexion, abduction, and external rotation and improved outcome scores (ASES and SST). Graft incorporation was good, with 88% and 79% incorporation in the metaphysis and diaphysis, respectively. This technique used a fresh-frozen proximal humeral allograft to fashion a custom proximal block with a lateral step-cut, which was fixed around the stem with cables. A long stem and cement were used. If there was no cement mantle remaining or if the medial portion of the graft was longer than 120 mm, the cement mantle was completely excised. The allograft stump of the subscapularis was used to repair the subscapularis tendon either end-to-end or pants-over-vest. The authors noted that the subscapularis repair provided increased stability; the only dislocation not caused by trauma did not have an identifiable tendon to repair. In this manner, APC reconstruction provided structural and rotational support to the humeral stem as well as bone stock for future revision.^1,20

One significant concern with APC reconstruction is the potential for graft resorption, which can lead to humeral stem loosening, loss of contour of the tuberosity, or weakening to the point of fracture.^24,25 This may be worsened by stress shielding of the allograft by distal stem cement fixation.²⁶ Other concerns include the cost of the allograft, increased risk of de novo infection, donor-to-host infection, increased operative time and complexity, and failure of allograft incorporation.

The use of a proximal femoral allograft has been described when there is a lack of a proximal humeral allograft.^1,27 Kelly and colleagues²⁷ described good results in 2 patients in whom proximal femoral allograft was used along with bone morphogenetic protein, cemented long-stemmed revision implants, and locking plate augmentation.

ENDOPROSTHETIC RECONSTRUCTION

Various forms of prosthetic augmentation have been described to compensate for proximal humeral bone loss, with the majority of reports involving the use of endoprosthetic replacement for tumor procedures.^28-31 Use of endoprostheses has also been described for revision procedures in patients with rheumatoid arthritis with massive bone loss, demonstrating modest improvements compared to severe preoperative functional limitations.³²

Tumor patients, as well as revision arthroplasty patients, may present difficulties with prosthetic fixation due to massive bone loss. Chao and colleagues²⁹ reported about the long-term outcomes after the use of implants with a porous ongrowth surface and extracortical bridging bone graft in multiple anatomic locations, including the proximal humerus, the proximal and distal femur, and the femoral diaphysis. In 3 patients with proximal humeral reconstruction, the measured ongrowth was only 30%. Given the small number of patients with a proximal humerus, no statistical significance was observed in the prosthesis location and the amount of bony ongrowth, but it was far less than that in the lower extremity.

Continue to: Endoprosthetic reconstruction...

Endoprosthetic reconstruction of the proximal humerus is commonly used for tumor resection that resulted in bone loss. Cannon and colleagues²⁸ reported a 97.6% survival rate at a mean follow-up of 30 months in 83 patients with modular and custom reconstruction with a unipolar head. The ROM was limited, but the prosthesis provided adequate stability to allow elbow and hand function. Proximal migration of the prosthetic head was noticed with increasing frequency as the length of follow-up increased.

Use of an endoprosthesis with compressive osteointegration (Zimmer Biomet) has been described in lower extremities and more recently with follow-up on several cases, including 2 proximal humeral replacements for oncology patients to treat severe bone loss. One case was for a primary sarcoma resection, and the other was for the revision of aseptic loosening of a previous endoprosthesis. Follow-up periods for these 2 patients were 54 and 141 months, respectively. Both these patients had complications, but both retained the endoprosthesis. The authors concluded that this is a salvage operation with high risk.³⁰ In another study, Guven and colleagues³¹ reported about reverse endoprosthetic reconstruction for tumor resection with bone loss. The ROM was improved, with a mean active forward elevation of 96° (range, 30°-160°), an abduction of 88° (range, 30-160°), and an external rotation of 13° (range, 0°-20°).

Modular endoprostheses have been evaluated as a method for improving bone fixation and restoring soft-tissue tension, while avoiding the complications associated with traditional endoprostheses or allografts (Figures 2A-2D). These systems allow precise adjustments of length using different trial lengths intraoperatively to obtain proper stability and deltoid tension. Of the 12 patients in a 2 center study, 11 had cementless components inserted using a press-fit technique (unpublished data, J. Feldman). At a minimum 2-year follow-up, the patients had an average improvement in forward elevation from 78° to 97°. Excluding 2 patients with loss of the deltoid tuberosity, the forward elevation averaged 109°. There were significant improvements in internal rotation (from 18° to 38°), as well as in the scores of Quick Disabilities of the Arm, Shoulder and Hand (DASH), forward elevation strength, ASES, and VAS pain. However, the overall complication rate was 41%. Therefore, despite these promising early results, longer-term studies are needed.

CONCLUSION

Proximal humeral bone loss remains a significant challenge for the shoulder arthroplasty surgeon. In the setting of a primary or a revision arthroplasty, the bone stock must be thoroughly evaluated during preoperative planning, and a surgical plan for addressing the deficits should be developed. Because proximal humeral bone loss may contribute to prosthetic failure, every effort should be made to reconstitute the bone stock.¹⁶ If the bone loss is less extensive, impaction grafting may be considered. Options to address massive proximal humeral bone loss include APCs and endoprosthetic reconstruction. The use of an allograft allows subscapularis repair, which may help stabilize the shoulder and restore the natural lever arm, as well as the tension of the deltoid.^1,21-23 In addition, it helps avoid rotational instability and micromotion and provides bone stock for future revisions. However, concern persists regarding allograft resorption over time. More recently, modular endoprosthetic reconstruction systems have been developed to address bone deficiency with metal augmentation. Early clinical results demonstrate a high complication rate in this complex cohort of patients, not unlike those in the series of APCs, but clinical outcomes were improved compared to those in historical series. Nevertheless, longer-term clinical studies are necessary to determine the role of these modular endoprosthetic implant systems.

JACKSONVILLE, FLA. – Super-obese patients who have laparoscopic repair for ventral hernias have complications at a rate more than twice that for overweight individuals undergoing the same operation, according to an analysis of 10-year data presented at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

“Patients with a body mass index of 40 kg/m² or greater were found to be significantly more likely to have a complication following laparoscopic ventral hernia repair,” said Robert A. Swendiman, MD, of the University of Pennsylvania, Philadelphia.

Dr. Swendiman and his colleagues analyzed outcomes of 57,957 patients in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database who had laparoscopic ventral hernia repair (VHR) from 2005 to 2015. The dataset was stratified into seven different BMI classes, and by hernia type (reducible or strangulated) and time of repair (initial or recurrent).

The overall complication rate for the study population was 4%, ranging from 3% in overweight patients (BMI of 25-29.99 kg/m²) to 6.9% for the super obese (BMI of 50 kg/m² or greater); 61.4% of the study population was obese. “Initial repair and reducible hernias had lower complication rates than recurrent and incarcerated/strangulated hernias,” Dr. Swendiman said. The study considered 1 of 19 different complications within 30 days of the operation.

SOURCE: Academic Surgical Congress. Abstract 50.02.

JACKSONVILLE, FLA. – Super-obese patients who have laparoscopic repair for ventral hernias have complications at a rate more than twice that for overweight individuals undergoing the same operation, according to an analysis of 10-year data presented at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

“Patients with a body mass index of 40 kg/m² or greater were found to be significantly more likely to have a complication following laparoscopic ventral hernia repair,” said Robert A. Swendiman, MD, of the University of Pennsylvania, Philadelphia.

Dr. Swendiman and his colleagues analyzed outcomes of 57,957 patients in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database who had laparoscopic ventral hernia repair (VHR) from 2005 to 2015. The dataset was stratified into seven different BMI classes, and by hernia type (reducible or strangulated) and time of repair (initial or recurrent).

The overall complication rate for the study population was 4%, ranging from 3% in overweight patients (BMI of 25-29.99 kg/m²) to 6.9% for the super obese (BMI of 50 kg/m² or greater); 61.4% of the study population was obese. “Initial repair and reducible hernias had lower complication rates than recurrent and incarcerated/strangulated hernias,” Dr. Swendiman said. The study considered 1 of 19 different complications within 30 days of the operation.

SOURCE: Academic Surgical Congress. Abstract 50.02.

JACKSONVILLE, FLA. – Super-obese patients who have laparoscopic repair for ventral hernias have complications at a rate more than twice that for overweight individuals undergoing the same operation, according to an analysis of 10-year data presented at the Association for Academic Surgery/Society of University Surgeons Academic Surgical Congress.

“Patients with a body mass index of 40 kg/m² or greater were found to be significantly more likely to have a complication following laparoscopic ventral hernia repair,” said Robert A. Swendiman, MD, of the University of Pennsylvania, Philadelphia.

Dr. Swendiman and his colleagues analyzed outcomes of 57,957 patients in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database who had laparoscopic ventral hernia repair (VHR) from 2005 to 2015. The dataset was stratified into seven different BMI classes, and by hernia type (reducible or strangulated) and time of repair (initial or recurrent).

The overall complication rate for the study population was 4%, ranging from 3% in overweight patients (BMI of 25-29.99 kg/m²) to 6.9% for the super obese (BMI of 50 kg/m² or greater); 61.4% of the study population was obese. “Initial repair and reducible hernias had lower complication rates than recurrent and incarcerated/strangulated hernias,” Dr. Swendiman said. The study considered 1 of 19 different complications within 30 days of the operation.

SOURCE: Academic Surgical Congress. Abstract 50.02.

Exposure to mercury from skin contact or vapor can be challenging to diagnose because of the wide variation in reactions, researchers at the University of Arizona, Tucson, found in the case of a toddler who presented with puzzling symptoms.

“Although mercury toxicity is rare and has variable symptoms, it is valuable for clinicians to consider this diagnosis in cases of unexplained hypertension and neurologic findings,” Michael R. Ori, MD, and his associates wrote in the Journal of Pediatrics.

U.S. federal law has prohibited mercury in cosmetics beyond trace amounts (1 mg/kg) since 1973 because of toxicity concerns, but mercury-containing skin creams remain a public health problem in the United States.

A 17-month-old previously healthy girl was seen by her pediatrician because of a 3-week history of fussiness, constipation, decreased appetite, and temperature to 37.7° C. A chest radiograph was normal, as was a urinalysis. Two days later, the child was taken to the emergency department with symptoms of rhinorrhea, congestion, fussiness, and a fever of 38.3° C. She was sent home with a presumptive diagnosis of a viral syndrome. Her symptoms had not resolved 1 week later, and she returned to the pediatrician, having developed a limp with tenderness in the right knee. A radiograph of the knee was unremarkable, repeat urinalysis showed no evidence of a urinary tract infection, and an abdominal x-ray showed a large stool burden. She had a 0.5-kg weight loss and new hypertension, and was afebrile.

The child was admitted to the hospital the next day for an endocrine work-up, but no noticeable abnormalities were found. She became increasingly fussy with a poor appetite and continued weight loss, persistent hypertension, and an inability to walk. Heavy metal screening on day 18 revealed an elevated whole blood mercury level of 26 mcg/L (normal is less than 10 mcg/L), with a random spot urine mercury level of 243 mcg/g creatinine (normal is less than 35 mcg/g creatinine). Repeated chelation with succimer was provided. On day 61, she had significant delay in receptive language and fine motor skills on a Bayley scale. On the most recent evaluation on day 222, she was shy and had stereotypical hand-flapping behavior when stressed, the investigators reported.

Multiple conversations with the patient’s mother eventually identified the source of mercury as a skin-lightening facial cream she had been using for 4 months, which she stored in the refrigerator. The cream was produced and purchased in a beauty salon in Mexico. Several containers of the cream were sent to an Arizona state laboratory; they were found to have mercury levels between 27,000 and 34,000 mg/kg. The mother and the grandmother had no symptoms or findings on physical exam, but had markedly elevated first-void urine mercury levels of 197 mcg/g creatinine for the mother and 222 mcg/g creatinine for the grandmother, the researchers reported.

Testing of the home the family rented found ambient air mercury vapor levels ranged from 1,900 to 2,800 ng/m³ for most areas. Federal agencies recommend remediation for levels greater than 1,000 ng/m³; remediation was performed in the home, with some household items disposed of in a hazardous waste landfill.

This toddler’s exposure to mercury was from contact with contaminated people, objects, and vapor, although the mercury-containing cream was not directly put on her skin. Of these sources of contact, vapor may have contributed the most. There likely was incidental dermal contact through contaminated bed linens, and she also likely had incidental oral contact from contaminated objects that she put in her mouth, Dr. Ori and his associates reported.

Over time, central nervous system penetration occurs with neurologic dysfunction; “this was the dominant feature of this patient’s presentation, with debilitating leg pain, anorexia, constipation, neurasthenia, and hypertension. Acrodynia, meaning extremity pain, is an idiosyncratic reaction to mercury exposure seen in childhood. Symptoms include irritability,weakness, paresthesias, a pink papular rash, and desquamation of the palms and soles. Our patient did not have the characteristic dermal findings but did have other symptoms consistent with acrodynia,” they noted.

The authors declared no conflicts of interest.

SOURCE: Ori MR et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2017.12.0.23.

Exposure to mercury from skin contact or vapor can be challenging to diagnose because of the wide variation in reactions, researchers at the University of Arizona, Tucson, found in the case of a toddler who presented with puzzling symptoms.

“Although mercury toxicity is rare and has variable symptoms, it is valuable for clinicians to consider this diagnosis in cases of unexplained hypertension and neurologic findings,” Michael R. Ori, MD, and his associates wrote in the Journal of Pediatrics.

U.S. federal law has prohibited mercury in cosmetics beyond trace amounts (1 mg/kg) since 1973 because of toxicity concerns, but mercury-containing skin creams remain a public health problem in the United States.

A 17-month-old previously healthy girl was seen by her pediatrician because of a 3-week history of fussiness, constipation, decreased appetite, and temperature to 37.7° C. A chest radiograph was normal, as was a urinalysis. Two days later, the child was taken to the emergency department with symptoms of rhinorrhea, congestion, fussiness, and a fever of 38.3° C. She was sent home with a presumptive diagnosis of a viral syndrome. Her symptoms had not resolved 1 week later, and she returned to the pediatrician, having developed a limp with tenderness in the right knee. A radiograph of the knee was unremarkable, repeat urinalysis showed no evidence of a urinary tract infection, and an abdominal x-ray showed a large stool burden. She had a 0.5-kg weight loss and new hypertension, and was afebrile.

The child was admitted to the hospital the next day for an endocrine work-up, but no noticeable abnormalities were found. She became increasingly fussy with a poor appetite and continued weight loss, persistent hypertension, and an inability to walk. Heavy metal screening on day 18 revealed an elevated whole blood mercury level of 26 mcg/L (normal is less than 10 mcg/L), with a random spot urine mercury level of 243 mcg/g creatinine (normal is less than 35 mcg/g creatinine). Repeated chelation with succimer was provided. On day 61, she had significant delay in receptive language and fine motor skills on a Bayley scale. On the most recent evaluation on day 222, she was shy and had stereotypical hand-flapping behavior when stressed, the investigators reported.

Multiple conversations with the patient’s mother eventually identified the source of mercury as a skin-lightening facial cream she had been using for 4 months, which she stored in the refrigerator. The cream was produced and purchased in a beauty salon in Mexico. Several containers of the cream were sent to an Arizona state laboratory; they were found to have mercury levels between 27,000 and 34,000 mg/kg. The mother and the grandmother had no symptoms or findings on physical exam, but had markedly elevated first-void urine mercury levels of 197 mcg/g creatinine for the mother and 222 mcg/g creatinine for the grandmother, the researchers reported.

Testing of the home the family rented found ambient air mercury vapor levels ranged from 1,900 to 2,800 ng/m³ for most areas. Federal agencies recommend remediation for levels greater than 1,000 ng/m³; remediation was performed in the home, with some household items disposed of in a hazardous waste landfill.

This toddler’s exposure to mercury was from contact with contaminated people, objects, and vapor, although the mercury-containing cream was not directly put on her skin. Of these sources of contact, vapor may have contributed the most. There likely was incidental dermal contact through contaminated bed linens, and she also likely had incidental oral contact from contaminated objects that she put in her mouth, Dr. Ori and his associates reported.

Over time, central nervous system penetration occurs with neurologic dysfunction; “this was the dominant feature of this patient’s presentation, with debilitating leg pain, anorexia, constipation, neurasthenia, and hypertension. Acrodynia, meaning extremity pain, is an idiosyncratic reaction to mercury exposure seen in childhood. Symptoms include irritability,weakness, paresthesias, a pink papular rash, and desquamation of the palms and soles. Our patient did not have the characteristic dermal findings but did have other symptoms consistent with acrodynia,” they noted.

The authors declared no conflicts of interest.

SOURCE: Ori MR et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2017.12.0.23.

Exposure to mercury from skin contact or vapor can be challenging to diagnose because of the wide variation in reactions, researchers at the University of Arizona, Tucson, found in the case of a toddler who presented with puzzling symptoms.

“Although mercury toxicity is rare and has variable symptoms, it is valuable for clinicians to consider this diagnosis in cases of unexplained hypertension and neurologic findings,” Michael R. Ori, MD, and his associates wrote in the Journal of Pediatrics.

U.S. federal law has prohibited mercury in cosmetics beyond trace amounts (1 mg/kg) since 1973 because of toxicity concerns, but mercury-containing skin creams remain a public health problem in the United States.

A 17-month-old previously healthy girl was seen by her pediatrician because of a 3-week history of fussiness, constipation, decreased appetite, and temperature to 37.7° C. A chest radiograph was normal, as was a urinalysis. Two days later, the child was taken to the emergency department with symptoms of rhinorrhea, congestion, fussiness, and a fever of 38.3° C. She was sent home with a presumptive diagnosis of a viral syndrome. Her symptoms had not resolved 1 week later, and she returned to the pediatrician, having developed a limp with tenderness in the right knee. A radiograph of the knee was unremarkable, repeat urinalysis showed no evidence of a urinary tract infection, and an abdominal x-ray showed a large stool burden. She had a 0.5-kg weight loss and new hypertension, and was afebrile.

The child was admitted to the hospital the next day for an endocrine work-up, but no noticeable abnormalities were found. She became increasingly fussy with a poor appetite and continued weight loss, persistent hypertension, and an inability to walk. Heavy metal screening on day 18 revealed an elevated whole blood mercury level of 26 mcg/L (normal is less than 10 mcg/L), with a random spot urine mercury level of 243 mcg/g creatinine (normal is less than 35 mcg/g creatinine). Repeated chelation with succimer was provided. On day 61, she had significant delay in receptive language and fine motor skills on a Bayley scale. On the most recent evaluation on day 222, she was shy and had stereotypical hand-flapping behavior when stressed, the investigators reported.

Multiple conversations with the patient’s mother eventually identified the source of mercury as a skin-lightening facial cream she had been using for 4 months, which she stored in the refrigerator. The cream was produced and purchased in a beauty salon in Mexico. Several containers of the cream were sent to an Arizona state laboratory; they were found to have mercury levels between 27,000 and 34,000 mg/kg. The mother and the grandmother had no symptoms or findings on physical exam, but had markedly elevated first-void urine mercury levels of 197 mcg/g creatinine for the mother and 222 mcg/g creatinine for the grandmother, the researchers reported.

Testing of the home the family rented found ambient air mercury vapor levels ranged from 1,900 to 2,800 ng/m³ for most areas. Federal agencies recommend remediation for levels greater than 1,000 ng/m³; remediation was performed in the home, with some household items disposed of in a hazardous waste landfill.

This toddler’s exposure to mercury was from contact with contaminated people, objects, and vapor, although the mercury-containing cream was not directly put on her skin. Of these sources of contact, vapor may have contributed the most. There likely was incidental dermal contact through contaminated bed linens, and she also likely had incidental oral contact from contaminated objects that she put in her mouth, Dr. Ori and his associates reported.

Over time, central nervous system penetration occurs with neurologic dysfunction; “this was the dominant feature of this patient’s presentation, with debilitating leg pain, anorexia, constipation, neurasthenia, and hypertension. Acrodynia, meaning extremity pain, is an idiosyncratic reaction to mercury exposure seen in childhood. Symptoms include irritability,weakness, paresthesias, a pink papular rash, and desquamation of the palms and soles. Our patient did not have the characteristic dermal findings but did have other symptoms consistent with acrodynia,” they noted.

The authors declared no conflicts of interest.

SOURCE: Ori MR et al. J Pediatr. 2018. doi: 10.1016/j.jpeds.2017.12.0.23.

DALLAS – A multigene skeletal dysplasia panel detected pathogenic variants in 55% of fetal tissue samples with abnormal ultrasound findings and correctly predicted fetal lethality or viability in 75% of these.

The prenatal skeletal dysplasia panel tests 23 genes implicated in 29 different clinical syndromes, Lisa M. Vincent, PhD, said at the meeting sponsored by the Society for Maternal-Fetal Medicine. The panel’s performance in a validation cohort of 280 fetal tissue specimens, said Dr. Vincent, “underscores the clinical utility of a comprehensive, multigene sequencing tool that can aid in the diagnosis of prenatal skeletal dysplasias, allowing physicians to better manage these pregnancies.”

Up to 5 pregnancies per 1,000 are affected by some form of skeletal dysplasia, said Dr. Vincent, a clinical molecular geneticist at GeneDx, which manufactures the test. Early findings are typically picked up on ultrasound; the most frequent include limb shortening, long bone angulation, bowing, or fracture; abnormal bone echogenicity; facial dysmorphism; platyspondyly; chest narrowing and abnormal ribs; and frontal bossing of the fetal skull. However, she noted, it’s not always easy to assign a firm diagnosis based on imaging alone.

“In the prenatal period, clinical diagnosis remains challenging because of lack of availability of high-resolution imaging and lack of experience in interpreting the imaging results. Additionally, these are a genetically heterogeneous group of disorders with overlapping clinical features.”

The testing cohort for this panel comprised 280 specimens. Most (84%) were obtained from amniocentesis; 5% were from chorionic villi sampling, and the remainder were derived from other sources. The median gestational age was 20 weeks and 5 days, but the samples ranged from 5 to 36 weeks’ gestation.

The most common imaging indication for testing was short limbs (87%). Other indications included abnormal ribs or small chest circumference (47%); bowed or fractured bones (28%); leg bowing (27%); upper limb deformity (12%); poly- or syndactyly (5%); and other findings, including facial dysmorphism (23%). About 5% of the samples had a family history of skeletal dysplasia.

The panel returned a positive clinical diagnosis for 55% of the specimens. It could not determine a genetic cause for the observed clinical phenotype in 28%, and the test returned uncertain results in 17%, Dr. Vincent said.

“In these cases, we were uncertain whether the variants we identified caused the clinical features.”

Of the 153 positive cases, 42% were affected by pathogenic variants in the collagen genes of COL1A1, COL1A2, and COL1A3. Variants in the FGFR3 gene (39%) were next most common. FGFR3 is associated with achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia. Mutations of the SOX-9 gene, responsible for campomelic dysplasia, accounted for 5%. The test also identified nine other genetic variants in small numbers of samples.

“About 90% of the genes were autosomal dominant, indicating they are typically de novo or sporadic,” Dr. Vincent said. “About 10% were autosomal recessive, and just 1% were linked to an X-linked mutation.”

The clinical syndromes identified through these genes included osteogenesis imperfecta and thanatophoric dysplasia (33% each); achondrogenesis and spondyloepiphyseal dysplasia (11%); asphyxiating thoracic dystrophy/short rib polydactyly syndrome and campomelic dysplasia (5% each). The remaining cases were atelosteogenesis, Apert syndrome, Crouzon syndrome, chondrodysplasia punctata, hypochondroplasia, and Ellis-van Creveld syndrome.

The test predicted that 64% of the cases would be lethal. In 26%, viability was uncertain, but 10% – including 5% of the osteogenesis imperfecta cases – could be viable.

“Most lethal cases tended to have several characteristics, including short limbs, abnormal ribs, and bowed or fracture bones,” Dr. Vincent said. “Short limbs were almost five times more common in the lethal cases than in those with variable severity. Abnormal ribs and small chest were five times more frequent in the lethal cases, and bowed or fractured bones were four times more common.”

Among the nonpositive cases, 32% had additional testing. Of these, 8% had cytogenetic or large-array abnormalities, and another 8% were positive for a skeletal dysplasia that was not caused by any of the genes on the test panel.

Dr. Vincent noted that the turnaround time for the test is generally 2-3 weeks.

[email protected]

SOURCE: Vincent L et al. Am J Obstet Gynecol. 2018;18:S57-8.

DALLAS – A multigene skeletal dysplasia panel detected pathogenic variants in 55% of fetal tissue samples with abnormal ultrasound findings and correctly predicted fetal lethality or viability in 75% of these.

The prenatal skeletal dysplasia panel tests 23 genes implicated in 29 different clinical syndromes, Lisa M. Vincent, PhD, said at the meeting sponsored by the Society for Maternal-Fetal Medicine. The panel’s performance in a validation cohort of 280 fetal tissue specimens, said Dr. Vincent, “underscores the clinical utility of a comprehensive, multigene sequencing tool that can aid in the diagnosis of prenatal skeletal dysplasias, allowing physicians to better manage these pregnancies.”

Up to 5 pregnancies per 1,000 are affected by some form of skeletal dysplasia, said Dr. Vincent, a clinical molecular geneticist at GeneDx, which manufactures the test. Early findings are typically picked up on ultrasound; the most frequent include limb shortening, long bone angulation, bowing, or fracture; abnormal bone echogenicity; facial dysmorphism; platyspondyly; chest narrowing and abnormal ribs; and frontal bossing of the fetal skull. However, she noted, it’s not always easy to assign a firm diagnosis based on imaging alone.

“In the prenatal period, clinical diagnosis remains challenging because of lack of availability of high-resolution imaging and lack of experience in interpreting the imaging results. Additionally, these are a genetically heterogeneous group of disorders with overlapping clinical features.”

The testing cohort for this panel comprised 280 specimens. Most (84%) were obtained from amniocentesis; 5% were from chorionic villi sampling, and the remainder were derived from other sources. The median gestational age was 20 weeks and 5 days, but the samples ranged from 5 to 36 weeks’ gestation.

The most common imaging indication for testing was short limbs (87%). Other indications included abnormal ribs or small chest circumference (47%); bowed or fractured bones (28%); leg bowing (27%); upper limb deformity (12%); poly- or syndactyly (5%); and other findings, including facial dysmorphism (23%). About 5% of the samples had a family history of skeletal dysplasia.

The panel returned a positive clinical diagnosis for 55% of the specimens. It could not determine a genetic cause for the observed clinical phenotype in 28%, and the test returned uncertain results in 17%, Dr. Vincent said.

“In these cases, we were uncertain whether the variants we identified caused the clinical features.”

Of the 153 positive cases, 42% were affected by pathogenic variants in the collagen genes of COL1A1, COL1A2, and COL1A3. Variants in the FGFR3 gene (39%) were next most common. FGFR3 is associated with achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia. Mutations of the SOX-9 gene, responsible for campomelic dysplasia, accounted for 5%. The test also identified nine other genetic variants in small numbers of samples.

“About 90% of the genes were autosomal dominant, indicating they are typically de novo or sporadic,” Dr. Vincent said. “About 10% were autosomal recessive, and just 1% were linked to an X-linked mutation.”

The clinical syndromes identified through these genes included osteogenesis imperfecta and thanatophoric dysplasia (33% each); achondrogenesis and spondyloepiphyseal dysplasia (11%); asphyxiating thoracic dystrophy/short rib polydactyly syndrome and campomelic dysplasia (5% each). The remaining cases were atelosteogenesis, Apert syndrome, Crouzon syndrome, chondrodysplasia punctata, hypochondroplasia, and Ellis-van Creveld syndrome.

The test predicted that 64% of the cases would be lethal. In 26%, viability was uncertain, but 10% – including 5% of the osteogenesis imperfecta cases – could be viable.

“Most lethal cases tended to have several characteristics, including short limbs, abnormal ribs, and bowed or fracture bones,” Dr. Vincent said. “Short limbs were almost five times more common in the lethal cases than in those with variable severity. Abnormal ribs and small chest were five times more frequent in the lethal cases, and bowed or fractured bones were four times more common.”

Among the nonpositive cases, 32% had additional testing. Of these, 8% had cytogenetic or large-array abnormalities, and another 8% were positive for a skeletal dysplasia that was not caused by any of the genes on the test panel.

Dr. Vincent noted that the turnaround time for the test is generally 2-3 weeks.

[email protected]

SOURCE: Vincent L et al. Am J Obstet Gynecol. 2018;18:S57-8.

DALLAS – A multigene skeletal dysplasia panel detected pathogenic variants in 55% of fetal tissue samples with abnormal ultrasound findings and correctly predicted fetal lethality or viability in 75% of these.

The prenatal skeletal dysplasia panel tests 23 genes implicated in 29 different clinical syndromes, Lisa M. Vincent, PhD, said at the meeting sponsored by the Society for Maternal-Fetal Medicine. The panel’s performance in a validation cohort of 280 fetal tissue specimens, said Dr. Vincent, “underscores the clinical utility of a comprehensive, multigene sequencing tool that can aid in the diagnosis of prenatal skeletal dysplasias, allowing physicians to better manage these pregnancies.”

Up to 5 pregnancies per 1,000 are affected by some form of skeletal dysplasia, said Dr. Vincent, a clinical molecular geneticist at GeneDx, which manufactures the test. Early findings are typically picked up on ultrasound; the most frequent include limb shortening, long bone angulation, bowing, or fracture; abnormal bone echogenicity; facial dysmorphism; platyspondyly; chest narrowing and abnormal ribs; and frontal bossing of the fetal skull. However, she noted, it’s not always easy to assign a firm diagnosis based on imaging alone.

“In the prenatal period, clinical diagnosis remains challenging because of lack of availability of high-resolution imaging and lack of experience in interpreting the imaging results. Additionally, these are a genetically heterogeneous group of disorders with overlapping clinical features.”

The testing cohort for this panel comprised 280 specimens. Most (84%) were obtained from amniocentesis; 5% were from chorionic villi sampling, and the remainder were derived from other sources. The median gestational age was 20 weeks and 5 days, but the samples ranged from 5 to 36 weeks’ gestation.

The most common imaging indication for testing was short limbs (87%). Other indications included abnormal ribs or small chest circumference (47%); bowed or fractured bones (28%); leg bowing (27%); upper limb deformity (12%); poly- or syndactyly (5%); and other findings, including facial dysmorphism (23%). About 5% of the samples had a family history of skeletal dysplasia.

The panel returned a positive clinical diagnosis for 55% of the specimens. It could not determine a genetic cause for the observed clinical phenotype in 28%, and the test returned uncertain results in 17%, Dr. Vincent said.

“In these cases, we were uncertain whether the variants we identified caused the clinical features.”

Of the 153 positive cases, 42% were affected by pathogenic variants in the collagen genes of COL1A1, COL1A2, and COL1A3. Variants in the FGFR3 gene (39%) were next most common. FGFR3 is associated with achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia. Mutations of the SOX-9 gene, responsible for campomelic dysplasia, accounted for 5%. The test also identified nine other genetic variants in small numbers of samples.

“About 90% of the genes were autosomal dominant, indicating they are typically de novo or sporadic,” Dr. Vincent said. “About 10% were autosomal recessive, and just 1% were linked to an X-linked mutation.”

The clinical syndromes identified through these genes included osteogenesis imperfecta and thanatophoric dysplasia (33% each); achondrogenesis and spondyloepiphyseal dysplasia (11%); asphyxiating thoracic dystrophy/short rib polydactyly syndrome and campomelic dysplasia (5% each). The remaining cases were atelosteogenesis, Apert syndrome, Crouzon syndrome, chondrodysplasia punctata, hypochondroplasia, and Ellis-van Creveld syndrome.

The test predicted that 64% of the cases would be lethal. In 26%, viability was uncertain, but 10% – including 5% of the osteogenesis imperfecta cases – could be viable.

“Most lethal cases tended to have several characteristics, including short limbs, abnormal ribs, and bowed or fracture bones,” Dr. Vincent said. “Short limbs were almost five times more common in the lethal cases than in those with variable severity. Abnormal ribs and small chest were five times more frequent in the lethal cases, and bowed or fractured bones were four times more common.”

Among the nonpositive cases, 32% had additional testing. Of these, 8% had cytogenetic or large-array abnormalities, and another 8% were positive for a skeletal dysplasia that was not caused by any of the genes on the test panel.

Dr. Vincent noted that the turnaround time for the test is generally 2-3 weeks.

[email protected]

SOURCE: Vincent L et al. Am J Obstet Gynecol. 2018;18:S57-8.

After surgery for complex ventral hernia repair, a significant number of patients make unscheduled calls or visits to the clinic or ED because of pain. And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.

Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.

The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.

All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”

SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.

After surgery for complex ventral hernia repair, a significant number of patients make unscheduled calls or visits to the clinic or ED because of pain. And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.

Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.

The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.

All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”

SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.

After surgery for complex ventral hernia repair, a significant number of patients make unscheduled calls or visits to the clinic or ED because of pain. And although these calls and visits are costly in health care resources, many patients do not receive an actionable diagnosis, according to a study published in The American Journal of Surgery.

Colin G. DeLong, MD, and his colleagues reviewed health records of patients who underwent an open procedure for complex ventral hernia repair (cVHR) at Penn State Milton S. Hershey Medical Center in Hershey, Penn., between January 2013 and August 2015 using the American College of Surgeons National Surgery Quality Improvement Project (NSQIP) data available at the institution. They identified a cohort of 177 patients, 79% of whom were reviewed for pain issues at 1 year.

The study focused on postoperative pain during the first year following open cVHR. The investigators looked at how patients registered postoperative discomfort, risk factors that predicted greater utilization of the health system for pain-related complaints, and how often complaints of chronic pain resulted in an actionable diagnosis.

All postop encounters in the year after surgery were documented, including the sequence of events in response to pain complaints. In addition, the investigators recorded “instances in which a diagnosis resulted from such actions and whether the diagnosis was actionable, meaning it led to a specific intervention that was expected to alleviate the pain.”

SOURCE: DeLong CG et al. Am J Surg. 2018. doi: 10.1016/j.amjsurg.2018.01.030.

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

Could bimekizumab reshape psoriasis treatment? Next-day discharge after TAVR shows promise.  Are fewer ultrasounds safe in high-risk pregnancies? And Medicare’s readmissions penalties are working – or not.

 

Listen to the MDedge Daily News podcast for all the details on today’s top news.

 

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

Could bimekizumab reshape psoriasis treatment? Next-day discharge after TAVR shows promise.  Are fewer ultrasounds safe in high-risk pregnancies? And Medicare’s readmissions penalties are working – or not.

 

Listen to the MDedge Daily News podcast for all the details on today’s top news.

 

 

The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel

Could bimekizumab reshape psoriasis treatment? Next-day discharge after TAVR shows promise.  Are fewer ultrasounds safe in high-risk pregnancies? And Medicare’s readmissions penalties are working – or not.

 

Listen to the MDedge Daily News podcast for all the details on today’s top news.

 

 

Cancer-related fatigue can linger long after treatments are ended, making daily activities harder and diminishing quality of life (QOL). But researchers from University of Alabama in Birmingham and Harvard Medical School in Boston suggest a nonpharmaceutical way to help patients feel better: placebo.

They compared an open-label placebo with treatment as usual in patients with cancer-related fatigue in a 21-day controlled trial. The patients had completed cancer treatment 6 months to 10 years prior to enrollment. Of 74 patients, 28 reported a moderate level of fatigue and 46 reported a severe level. The mean fatigue scores at baseline were similar for both groups.

The participants randomly assigned to placebo took 2 placebo pills twice a day. At 21 days, the average difference in scores was statistically significant. The placebo group reported a 29% improvement in fatigue severity and a 39% improvement in fatigue-disrupted QOL. Put another way, 76% of the placebo group had a change score above the mean change score of the usual-treatment group. The results were clinically meaningful, the researchers say. Moreover, there were no reported adverse events or adverse effects.

After that main study, the researchers also conducted a 21-day exploratory crossover extension, which began 1 week later. Their findings supported the main study results, with the same magnitude of improvement. The usual-treatment patients who chose to try the placebo also reported a similar magnitude of reductions in fatigue severity (23%) and fatigue-disrupted QOL (35%).

Interestingly, the effects seemed to be sustained, the researchers say. At day 48, there was no significant change in fatigue scores compared with day 21, an “exciting” preliminary finding they say that needs further exploration.

Source:
Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Scientific Reports. 2018;8:2784.
doi:10.1038/s41598-018-20993-y.

Cancer-related fatigue can linger long after treatments are ended, making daily activities harder and diminishing quality of life (QOL). But researchers from University of Alabama in Birmingham and Harvard Medical School in Boston suggest a nonpharmaceutical way to help patients feel better: placebo.

They compared an open-label placebo with treatment as usual in patients with cancer-related fatigue in a 21-day controlled trial. The patients had completed cancer treatment 6 months to 10 years prior to enrollment. Of 74 patients, 28 reported a moderate level of fatigue and 46 reported a severe level. The mean fatigue scores at baseline were similar for both groups.

The participants randomly assigned to placebo took 2 placebo pills twice a day. At 21 days, the average difference in scores was statistically significant. The placebo group reported a 29% improvement in fatigue severity and a 39% improvement in fatigue-disrupted QOL. Put another way, 76% of the placebo group had a change score above the mean change score of the usual-treatment group. The results were clinically meaningful, the researchers say. Moreover, there were no reported adverse events or adverse effects.

After that main study, the researchers also conducted a 21-day exploratory crossover extension, which began 1 week later. Their findings supported the main study results, with the same magnitude of improvement. The usual-treatment patients who chose to try the placebo also reported a similar magnitude of reductions in fatigue severity (23%) and fatigue-disrupted QOL (35%).

Interestingly, the effects seemed to be sustained, the researchers say. At day 48, there was no significant change in fatigue scores compared with day 21, an “exciting” preliminary finding they say that needs further exploration.

Source:
Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Scientific Reports. 2018;8:2784.
doi:10.1038/s41598-018-20993-y.

Cancer-related fatigue can linger long after treatments are ended, making daily activities harder and diminishing quality of life (QOL). But researchers from University of Alabama in Birmingham and Harvard Medical School in Boston suggest a nonpharmaceutical way to help patients feel better: placebo.

They compared an open-label placebo with treatment as usual in patients with cancer-related fatigue in a 21-day controlled trial. The patients had completed cancer treatment 6 months to 10 years prior to enrollment. Of 74 patients, 28 reported a moderate level of fatigue and 46 reported a severe level. The mean fatigue scores at baseline were similar for both groups.

The participants randomly assigned to placebo took 2 placebo pills twice a day. At 21 days, the average difference in scores was statistically significant. The placebo group reported a 29% improvement in fatigue severity and a 39% improvement in fatigue-disrupted QOL. Put another way, 76% of the placebo group had a change score above the mean change score of the usual-treatment group. The results were clinically meaningful, the researchers say. Moreover, there were no reported adverse events or adverse effects.

After that main study, the researchers also conducted a 21-day exploratory crossover extension, which began 1 week later. Their findings supported the main study results, with the same magnitude of improvement. The usual-treatment patients who chose to try the placebo also reported a similar magnitude of reductions in fatigue severity (23%) and fatigue-disrupted QOL (35%).

Interestingly, the effects seemed to be sustained, the researchers say. At day 48, there was no significant change in fatigue scores compared with day 21, an “exciting” preliminary finding they say that needs further exploration.

Source:
Hoenemeyer TW, Kaptchuk TJ, Mehta TS, Fontaine KR. Scientific Reports. 2018;8:2784.
doi:10.1038/s41598-018-20993-y.

Fecal microbiota transplants (FMTs) should be considered for use in patients with recurrent Clostridium difficile infection that has not responded to antibiotic therapy, according to new guidelines.

The updated Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children, published in the Feb. 15 edition of Clinical Infectious Diseases (doi: 10.1093/cid/cix1085), address changes in management and diagnosis of the infection, and include recommendations for pediatric infection. The guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America were lasted published in 2010.

One of the strongest recommendations was on the use of FMTs to treat recurrent C. difficile infection after the failure of antibiotic therapy.

Courtesy CDC/Dr. Gilda Jones

SOURCE: McDonald CL et al. Clin Infect Dis. 2018 Feb 15. doi: 10.1093/cid/cix1085.
 

Fecal microbiota transplants (FMTs) should be considered for use in patients with recurrent Clostridium difficile infection that has not responded to antibiotic therapy, according to new guidelines.

The updated Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children, published in the Feb. 15 edition of Clinical Infectious Diseases (doi: 10.1093/cid/cix1085), address changes in management and diagnosis of the infection, and include recommendations for pediatric infection. The guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America were lasted published in 2010.

One of the strongest recommendations was on the use of FMTs to treat recurrent C. difficile infection after the failure of antibiotic therapy.

Courtesy CDC/Dr. Gilda Jones

SOURCE: McDonald CL et al. Clin Infect Dis. 2018 Feb 15. doi: 10.1093/cid/cix1085.
 

Fecal microbiota transplants (FMTs) should be considered for use in patients with recurrent Clostridium difficile infection that has not responded to antibiotic therapy, according to new guidelines.

The updated Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children, published in the Feb. 15 edition of Clinical Infectious Diseases (doi: 10.1093/cid/cix1085), address changes in management and diagnosis of the infection, and include recommendations for pediatric infection. The guidelines from the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America were lasted published in 2010.

One of the strongest recommendations was on the use of FMTs to treat recurrent C. difficile infection after the failure of antibiotic therapy.

Courtesy CDC/Dr. Gilda Jones

SOURCE: McDonald CL et al. Clin Infect Dis. 2018 Feb 15. doi: 10.1093/cid/cix1085.
 

Photo by Larry Young

LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.

The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).

There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.

Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.

“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”

“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”

Patients

Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).

The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.

Treatment

This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.

Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.

The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.

Safety

There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.

The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).

Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).

Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.

One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.

The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).

This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.

“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”

Efficacy

The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.

In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.

Four responses were ongoing at last follow-up. The median follow-up was 15 months.

The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).

The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).

“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.

Photo by Larry Young

LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.

The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).

There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.

Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.

“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”

“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”

Patients

Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).

The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.

Treatment

This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.

Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.

The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.

Safety

There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.

The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).

Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).

Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.

One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.

The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).

This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.

“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”

Efficacy

The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.

In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.

Four responses were ongoing at last follow-up. The median follow-up was 15 months.

The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).

The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).

“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.

Photo by Larry Young

LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.

The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).

There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.

Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.

“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”

“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”

Patients

Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).

The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.

Treatment

This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.

Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.

The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.

Safety

There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.

The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).

Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).

Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.

One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.

The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).

This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.

“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”

Efficacy

The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.

In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.

Four responses were ongoing at last follow-up. The median follow-up was 15 months.

The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).

The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).

“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.