CHEST is excited to announce that CHEST 2021 will be held in Orlando, Florida, from October 17-21 at the Orange County Convention Center. CHEST 2021 will be offered as both an in-person and online experience. Since travel restrictions remain unknown, CHEST is working to ensure that everyone has access to the same top-tier learning – wherever they are.

“Learning together as a community is an important aspect of the CHEST annual meeting. Whether we are face-to-face or online, the knowledge gained from expert presenters, simulations and games, and talking with one another can’t be duplicated elsewhere. In whatever way you can attend, join us at CHEST 2021 to discuss the critically relevant topics affecting our patients and chest medicine,” said CHEST President Steve Simpson, MD, FCCP.

It is also essential that those who cannot travel can still avail themselves of the engaging and interactive learning offered at the CHEST conference. Everyone – whether online or in-person – will be able to experience the meeting in real-time, including expert faculty presentations, simulated learning experiences, gaming, and more.
 

What to expect

Through bite-sized, immersive learning, experts in the field will cover the latest updates in pulmonary, critical care, and sleep medicine. CHEST 2021 offers you the opportunity to learn from a diverse set of knowledgeable educators representing different viewpoints and experiences.

Team-based learning is an indispensable component of the annual meeting. The activities support collaborative discovery and help you build relationships with your peers. Known for its development of simulation courses, at CHEST 2021, you can take part in the latest in “hands-on” learning. In addition, gaming will allow for friendly competition among colleagues, whether playing from home or on-site.
 

Getting involved

Make your mark by submitting your original abstracts and case reports to be presented at CHEST 2021. Because of the past year’s challenges, new discoveries were made in the treatment and approaches to managing chest medicine diseases. This work is important and will inform the way patients receive care in the future.

Showcase COVID-19 research, among other topics you are working on, for a chance to share your findings with colleagues, gain feedback from expert faculty, collaborate with other professionals in the field, and expand your professional portfolio. The deadline to submit is April 28. [link]
 

Keeping safe

It’s been a long time since in-person conferences were possible. CHEST is closely monitoring the status of the pandemic throughout the planning process. The Orange County Convention Center was selected because the venue is large enough to support social distancing. The CHEST team is establishing protocols that limit the number of individuals in a space, promote good traffic flow, require the wearing of masks, and other safety measures. All on-site participants and CHEST support staff will be required to attest to having received a COVID-19 vaccination to attend.

Continue to watch for more information. Registration for CHEST 2021 will open in May. We’ve missed you, and we look forward to seeing you in Orlando, Florida, October 17-20.

CHEST is excited to announce that CHEST 2021 will be held in Orlando, Florida, from October 17-21 at the Orange County Convention Center. CHEST 2021 will be offered as both an in-person and online experience. Since travel restrictions remain unknown, CHEST is working to ensure that everyone has access to the same top-tier learning – wherever they are.

“Learning together as a community is an important aspect of the CHEST annual meeting. Whether we are face-to-face or online, the knowledge gained from expert presenters, simulations and games, and talking with one another can’t be duplicated elsewhere. In whatever way you can attend, join us at CHEST 2021 to discuss the critically relevant topics affecting our patients and chest medicine,” said CHEST President Steve Simpson, MD, FCCP.

It is also essential that those who cannot travel can still avail themselves of the engaging and interactive learning offered at the CHEST conference. Everyone – whether online or in-person – will be able to experience the meeting in real-time, including expert faculty presentations, simulated learning experiences, gaming, and more.
 

What to expect

Through bite-sized, immersive learning, experts in the field will cover the latest updates in pulmonary, critical care, and sleep medicine. CHEST 2021 offers you the opportunity to learn from a diverse set of knowledgeable educators representing different viewpoints and experiences.

Team-based learning is an indispensable component of the annual meeting. The activities support collaborative discovery and help you build relationships with your peers. Known for its development of simulation courses, at CHEST 2021, you can take part in the latest in “hands-on” learning. In addition, gaming will allow for friendly competition among colleagues, whether playing from home or on-site.
 

Getting involved

Make your mark by submitting your original abstracts and case reports to be presented at CHEST 2021. Because of the past year’s challenges, new discoveries were made in the treatment and approaches to managing chest medicine diseases. This work is important and will inform the way patients receive care in the future.

Showcase COVID-19 research, among other topics you are working on, for a chance to share your findings with colleagues, gain feedback from expert faculty, collaborate with other professionals in the field, and expand your professional portfolio. The deadline to submit is April 28. [link]
 

Keeping safe

It’s been a long time since in-person conferences were possible. CHEST is closely monitoring the status of the pandemic throughout the planning process. The Orange County Convention Center was selected because the venue is large enough to support social distancing. The CHEST team is establishing protocols that limit the number of individuals in a space, promote good traffic flow, require the wearing of masks, and other safety measures. All on-site participants and CHEST support staff will be required to attest to having received a COVID-19 vaccination to attend.

Continue to watch for more information. Registration for CHEST 2021 will open in May. We’ve missed you, and we look forward to seeing you in Orlando, Florida, October 17-20.

CHEST is excited to announce that CHEST 2021 will be held in Orlando, Florida, from October 17-21 at the Orange County Convention Center. CHEST 2021 will be offered as both an in-person and online experience. Since travel restrictions remain unknown, CHEST is working to ensure that everyone has access to the same top-tier learning – wherever they are.

“Learning together as a community is an important aspect of the CHEST annual meeting. Whether we are face-to-face or online, the knowledge gained from expert presenters, simulations and games, and talking with one another can’t be duplicated elsewhere. In whatever way you can attend, join us at CHEST 2021 to discuss the critically relevant topics affecting our patients and chest medicine,” said CHEST President Steve Simpson, MD, FCCP.

It is also essential that those who cannot travel can still avail themselves of the engaging and interactive learning offered at the CHEST conference. Everyone – whether online or in-person – will be able to experience the meeting in real-time, including expert faculty presentations, simulated learning experiences, gaming, and more.
 

What to expect

Through bite-sized, immersive learning, experts in the field will cover the latest updates in pulmonary, critical care, and sleep medicine. CHEST 2021 offers you the opportunity to learn from a diverse set of knowledgeable educators representing different viewpoints and experiences.

Team-based learning is an indispensable component of the annual meeting. The activities support collaborative discovery and help you build relationships with your peers. Known for its development of simulation courses, at CHEST 2021, you can take part in the latest in “hands-on” learning. In addition, gaming will allow for friendly competition among colleagues, whether playing from home or on-site.
 

Getting involved

Make your mark by submitting your original abstracts and case reports to be presented at CHEST 2021. Because of the past year’s challenges, new discoveries were made in the treatment and approaches to managing chest medicine diseases. This work is important and will inform the way patients receive care in the future.

Showcase COVID-19 research, among other topics you are working on, for a chance to share your findings with colleagues, gain feedback from expert faculty, collaborate with other professionals in the field, and expand your professional portfolio. The deadline to submit is April 28. [link]
 

Keeping safe

It’s been a long time since in-person conferences were possible. CHEST is closely monitoring the status of the pandemic throughout the planning process. The Orange County Convention Center was selected because the venue is large enough to support social distancing. The CHEST team is establishing protocols that limit the number of individuals in a space, promote good traffic flow, require the wearing of masks, and other safety measures. All on-site participants and CHEST support staff will be required to attest to having received a COVID-19 vaccination to attend.

Continue to watch for more information. Registration for CHEST 2021 will open in May. We’ve missed you, and we look forward to seeing you in Orlando, Florida, October 17-20.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

Patients with COPD may develop sustained hypercapnia, often defined as an awake arterial PCO2 of >45 mm Hg. Other synonymous terms include alveolar hypoventilation or chronic hypercapnic respiratory failure, noting that the specific terminology used may reflect local practice, an assessment of patient severity, or specific insurance requirements. Regardless, available data suggest that hypercapnic COPD patients are at high risk for adverse health outcomes (Yang H, et al. BMJ Open. 2015;5[12]:e008909). Moreover, there appears to have been a growing interest in this population driven by a focus on reducing COPD hospitalizations, increasing recognition of sleep disordered breathing, and progress in potential therapeutic strategies.

There are a number of factors that might drive COPD patients to develop hypercapnia. Lower airway obstruction, expiratory flow limitation and air trapping cause mechanical load on breathing, as well as a trade-off between time spent in inspiration vs prolonged expiration. The function of the diaphragm is impacted by hyperinflation leading to mal-positioning, as well as possibly by local and/or systemic myopathy. The net result is often decreased overall minute ventilation. In terms of gas exchange, increased dead space and ventilation-perfusion mismatching leads to reduced efficiency of ventilation towards CO₂ removal. Breathing changes during sleep play an important role, as evidenced by worsened hypercapnia during sleep that can drive chronic CO₂ retention (O’Donoghue FJ, et al. Eur Respir J. 2003;21[6]:977). The pathogenesis includes reduced central respiratory drive, increased upper airway resistance and/or obstructive hypopneas and apneas, and respiratory muscle atonia, particularly during REM sleep. The extent to which each of these factors contributes to hypercapnia varies across individual patients, in accordance with the known substantial heterogeneity of COPD. Regardless of underlying traits, patients with COPD who develop hypercapnia have sufficiently severe perturbations to disrupt the normally tight control over CO₂ homeostasis.

Nocturnal home noninvasive ventilation (NIV) has been examined as a potential therapeutic strategy for patients with hypercapnic COPD. While older studies have not shown consistent benefits, more recent evidence suggests that NIV can reduce hospitalizations, improve quality of life, and potentially reduce mortality among those with hypercapnic COPD. Accordingly, the American Thoracic Society recently released a clinical practice guideline regarding the use of NIV in patients with chronic stable hypercapnic COPD (Macrea M, et al. Am J Respir Crit Care Med. 2020;202[4]:e74-e87). Recommendations from the guideline included:

1) The use of nocturnal NIV for patients with chronic stable hypercapnic COPD

2) Screening for OSA before initiation of long-term NIV

3) Not using in-hospital initiation of long-term NIV after an episode of acute or chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution

4) Not using an in-laboratory overnight PSG to initially titrate NIV

5) Targeting normalization of PaCO₂.

Although it now seems clear that efforts should be made to use NIV in COPD to decrease chronic hypercapnia, there are a number of important questions that remain, particularly surrounding the topic of concurrent OSA, titration, and devices:

• What is the appropriate approach towards patients with suspected concurrent OSA? Most studies of NIV have excluded patients with OSA, or otherwise at higher risk of OSA. Nonetheless, such patients may be common, both based on continued high prevalence of obesity, as well as the potential role that upper airway obstructive events may play towards elevations in CO₂ (Resta O., et al. Sleep Breath. 2002;6[1]:11-8). COPD epidemiological studies indicate obesity as a risk factor for several poor outcomes, including severe COPD exacerbation (Lambert AA, et al. Chest. 2017;151[1]:68-77), while studies of COPD and OSA suggest that the presence of hypercapnia defines a high-risk group Jaoude P., Lung. 2014;192:215). Recognizing the potential importance of OSA in this group, ATS guidelines recommend that a general questionnaire-based screening be performed. If screening is positive, the implication would be to perform diagnostic polysomnography to confirm the diagnosis of OSA. However, this may be a challenge for chronically ill patients, and likely would result in delays in NIV initiation. Of note, emerging evidence suggests that home sleep apnea testing (HSAT) might have reasonable accuracy in this group, which may facilitate formal diagnosis. Other concerns in this area include the lack of questionnaire validation in COPD patients.

• Should patients with OSA be managed differently than those without OSA? A diagnosis of OSA might impact several subsequent management decisions related to appropriate NIV therapy and titration. Patients with OSA have increased upper airway collapsibility, which might necessitate higher EPAP support than the minimal EPAP used in NIV trials with non-OSA patients (often fixed at 4 cm water). Potential strategies for optimizing EPAP include use of an NIV device with auto-titrating EPAP, titration in the sleep laboratory (discussed below), or outpatient titration based on clinical parameters and subsequent device download follow-up. On the other hand, one might consider all patients to be at risk for upper airway obstruction and need for additional EPAP titration, which would obviate the need for OSA diagnostic testing.

• What is the role of the sleep laboratory towards successful titration? The inpatient hospital setting has been the traditional site to initiate home NIV in some institutions but is highly resource intensive and increasingly impractical in many health systems. On the other hand, advances in home remote device monitoring now provide the clinician with the ability to examine daily usage, estimated leak, tidal volumes, respiratory rate, and other parameters – often reported as recently as the prior night. In addition, setting changes can be made via these remote monitoring tools (for nonventilator devices), allowing titration to be performed over time on outpatients. Several studies support the effectiveness of this approach over hospital titration in neuromuscular disease and now in COPD (Duiverman ML, et al. Thorax. 2020;75[3]:244-52). Similarly, data suggest that titration under polysomnographic guidance might not be necessary (Patout M, Arbane G, Cuvelier A, Muir JF, Hart N, Murphy PB. Polysomnography versus limited respiratory monitoring and nurse-led titration to optimize non-invasive ventilation set-up: a pilot randomised clinical trial. Thorax. 2019;74:83-86).

Limitations towards the sleep lab as the site of initial titration include waiting time, cost and insurance coverage, and the need to accommodate issues such as impaired mobility or reliance on a caretaker. In addition, titration goals must be clearly outlined in protocols and via staff training specific to NIV. The sleep laboratory may be most appropriately utilized in the minority of patients in whom outpatient titration is unsuccessful. Relatively common issues that might be best addressed in the lab setting include excessive mask leaks, residual apneas and hypopneas, failure to control CO₂, or other sleep complaints. In general, studies should probably be focused primarily on titrating EPAP to alleviate upper airway obstructive events. The goals in terms of IPAP titration (or ventilation titration, in the case of “VAPS” modes) are less clear, and overly aggressive increases may complicate the picture with excessive leaks or airway obstruction due to glottic closure. Attempting to accomplish “too much” often leads to a study with limited utility. In contrast, simply performing the study in the patient’s home settings can provide useful diagnostic information regarding the problem one is trying to solve.

• When and where should one initiate NIV following a severe COPD exacerbation? In contrast to the ATS guidelines, the European Respiratory Society guidelines suggest that patients recovering from severe COPD exacerbations be initiated on NIV during that hospitalization, noting that this is a group at high risk for early rehospitalization and mortality (Ergan B, et al. Eur Respir J. 2019;54[3]:1901003). ATS guidelines had the concern of unnecessary start of NIV in those who might normalize their CO₂ after recovery, and the possibility of prolonging hospitalizations for titration. For the clinician, the decision will probably be individualized based on risk and available resources. For patients with frequent ICU admissions and/or difficulty with close outpatient follow-up, earlier NIV initiation is certainly a reasonable approach, but adherence and effectiveness remains a concern and, thus, more data are needed.

• Which patients should receive a bedside respiratory assist device (RAD, i.e., BIPAP machine) vs. a noninvasive ventilator? Two classes of devices can be used for home NIV. While both can provide similar positive pressure ventilation, ventilators are designed as life support with alarms and batteries, and may have modes not otherwise available (e.g., auto-titrating EPAP). On the other hand, RAD devices are more convenient for patients and less expensive, but difficult qualification requirements (particularly for devices capable of Bilevel ST or VAPS) have likely resulted in their underutilization. CHEST is spearheading an effort to reconsider Medicare coverage determinations (current rules are from 1998), which will hopefully better align device qualification requirements with emerging evidence regarding patient needs and preferences.

Home non-invasive ventilation can improve outcomes in these high-risk patients with hypercapnic COPD, and the new clinical practice guidelines are an important step in outlining appropriate management. Further progress is needed to delineate an individualized approach based on underlying patient pathophysiology, COPD manifestations/phenotypes, and systems-based practice considerations.

Dr. Orr is Assistant Professor, Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego.

Disaster response and global health

One step forward, two back…

No adult alive today will live to see global gender parity. The 2020 World Economic Forum Global Gender Gap Report, published December 2019, assessed four dimensions of gender inequality – health, economic opportunities, educational advancement, and political empowerment.

The report stated that despite some advances, overall global gender parity would not be reached for 99 years. The gender gap is not solely a developing nation’s problem. The US standing as the 51st in gender parity fell to 53rd during the previous 2-year period. And these numbers were before Covid COVID-19.

Disasters, including pandemics, negatively affect female subjects disproportionately. Covid COVID-19 has unmasked and exacerbated both gender and minority disparity. Global health care workers (HCW) are overwhelmingly female, exposing them to a higher risk of contagion. This risk was exceptionally high among Black, Asian, and minority ethnic HCW (Nguyen et al. Lancet Public Health. 2020;5[9]:E475). The gender pay gap, where women are paid 80% of their male counterparts and women of color make 63%, has led to a greater financial burden among female HCW during Covid COVID-19. Women, including HCW, provide the majority of the unpaid work, i.e., childcare, elder care, and home care. 2020 saw an unprecedented loss of women in the workplace, including health care. Both clinical practice and research have been affected. The long- term effect on women HCW careers is unknown at present. Global gross domestic product growth loss due to this decline in the female workforce is estimated at 1 trillion USD over the next decade.

Disaster and gender parity are entwined. Covid COVID-19 has revealed the persistence of inequalities that nees to be considered in future disaster planning.

Mary Jane Reed, MD, FCCP

Steering Committee Ex-Officio


 

Interstitial and diffuse lung disease

Emergence and benefits of home monitoring and telemedicine for patients with ILD

Patients with interstitial lung disease (ILD) require regular monitoring with outpatient clinic visits and pulmonary function tests.

The emergence of COVID-19 forced an unprecedented transition to telemedicine and a new reliance on home monitoring. Home spirometry enables quick detection of rapidly progressive disease and is more sensitive than hospital-based spirometry in predicting prognosis (Russel, et al. Am J Respir Crit Care Med. 2016;194[8]:989). Patients with idiopathic pulmonary fibrosis randomized to a home monitoring program had improved psychological wellbeing and higher patient satisfaction with individually tailored treatment decisions (Moor, et al. Am J Respir Crit Care Med. 2020;202[3]:393). However, there are some inaccuracies in home monitoring. For instance, pulse oximetry is less reliable in African American patients receiving supplemental oxygen (Sjoding, et al. N Engl J Med. 2020;383:2477). It is critical to protect ILD patients from potential COVID-19 exposure given the high risk of serious complications. Telemedicine should be offered to all patients and may actually increase access to care in ILD patients, a population with disabling dyspnea and supplemental oxygen needs that requires specialist care unavailable in many geographic regions. African American patients, those older than 65, and patients with lower socioeconomic status are less willing to engage in videoconferencing (Fischer, et al. JAMA Netw Open. 2020;3[10]:e2022302). It is essential that telephone visits be offered to minimize disparities in access to care. Many telemedicine platforms enable caregivers and family members to attend visits from separate locations and provide a unique opportunity to address advance care planning. In-person visits should be arranged for patients with no access to internet or telephone or those with poor medical literacy or insufficient social support to conduct a productive remote visit. Telemedicine and home monitoring have proved invaluable during the COVID-19 pandemic and have the potential to continually increase access to and quality of care.

Rebecca Anna Gersten, MD

Steering Committee Member

Practice operations

Use of media platforms to eliminate the COVID-19 infodemic

We were shocked when we read a tweet in December 2020 from a health care worker stating, “My biggest concern is the lack of data and the quick development time. Feels like we are a bunch of guinea pigs” in reference to the new COVID-19 vaccine.

References

1. The Lancet Infectious Diseases-Editorial. The COVID-19 infodemic. Lancet Infect Dis. 2020;20(8):875.

2. Tangcharoensathien V, et al. Framework for managing the COVID-19 infodemic: methods and results of an online, crowdsourced WHO technical consultation. J Med Internet Res. 2020;22e19659.

3. Verified. https://shareverified.com/en/about. Accessed Feb 18, 2021.




 

Transplant

COVID-19 + lung transplant

The COVID-19 pandemic has created a dilemma for lung transplantation, with a new group of patients with refractory respiratory failure secondary to the viral illness. As transplant centers worldwide receive referrals for COVID-19 related respiratory failure, information regarding evaluation, listing, and posttransplant care continues to be published, but further research will be needed to care for this complex population. 

The first lung transplant for COVID-19 in the United States occurred at Northwestern Hospital on June 5th, 2020,and was publicized for its innovativeness. Information from their three lung transplants completed thus far includes information regarding pathologic findings of the explanted lung tissue; pulmonary fibrosis was the dominant feature, suggesting COVID-19-induced acute respiratory distress syndrome with prolonged time supported by mechanical support may only be survivable with the use of lung transplant (Bharat, et al. Sci Transl Med. 2020;12(574):eabe4282).

Women’s lung health

Pregnancy in cystic fibrosis

The newest in the line of modulator therapy, Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor), is expected to improve life expectancy and quality of life for patients with cystic fibrosis (CF). This evolution in therapy will shape how providers care for their patients, particularly women of reproductive age. Conventionally, women with significantly impaired lung function due to CF have been advised to avoid pregnancy due to potential complications for mother and baby. It is likely that now, with improved lung function while receiving Trikafta, more women will feel better equipped to attempt pregnancy.

Disaster response and global health

One step forward, two back…

No adult alive today will live to see global gender parity. The 2020 World Economic Forum Global Gender Gap Report, published December 2019, assessed four dimensions of gender inequality – health, economic opportunities, educational advancement, and political empowerment.

The report stated that despite some advances, overall global gender parity would not be reached for 99 years. The gender gap is not solely a developing nation’s problem. The US standing as the 51st in gender parity fell to 53rd during the previous 2-year period. And these numbers were before Covid COVID-19.

Disasters, including pandemics, negatively affect female subjects disproportionately. Covid COVID-19 has unmasked and exacerbated both gender and minority disparity. Global health care workers (HCW) are overwhelmingly female, exposing them to a higher risk of contagion. This risk was exceptionally high among Black, Asian, and minority ethnic HCW (Nguyen et al. Lancet Public Health. 2020;5[9]:E475). The gender pay gap, where women are paid 80% of their male counterparts and women of color make 63%, has led to a greater financial burden among female HCW during Covid COVID-19. Women, including HCW, provide the majority of the unpaid work, i.e., childcare, elder care, and home care. 2020 saw an unprecedented loss of women in the workplace, including health care. Both clinical practice and research have been affected. The long- term effect on women HCW careers is unknown at present. Global gross domestic product growth loss due to this decline in the female workforce is estimated at 1 trillion USD over the next decade.

Disaster and gender parity are entwined. Covid COVID-19 has revealed the persistence of inequalities that nees to be considered in future disaster planning.

Mary Jane Reed, MD, FCCP

Steering Committee Ex-Officio


 

Interstitial and diffuse lung disease

Emergence and benefits of home monitoring and telemedicine for patients with ILD

Patients with interstitial lung disease (ILD) require regular monitoring with outpatient clinic visits and pulmonary function tests.

The emergence of COVID-19 forced an unprecedented transition to telemedicine and a new reliance on home monitoring. Home spirometry enables quick detection of rapidly progressive disease and is more sensitive than hospital-based spirometry in predicting prognosis (Russel, et al. Am J Respir Crit Care Med. 2016;194[8]:989). Patients with idiopathic pulmonary fibrosis randomized to a home monitoring program had improved psychological wellbeing and higher patient satisfaction with individually tailored treatment decisions (Moor, et al. Am J Respir Crit Care Med. 2020;202[3]:393). However, there are some inaccuracies in home monitoring. For instance, pulse oximetry is less reliable in African American patients receiving supplemental oxygen (Sjoding, et al. N Engl J Med. 2020;383:2477). It is critical to protect ILD patients from potential COVID-19 exposure given the high risk of serious complications. Telemedicine should be offered to all patients and may actually increase access to care in ILD patients, a population with disabling dyspnea and supplemental oxygen needs that requires specialist care unavailable in many geographic regions. African American patients, those older than 65, and patients with lower socioeconomic status are less willing to engage in videoconferencing (Fischer, et al. JAMA Netw Open. 2020;3[10]:e2022302). It is essential that telephone visits be offered to minimize disparities in access to care. Many telemedicine platforms enable caregivers and family members to attend visits from separate locations and provide a unique opportunity to address advance care planning. In-person visits should be arranged for patients with no access to internet or telephone or those with poor medical literacy or insufficient social support to conduct a productive remote visit. Telemedicine and home monitoring have proved invaluable during the COVID-19 pandemic and have the potential to continually increase access to and quality of care.

Rebecca Anna Gersten, MD

Steering Committee Member

Practice operations

Use of media platforms to eliminate the COVID-19 infodemic

We were shocked when we read a tweet in December 2020 from a health care worker stating, “My biggest concern is the lack of data and the quick development time. Feels like we are a bunch of guinea pigs” in reference to the new COVID-19 vaccine.

References

1. The Lancet Infectious Diseases-Editorial. The COVID-19 infodemic. Lancet Infect Dis. 2020;20(8):875.

2. Tangcharoensathien V, et al. Framework for managing the COVID-19 infodemic: methods and results of an online, crowdsourced WHO technical consultation. J Med Internet Res. 2020;22e19659.

3. Verified. https://shareverified.com/en/about. Accessed Feb 18, 2021.




 

Transplant

COVID-19 + lung transplant

The COVID-19 pandemic has created a dilemma for lung transplantation, with a new group of patients with refractory respiratory failure secondary to the viral illness. As transplant centers worldwide receive referrals for COVID-19 related respiratory failure, information regarding evaluation, listing, and posttransplant care continues to be published, but further research will be needed to care for this complex population. 

The first lung transplant for COVID-19 in the United States occurred at Northwestern Hospital on June 5th, 2020,and was publicized for its innovativeness. Information from their three lung transplants completed thus far includes information regarding pathologic findings of the explanted lung tissue; pulmonary fibrosis was the dominant feature, suggesting COVID-19-induced acute respiratory distress syndrome with prolonged time supported by mechanical support may only be survivable with the use of lung transplant (Bharat, et al. Sci Transl Med. 2020;12(574):eabe4282).

Women’s lung health

Pregnancy in cystic fibrosis

The newest in the line of modulator therapy, Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor), is expected to improve life expectancy and quality of life for patients with cystic fibrosis (CF). This evolution in therapy will shape how providers care for their patients, particularly women of reproductive age. Conventionally, women with significantly impaired lung function due to CF have been advised to avoid pregnancy due to potential complications for mother and baby. It is likely that now, with improved lung function while receiving Trikafta, more women will feel better equipped to attempt pregnancy.

Disaster response and global health

One step forward, two back…

No adult alive today will live to see global gender parity. The 2020 World Economic Forum Global Gender Gap Report, published December 2019, assessed four dimensions of gender inequality – health, economic opportunities, educational advancement, and political empowerment.

The report stated that despite some advances, overall global gender parity would not be reached for 99 years. The gender gap is not solely a developing nation’s problem. The US standing as the 51st in gender parity fell to 53rd during the previous 2-year period. And these numbers were before Covid COVID-19.

Disasters, including pandemics, negatively affect female subjects disproportionately. Covid COVID-19 has unmasked and exacerbated both gender and minority disparity. Global health care workers (HCW) are overwhelmingly female, exposing them to a higher risk of contagion. This risk was exceptionally high among Black, Asian, and minority ethnic HCW (Nguyen et al. Lancet Public Health. 2020;5[9]:E475). The gender pay gap, where women are paid 80% of their male counterparts and women of color make 63%, has led to a greater financial burden among female HCW during Covid COVID-19. Women, including HCW, provide the majority of the unpaid work, i.e., childcare, elder care, and home care. 2020 saw an unprecedented loss of women in the workplace, including health care. Both clinical practice and research have been affected. The long- term effect on women HCW careers is unknown at present. Global gross domestic product growth loss due to this decline in the female workforce is estimated at 1 trillion USD over the next decade.

Disaster and gender parity are entwined. Covid COVID-19 has revealed the persistence of inequalities that nees to be considered in future disaster planning.

Mary Jane Reed, MD, FCCP

Steering Committee Ex-Officio


 

Interstitial and diffuse lung disease

Emergence and benefits of home monitoring and telemedicine for patients with ILD

Patients with interstitial lung disease (ILD) require regular monitoring with outpatient clinic visits and pulmonary function tests.

The emergence of COVID-19 forced an unprecedented transition to telemedicine and a new reliance on home monitoring. Home spirometry enables quick detection of rapidly progressive disease and is more sensitive than hospital-based spirometry in predicting prognosis (Russel, et al. Am J Respir Crit Care Med. 2016;194[8]:989). Patients with idiopathic pulmonary fibrosis randomized to a home monitoring program had improved psychological wellbeing and higher patient satisfaction with individually tailored treatment decisions (Moor, et al. Am J Respir Crit Care Med. 2020;202[3]:393). However, there are some inaccuracies in home monitoring. For instance, pulse oximetry is less reliable in African American patients receiving supplemental oxygen (Sjoding, et al. N Engl J Med. 2020;383:2477). It is critical to protect ILD patients from potential COVID-19 exposure given the high risk of serious complications. Telemedicine should be offered to all patients and may actually increase access to care in ILD patients, a population with disabling dyspnea and supplemental oxygen needs that requires specialist care unavailable in many geographic regions. African American patients, those older than 65, and patients with lower socioeconomic status are less willing to engage in videoconferencing (Fischer, et al. JAMA Netw Open. 2020;3[10]:e2022302). It is essential that telephone visits be offered to minimize disparities in access to care. Many telemedicine platforms enable caregivers and family members to attend visits from separate locations and provide a unique opportunity to address advance care planning. In-person visits should be arranged for patients with no access to internet or telephone or those with poor medical literacy or insufficient social support to conduct a productive remote visit. Telemedicine and home monitoring have proved invaluable during the COVID-19 pandemic and have the potential to continually increase access to and quality of care.

Rebecca Anna Gersten, MD

Steering Committee Member

Practice operations

Use of media platforms to eliminate the COVID-19 infodemic

We were shocked when we read a tweet in December 2020 from a health care worker stating, “My biggest concern is the lack of data and the quick development time. Feels like we are a bunch of guinea pigs” in reference to the new COVID-19 vaccine.

References

1. The Lancet Infectious Diseases-Editorial. The COVID-19 infodemic. Lancet Infect Dis. 2020;20(8):875.

2. Tangcharoensathien V, et al. Framework for managing the COVID-19 infodemic: methods and results of an online, crowdsourced WHO technical consultation. J Med Internet Res. 2020;22e19659.

3. Verified. https://shareverified.com/en/about. Accessed Feb 18, 2021.




 

Transplant

COVID-19 + lung transplant

The COVID-19 pandemic has created a dilemma for lung transplantation, with a new group of patients with refractory respiratory failure secondary to the viral illness. As transplant centers worldwide receive referrals for COVID-19 related respiratory failure, information regarding evaluation, listing, and posttransplant care continues to be published, but further research will be needed to care for this complex population. 

The first lung transplant for COVID-19 in the United States occurred at Northwestern Hospital on June 5th, 2020,and was publicized for its innovativeness. Information from their three lung transplants completed thus far includes information regarding pathologic findings of the explanted lung tissue; pulmonary fibrosis was the dominant feature, suggesting COVID-19-induced acute respiratory distress syndrome with prolonged time supported by mechanical support may only be survivable with the use of lung transplant (Bharat, et al. Sci Transl Med. 2020;12(574):eabe4282).

Women’s lung health

Pregnancy in cystic fibrosis

The newest in the line of modulator therapy, Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor), is expected to improve life expectancy and quality of life for patients with cystic fibrosis (CF). This evolution in therapy will shape how providers care for their patients, particularly women of reproductive age. Conventionally, women with significantly impaired lung function due to CF have been advised to avoid pregnancy due to potential complications for mother and baby. It is likely that now, with improved lung function while receiving Trikafta, more women will feel better equipped to attempt pregnancy.

As I write, it is 1 degree Fahrenheit and dreary in Kansas City, where I live. That’s minus 17 degrees Celsius for many of you. I hope that it is cheerier and bordering on springtime when you’re reading. You’ll understand, though, why I say Happy 2021! 2020 was a humdinger in many ways.

As I write, it is 1 degree Fahrenheit and dreary in Kansas City, where I live. That’s minus 17 degrees Celsius for many of you. I hope that it is cheerier and bordering on springtime when you’re reading. You’ll understand, though, why I say Happy 2021! 2020 was a humdinger in many ways.

As I write, it is 1 degree Fahrenheit and dreary in Kansas City, where I live. That’s minus 17 degrees Celsius for many of you. I hope that it is cheerier and bordering on springtime when you’re reading. You’ll understand, though, why I say Happy 2021! 2020 was a humdinger in many ways.

CHEST Analytics has announced its new resource for members interested in serving as investigators in industry-sponsored clinical trials.

The new program, CHEST Clinical Trials Solutions, will pair members who have indicated their interest in specific research topics with companies seeking investigators. According to CHEST President Steven Q. Simpson, MD, FCCP: “For members who would like to be involved in research and for companies that have defined distinct criteria for their studies, CHEST Analytics can pair qualifying parties to facilitate communication between researcher and sponsor. It’s a great way for young investigators to get started or accomplished members to share their experience while helping industry expedite introducing new products that improve patient care.” More information regarding enrollment will be available at info.chestnet.org/clinical-trials.

CHEST Analytics has announced its new resource for members interested in serving as investigators in industry-sponsored clinical trials.

The new program, CHEST Clinical Trials Solutions, will pair members who have indicated their interest in specific research topics with companies seeking investigators. According to CHEST President Steven Q. Simpson, MD, FCCP: “For members who would like to be involved in research and for companies that have defined distinct criteria for their studies, CHEST Analytics can pair qualifying parties to facilitate communication between researcher and sponsor. It’s a great way for young investigators to get started or accomplished members to share their experience while helping industry expedite introducing new products that improve patient care.” More information regarding enrollment will be available at info.chestnet.org/clinical-trials.

CHEST Analytics has announced its new resource for members interested in serving as investigators in industry-sponsored clinical trials.

The new program, CHEST Clinical Trials Solutions, will pair members who have indicated their interest in specific research topics with companies seeking investigators. According to CHEST President Steven Q. Simpson, MD, FCCP: “For members who would like to be involved in research and for companies that have defined distinct criteria for their studies, CHEST Analytics can pair qualifying parties to facilitate communication between researcher and sponsor. It’s a great way for young investigators to get started or accomplished members to share their experience while helping industry expedite introducing new products that improve patient care.” More information regarding enrollment will be available at info.chestnet.org/clinical-trials.

Doreen J. Addrizzo-Harris, MD, FCCP, is a pulmonary/critical care physician with an extensive background in bronchiectasis and non-tuberculous mycobacterial infection and medical education. 

Doreen J. Addrizzo-Harris, MD, FCCP, is a pulmonary/critical care physician with an extensive background in bronchiectasis and non-tuberculous mycobacterial infection and medical education. 

Doreen J. Addrizzo-Harris, MD, FCCP, is a pulmonary/critical care physician with an extensive background in bronchiectasis and non-tuberculous mycobacterial infection and medical education. 

Broadening the diagnosis of gestational diabetes mellitus (GDM) with a one-step screening approach does not lead to significant differences in maternal or perinatal outcomes, compared with a two-step approach. Investigators reported these findings in the New England Journal of Medicine after testing the two screening methods in more than 23,000 pregnant women.

GDM affects 6%-25% of pregnant women, increasing the risk of neonatal death and stillborn births. It can also lead to serious complications such as fetal overgrowth. Clinical guidelines recommend GDM screening between 24 and 28 weeks’ gestation to improve outcomes in mothers and infants. However, the scientific community has struggled to reach a consensus on testing approach.

For decades, clinicians used a two-step screening approach: a nonfasting 1-hour glucose challenge test and a longer 3-hour fasting oral glucose tolerance test to diagnose GDM; roughly 20% who test positive on this glucose challenge test require the second step. Results of a large study led to new diagnostic criteria on a one-step 75-g oral glucose tolerance test. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study “found a linear relationship with hyperglycemia and outcomes – the higher the glucose, the worse the outcomes,” said Teresa Hillier, MD, MS, an endocrinologist and investigator with Kaiser Permanente Center for Health Research Northwest and CHR-Hawaii. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) made a clinical recommendation on the one-step approach, now a common screening tool in the United States.
 

A focus on rare GDM outcomes

The IADPSG fasting one-step criteria typically identifies women with milder symptoms as having gestational diabetes, a factor expected to increase diagnosis rates by two- or threefold, said Dr. Hillier. “The unknown question was whether diagnosing and treating more women would be associated with any differences in any of the multiple GDM-associated outcomes for mother and baby.”

She and her colleagues conducted a large-scale randomized trial at two Kaiser sites to assess multiple maternal and perinatal outcomes including rare but important GDM-associated outcomes such as stillbirth and neonatal death between the two screening methods.

They randomized 23,792 pregnant women 1:1 to the one- or two-step gestational diabetes test at their first prenatal visit. Primary outcomes included diagnosis of gestational diabetes; large-for-gestational-age infants; primary cesarean section, and gestational hypertension or preeclampsia; and a composite perinatal outcome of any stillbirth, neonatal death, shoulder dystocia, bone fracture, or arm or hand nerve palsy related to birth injury.

Most participants (94%) completed screening, although there was lower adherence to screening in the one-step approach. The reasons for this aren’t entirely clear, said Dr. Hillier. Convenience may be a factor; patients have to fast for several hours to complete the one-step test, whereas the first test of the two-step screening approach can be done at any time of day, and most patients pass this test.

Corroborating HAPO’s results, twice as many women in the one-step group (16.5%) received a GDM diagnosis, compared with 8.5% in the two-step group (unadjusted relative risk, 1.94; 97.5% confidence interval, 1.79-2.11). However, for the other primary outcomes, investigators found no significant differences in incidences or unadjusted risks. Perinatal composite outcomes for the one- and two-step groups were 3.1% and 3.0%, respectively, and primary cesarean section outcomes were 24.0% and 24.6%.

In the one-step group, 8.9% experienced large-for-gestational-age infants outcomes, compared with 9.2% in the two-step group (RR, 0.95; 97.5% CI, 0.87-1.05). Among those diagnosed with gestational diabetes, similar percentages of women in the one- and two-step groups received insulin or hypoglycemic medication (42.6% and 45.6%, respectively).

Dr. Hillier and colleagues also reported comparable results among the two groups on safety outcomes and secondary outcomes such as macrosomia incidence, small-for-gestational-age infants, and factors such as neonatal hypoglycemia and respiratory distress.

“Although we did not find increased harms associated with the diagnosis and treatment of gestational diabetes in many more women with the one-step approach, some retrospective observational cohort studies have shown higher incidences of primary cesarean delivery and neonatal hypoglycemia with one-step screening after conversion from two-step protocols, with no substantive improvement in outcomes,” Dr. Hillier and colleagues noted.

The trial had several limitations. Adjustments made to address lower adherence to the one-step approach might not have accounted for all nonadherence differences. Another issue is the two sites didn’t use identical thresholds for the glucose challenge test in the two-step cohort. Demographically, the study lacked Black and American Indian representation.

“Moreover, the potential long-term benefits of increased diagnoses of gestational diabetes – such as the identification of more women at high risk for subsequent diabetes who might benefit from risk-reduction strategies – were not addressed by the trial,” Brian Casey, MD, wrote in a related editorial. Based on the study’s findings, “the perinatal benefits of the diagnosis of gestational diabetes with the use of the IADPSG single-step approach appear to be insufficient to justify the associated patient and health care costs of broadening the diagnosis” of GDM, added Dr. Casey, a professor with the department of obstetrics and gynecology at the University of Alabama at Birmingham.
 

U.S. doctors unlikely to change behaviors

Most U.S. physicians favor the two-step method. This has been a huge controversy worldwide, with other countries pushing the United States to use the one-step method, Vincenzo Berghella, MD, a professor with Thomas Jefferson University, Philadelphia, said in an interview. “I expect this study will increase the divide between the U.S. and the rest of the world,” since U.S. physicians will see no benefit to the one-step method, and continue to use the two-step method. 

It’s not surprising that GDM diagnosis incidence went up to 16.5% with the inclusion of the one-step test, compared with 8.5% with the two-step test, Dr. Berghella continued. What’s less clear, are the details of treatment among the 8% diagnosed to have GDM with the one-step test, but not the two-step test. 

These women were likely to have milder degrees of insulin resistance or GDM. Dr. Berghella, who has advocated in the past for the one-step approach, said it would be important to find out if these women, who test positive at the one-step test but would test negative at the two-step test, were treated properly with diet, exercise, and possibly insulin or other hypoglycemic agents for their mild degree of insulin resistance. The researchers concluded that expanding the definition of GDM through the one-step test didn’t make a difference. However, “it’s not just the test that will make the difference in maternal and baby outcomes, but the aggressive management of diabetes with diet, exercise, and medications as needed once that test comes back abnormal,” he said.

The randomized trial was a massive undertaking, said Dr. Hillier.

“We are still evaluating our future plans,” she added. Forthcoming subgroup analyses from the trial could further help inform clinical practice guidelines.

Dr. Hillier received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to support this study. The investigators reported no potential conflict of interest relevant to this article.

Broadening the diagnosis of gestational diabetes mellitus (GDM) with a one-step screening approach does not lead to significant differences in maternal or perinatal outcomes, compared with a two-step approach. Investigators reported these findings in the New England Journal of Medicine after testing the two screening methods in more than 23,000 pregnant women.

GDM affects 6%-25% of pregnant women, increasing the risk of neonatal death and stillborn births. It can also lead to serious complications such as fetal overgrowth. Clinical guidelines recommend GDM screening between 24 and 28 weeks’ gestation to improve outcomes in mothers and infants. However, the scientific community has struggled to reach a consensus on testing approach.

For decades, clinicians used a two-step screening approach: a nonfasting 1-hour glucose challenge test and a longer 3-hour fasting oral glucose tolerance test to diagnose GDM; roughly 20% who test positive on this glucose challenge test require the second step. Results of a large study led to new diagnostic criteria on a one-step 75-g oral glucose tolerance test. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study “found a linear relationship with hyperglycemia and outcomes – the higher the glucose, the worse the outcomes,” said Teresa Hillier, MD, MS, an endocrinologist and investigator with Kaiser Permanente Center for Health Research Northwest and CHR-Hawaii. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) made a clinical recommendation on the one-step approach, now a common screening tool in the United States.
 

A focus on rare GDM outcomes

The IADPSG fasting one-step criteria typically identifies women with milder symptoms as having gestational diabetes, a factor expected to increase diagnosis rates by two- or threefold, said Dr. Hillier. “The unknown question was whether diagnosing and treating more women would be associated with any differences in any of the multiple GDM-associated outcomes for mother and baby.”

She and her colleagues conducted a large-scale randomized trial at two Kaiser sites to assess multiple maternal and perinatal outcomes including rare but important GDM-associated outcomes such as stillbirth and neonatal death between the two screening methods.

They randomized 23,792 pregnant women 1:1 to the one- or two-step gestational diabetes test at their first prenatal visit. Primary outcomes included diagnosis of gestational diabetes; large-for-gestational-age infants; primary cesarean section, and gestational hypertension or preeclampsia; and a composite perinatal outcome of any stillbirth, neonatal death, shoulder dystocia, bone fracture, or arm or hand nerve palsy related to birth injury.

Most participants (94%) completed screening, although there was lower adherence to screening in the one-step approach. The reasons for this aren’t entirely clear, said Dr. Hillier. Convenience may be a factor; patients have to fast for several hours to complete the one-step test, whereas the first test of the two-step screening approach can be done at any time of day, and most patients pass this test.

Corroborating HAPO’s results, twice as many women in the one-step group (16.5%) received a GDM diagnosis, compared with 8.5% in the two-step group (unadjusted relative risk, 1.94; 97.5% confidence interval, 1.79-2.11). However, for the other primary outcomes, investigators found no significant differences in incidences or unadjusted risks. Perinatal composite outcomes for the one- and two-step groups were 3.1% and 3.0%, respectively, and primary cesarean section outcomes were 24.0% and 24.6%.

In the one-step group, 8.9% experienced large-for-gestational-age infants outcomes, compared with 9.2% in the two-step group (RR, 0.95; 97.5% CI, 0.87-1.05). Among those diagnosed with gestational diabetes, similar percentages of women in the one- and two-step groups received insulin or hypoglycemic medication (42.6% and 45.6%, respectively).

Dr. Hillier and colleagues also reported comparable results among the two groups on safety outcomes and secondary outcomes such as macrosomia incidence, small-for-gestational-age infants, and factors such as neonatal hypoglycemia and respiratory distress.

“Although we did not find increased harms associated with the diagnosis and treatment of gestational diabetes in many more women with the one-step approach, some retrospective observational cohort studies have shown higher incidences of primary cesarean delivery and neonatal hypoglycemia with one-step screening after conversion from two-step protocols, with no substantive improvement in outcomes,” Dr. Hillier and colleagues noted.

The trial had several limitations. Adjustments made to address lower adherence to the one-step approach might not have accounted for all nonadherence differences. Another issue is the two sites didn’t use identical thresholds for the glucose challenge test in the two-step cohort. Demographically, the study lacked Black and American Indian representation.

“Moreover, the potential long-term benefits of increased diagnoses of gestational diabetes – such as the identification of more women at high risk for subsequent diabetes who might benefit from risk-reduction strategies – were not addressed by the trial,” Brian Casey, MD, wrote in a related editorial. Based on the study’s findings, “the perinatal benefits of the diagnosis of gestational diabetes with the use of the IADPSG single-step approach appear to be insufficient to justify the associated patient and health care costs of broadening the diagnosis” of GDM, added Dr. Casey, a professor with the department of obstetrics and gynecology at the University of Alabama at Birmingham.
 

U.S. doctors unlikely to change behaviors

Most U.S. physicians favor the two-step method. This has been a huge controversy worldwide, with other countries pushing the United States to use the one-step method, Vincenzo Berghella, MD, a professor with Thomas Jefferson University, Philadelphia, said in an interview. “I expect this study will increase the divide between the U.S. and the rest of the world,” since U.S. physicians will see no benefit to the one-step method, and continue to use the two-step method. 

It’s not surprising that GDM diagnosis incidence went up to 16.5% with the inclusion of the one-step test, compared with 8.5% with the two-step test, Dr. Berghella continued. What’s less clear, are the details of treatment among the 8% diagnosed to have GDM with the one-step test, but not the two-step test. 

These women were likely to have milder degrees of insulin resistance or GDM. Dr. Berghella, who has advocated in the past for the one-step approach, said it would be important to find out if these women, who test positive at the one-step test but would test negative at the two-step test, were treated properly with diet, exercise, and possibly insulin or other hypoglycemic agents for their mild degree of insulin resistance. The researchers concluded that expanding the definition of GDM through the one-step test didn’t make a difference. However, “it’s not just the test that will make the difference in maternal and baby outcomes, but the aggressive management of diabetes with diet, exercise, and medications as needed once that test comes back abnormal,” he said.

The randomized trial was a massive undertaking, said Dr. Hillier.

“We are still evaluating our future plans,” she added. Forthcoming subgroup analyses from the trial could further help inform clinical practice guidelines.

Dr. Hillier received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to support this study. The investigators reported no potential conflict of interest relevant to this article.

Broadening the diagnosis of gestational diabetes mellitus (GDM) with a one-step screening approach does not lead to significant differences in maternal or perinatal outcomes, compared with a two-step approach. Investigators reported these findings in the New England Journal of Medicine after testing the two screening methods in more than 23,000 pregnant women.

GDM affects 6%-25% of pregnant women, increasing the risk of neonatal death and stillborn births. It can also lead to serious complications such as fetal overgrowth. Clinical guidelines recommend GDM screening between 24 and 28 weeks’ gestation to improve outcomes in mothers and infants. However, the scientific community has struggled to reach a consensus on testing approach.

For decades, clinicians used a two-step screening approach: a nonfasting 1-hour glucose challenge test and a longer 3-hour fasting oral glucose tolerance test to diagnose GDM; roughly 20% who test positive on this glucose challenge test require the second step. Results of a large study led to new diagnostic criteria on a one-step 75-g oral glucose tolerance test. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study “found a linear relationship with hyperglycemia and outcomes – the higher the glucose, the worse the outcomes,” said Teresa Hillier, MD, MS, an endocrinologist and investigator with Kaiser Permanente Center for Health Research Northwest and CHR-Hawaii. The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) made a clinical recommendation on the one-step approach, now a common screening tool in the United States.
 

A focus on rare GDM outcomes

The IADPSG fasting one-step criteria typically identifies women with milder symptoms as having gestational diabetes, a factor expected to increase diagnosis rates by two- or threefold, said Dr. Hillier. “The unknown question was whether diagnosing and treating more women would be associated with any differences in any of the multiple GDM-associated outcomes for mother and baby.”

She and her colleagues conducted a large-scale randomized trial at two Kaiser sites to assess multiple maternal and perinatal outcomes including rare but important GDM-associated outcomes such as stillbirth and neonatal death between the two screening methods.

They randomized 23,792 pregnant women 1:1 to the one- or two-step gestational diabetes test at their first prenatal visit. Primary outcomes included diagnosis of gestational diabetes; large-for-gestational-age infants; primary cesarean section, and gestational hypertension or preeclampsia; and a composite perinatal outcome of any stillbirth, neonatal death, shoulder dystocia, bone fracture, or arm or hand nerve palsy related to birth injury.

Most participants (94%) completed screening, although there was lower adherence to screening in the one-step approach. The reasons for this aren’t entirely clear, said Dr. Hillier. Convenience may be a factor; patients have to fast for several hours to complete the one-step test, whereas the first test of the two-step screening approach can be done at any time of day, and most patients pass this test.

Corroborating HAPO’s results, twice as many women in the one-step group (16.5%) received a GDM diagnosis, compared with 8.5% in the two-step group (unadjusted relative risk, 1.94; 97.5% confidence interval, 1.79-2.11). However, for the other primary outcomes, investigators found no significant differences in incidences or unadjusted risks. Perinatal composite outcomes for the one- and two-step groups were 3.1% and 3.0%, respectively, and primary cesarean section outcomes were 24.0% and 24.6%.

In the one-step group, 8.9% experienced large-for-gestational-age infants outcomes, compared with 9.2% in the two-step group (RR, 0.95; 97.5% CI, 0.87-1.05). Among those diagnosed with gestational diabetes, similar percentages of women in the one- and two-step groups received insulin or hypoglycemic medication (42.6% and 45.6%, respectively).

Dr. Hillier and colleagues also reported comparable results among the two groups on safety outcomes and secondary outcomes such as macrosomia incidence, small-for-gestational-age infants, and factors such as neonatal hypoglycemia and respiratory distress.

“Although we did not find increased harms associated with the diagnosis and treatment of gestational diabetes in many more women with the one-step approach, some retrospective observational cohort studies have shown higher incidences of primary cesarean delivery and neonatal hypoglycemia with one-step screening after conversion from two-step protocols, with no substantive improvement in outcomes,” Dr. Hillier and colleagues noted.

The trial had several limitations. Adjustments made to address lower adherence to the one-step approach might not have accounted for all nonadherence differences. Another issue is the two sites didn’t use identical thresholds for the glucose challenge test in the two-step cohort. Demographically, the study lacked Black and American Indian representation.

“Moreover, the potential long-term benefits of increased diagnoses of gestational diabetes – such as the identification of more women at high risk for subsequent diabetes who might benefit from risk-reduction strategies – were not addressed by the trial,” Brian Casey, MD, wrote in a related editorial. Based on the study’s findings, “the perinatal benefits of the diagnosis of gestational diabetes with the use of the IADPSG single-step approach appear to be insufficient to justify the associated patient and health care costs of broadening the diagnosis” of GDM, added Dr. Casey, a professor with the department of obstetrics and gynecology at the University of Alabama at Birmingham.
 

U.S. doctors unlikely to change behaviors

Most U.S. physicians favor the two-step method. This has been a huge controversy worldwide, with other countries pushing the United States to use the one-step method, Vincenzo Berghella, MD, a professor with Thomas Jefferson University, Philadelphia, said in an interview. “I expect this study will increase the divide between the U.S. and the rest of the world,” since U.S. physicians will see no benefit to the one-step method, and continue to use the two-step method. 

It’s not surprising that GDM diagnosis incidence went up to 16.5% with the inclusion of the one-step test, compared with 8.5% with the two-step test, Dr. Berghella continued. What’s less clear, are the details of treatment among the 8% diagnosed to have GDM with the one-step test, but not the two-step test. 

These women were likely to have milder degrees of insulin resistance or GDM. Dr. Berghella, who has advocated in the past for the one-step approach, said it would be important to find out if these women, who test positive at the one-step test but would test negative at the two-step test, were treated properly with diet, exercise, and possibly insulin or other hypoglycemic agents for their mild degree of insulin resistance. The researchers concluded that expanding the definition of GDM through the one-step test didn’t make a difference. However, “it’s not just the test that will make the difference in maternal and baby outcomes, but the aggressive management of diabetes with diet, exercise, and medications as needed once that test comes back abnormal,” he said.

The randomized trial was a massive undertaking, said Dr. Hillier.

“We are still evaluating our future plans,” she added. Forthcoming subgroup analyses from the trial could further help inform clinical practice guidelines.

Dr. Hillier received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to support this study. The investigators reported no potential conflict of interest relevant to this article.

Proton pump inhibitors (PPIs) improve functional dyspepsia (FD) by reducing duodenal eosinophils and mast cells, according to a prospective study.

This suggests that the anti-inflammatory effects of PPIs are responsible for symptom improvement, and not barrier-protective or acid-suppressive effects, a finding that may guide future therapies and biomarkers, reported lead author Lucas Wauters, PhD, of University Hospitals Leuven (Belgium), and colleagues reported in Gastroenterology.

“FD is a common and unexplained disorder with unknown pathophysiology, hampering a conclusive diagnosis and the development of effective drugs,” the investigators wrote.

Although PPIs are currently used as first-line FD therapy, ostensibly for acid suppression, “the exact mechanism of action of PPIs in FD is unknown,” the investigators noted.

According to Dr. Wauters and colleagues, previous FD studies, such as a 2020 study published in Gut, have reported a variety of pathophysiological findings in the duodenum, including increased eosinophils and mast cells, as well as activation of duodenogastric reflexes, which suggests “a primary role for duodenal pathology in FD symptom generation.” Several drivers of this pathology have been proposed. Some, such as aberrations in bile salts and acidity, point to local, luminal changes, whereas others, such as dysregulated hypothalamic-pituitary-adrenal axis responsiveness and psychosocial factors, implicate a broader set of drivers, the investigators wrote.

The present study explored this landscape through a prospective trial that enrolled 30 healthy volunteers and 47 patients with FD (2 patients with FD did not complete the study).

Patients with FD were subgrouped into “FD-starters” who had not taken PPIs and/or acid suppression for at least 3 months leading up to the trial (n = 28) and “FD-stoppers” who had refractory symptoms after at least 1 month of daily PPI usage (n = 19). Among participants with FD, 25 had postprandial distress syndrome (PDS), 9 had epigastric pain syndrome (EPS), and 13 had subtype overlap.

For the trial, FD-starters and healthy volunteers took 4 weeks of pantoprazole 40 mg once daily, whereas FD-stoppers ceased PPI therapy for 8 weeks. Before and after these respective periods, certain study procedures were conducted, including duodenal biopsy collection, duodenal fluid aspiration, and questionnaires for symptoms and stress. The study also included use of Ussing chambers for biopsies, immunohistochemistry, and bile salt measurements.

FD-starters were significantly more symptomatic than healthy volunteers were at baseline. After starting PPIs, those with FD had symptom improvements, confirming “clinical efficacy of a standard course of PPIs in all FD subtypes,” whereas healthy volunteers showed no significant change in symptoms.

Similarly, baseline duodenal eosinophil counts were higher in FD-starters than in healthy volunteers. On starting PPIs, however, eosinophil counts in these two groups moved in opposite directions: FD-starters’ counts dropped from a mean of 331 to 183 eosinophils/mm², whereas healthy volunteers’ counts rose from a mean of 115 to 229 eosinophils/mm² (P < .0001). Changes in mast cells and paracellular passage followed the same pattern, falling in FD-starters and rising in healthy volunteers. On the other hand, symptoms actually improved in the FD-stoppers after they went off PPIs, although they did not reach symptom levels of the healthy volunteers.

“Differential effects of PPIs in healthy volunteers point to the role of luminal changes in determining low-grade mucosal immune activation in the duodenum, which can also occur in FD after long-term use and provide arguments against continued use in refractory patients,” the investigators wrote.

Dr. Wauters and colleagues suggested that their findings could guide future approaches to FD management.

“Our results suggest that quantification of duodenal eosinophils has the potential to become part of diagnostic workup and guide therapeutic decisions in FD,” they wrote. “Additional study of the underlying mediators might lead to the discovery of new potential biomarkers or novel therapeutic targets, potentially allowing the identification of subgroups responding to biologically targeted rather than symptom-based treatments.”

The study was supported by the clinical research fund of the University Hospitals Leuven. The investigators reported no conflicts of interest.

Proton pump inhibitors (PPIs) improve functional dyspepsia (FD) by reducing duodenal eosinophils and mast cells, according to a prospective study.

This suggests that the anti-inflammatory effects of PPIs are responsible for symptom improvement, and not barrier-protective or acid-suppressive effects, a finding that may guide future therapies and biomarkers, reported lead author Lucas Wauters, PhD, of University Hospitals Leuven (Belgium), and colleagues reported in Gastroenterology.

“FD is a common and unexplained disorder with unknown pathophysiology, hampering a conclusive diagnosis and the development of effective drugs,” the investigators wrote.

Although PPIs are currently used as first-line FD therapy, ostensibly for acid suppression, “the exact mechanism of action of PPIs in FD is unknown,” the investigators noted.

According to Dr. Wauters and colleagues, previous FD studies, such as a 2020 study published in Gut, have reported a variety of pathophysiological findings in the duodenum, including increased eosinophils and mast cells, as well as activation of duodenogastric reflexes, which suggests “a primary role for duodenal pathology in FD symptom generation.” Several drivers of this pathology have been proposed. Some, such as aberrations in bile salts and acidity, point to local, luminal changes, whereas others, such as dysregulated hypothalamic-pituitary-adrenal axis responsiveness and psychosocial factors, implicate a broader set of drivers, the investigators wrote.

The present study explored this landscape through a prospective trial that enrolled 30 healthy volunteers and 47 patients with FD (2 patients with FD did not complete the study).

Patients with FD were subgrouped into “FD-starters” who had not taken PPIs and/or acid suppression for at least 3 months leading up to the trial (n = 28) and “FD-stoppers” who had refractory symptoms after at least 1 month of daily PPI usage (n = 19). Among participants with FD, 25 had postprandial distress syndrome (PDS), 9 had epigastric pain syndrome (EPS), and 13 had subtype overlap.

For the trial, FD-starters and healthy volunteers took 4 weeks of pantoprazole 40 mg once daily, whereas FD-stoppers ceased PPI therapy for 8 weeks. Before and after these respective periods, certain study procedures were conducted, including duodenal biopsy collection, duodenal fluid aspiration, and questionnaires for symptoms and stress. The study also included use of Ussing chambers for biopsies, immunohistochemistry, and bile salt measurements.

FD-starters were significantly more symptomatic than healthy volunteers were at baseline. After starting PPIs, those with FD had symptom improvements, confirming “clinical efficacy of a standard course of PPIs in all FD subtypes,” whereas healthy volunteers showed no significant change in symptoms.

Similarly, baseline duodenal eosinophil counts were higher in FD-starters than in healthy volunteers. On starting PPIs, however, eosinophil counts in these two groups moved in opposite directions: FD-starters’ counts dropped from a mean of 331 to 183 eosinophils/mm², whereas healthy volunteers’ counts rose from a mean of 115 to 229 eosinophils/mm² (P < .0001). Changes in mast cells and paracellular passage followed the same pattern, falling in FD-starters and rising in healthy volunteers. On the other hand, symptoms actually improved in the FD-stoppers after they went off PPIs, although they did not reach symptom levels of the healthy volunteers.

“Differential effects of PPIs in healthy volunteers point to the role of luminal changes in determining low-grade mucosal immune activation in the duodenum, which can also occur in FD after long-term use and provide arguments against continued use in refractory patients,” the investigators wrote.

Dr. Wauters and colleagues suggested that their findings could guide future approaches to FD management.

“Our results suggest that quantification of duodenal eosinophils has the potential to become part of diagnostic workup and guide therapeutic decisions in FD,” they wrote. “Additional study of the underlying mediators might lead to the discovery of new potential biomarkers or novel therapeutic targets, potentially allowing the identification of subgroups responding to biologically targeted rather than symptom-based treatments.”

The study was supported by the clinical research fund of the University Hospitals Leuven. The investigators reported no conflicts of interest.

Proton pump inhibitors (PPIs) improve functional dyspepsia (FD) by reducing duodenal eosinophils and mast cells, according to a prospective study.

This suggests that the anti-inflammatory effects of PPIs are responsible for symptom improvement, and not barrier-protective or acid-suppressive effects, a finding that may guide future therapies and biomarkers, reported lead author Lucas Wauters, PhD, of University Hospitals Leuven (Belgium), and colleagues reported in Gastroenterology.

“FD is a common and unexplained disorder with unknown pathophysiology, hampering a conclusive diagnosis and the development of effective drugs,” the investigators wrote.

Although PPIs are currently used as first-line FD therapy, ostensibly for acid suppression, “the exact mechanism of action of PPIs in FD is unknown,” the investigators noted.

According to Dr. Wauters and colleagues, previous FD studies, such as a 2020 study published in Gut, have reported a variety of pathophysiological findings in the duodenum, including increased eosinophils and mast cells, as well as activation of duodenogastric reflexes, which suggests “a primary role for duodenal pathology in FD symptom generation.” Several drivers of this pathology have been proposed. Some, such as aberrations in bile salts and acidity, point to local, luminal changes, whereas others, such as dysregulated hypothalamic-pituitary-adrenal axis responsiveness and psychosocial factors, implicate a broader set of drivers, the investigators wrote.

The present study explored this landscape through a prospective trial that enrolled 30 healthy volunteers and 47 patients with FD (2 patients with FD did not complete the study).

Patients with FD were subgrouped into “FD-starters” who had not taken PPIs and/or acid suppression for at least 3 months leading up to the trial (n = 28) and “FD-stoppers” who had refractory symptoms after at least 1 month of daily PPI usage (n = 19). Among participants with FD, 25 had postprandial distress syndrome (PDS), 9 had epigastric pain syndrome (EPS), and 13 had subtype overlap.

For the trial, FD-starters and healthy volunteers took 4 weeks of pantoprazole 40 mg once daily, whereas FD-stoppers ceased PPI therapy for 8 weeks. Before and after these respective periods, certain study procedures were conducted, including duodenal biopsy collection, duodenal fluid aspiration, and questionnaires for symptoms and stress. The study also included use of Ussing chambers for biopsies, immunohistochemistry, and bile salt measurements.

FD-starters were significantly more symptomatic than healthy volunteers were at baseline. After starting PPIs, those with FD had symptom improvements, confirming “clinical efficacy of a standard course of PPIs in all FD subtypes,” whereas healthy volunteers showed no significant change in symptoms.

Similarly, baseline duodenal eosinophil counts were higher in FD-starters than in healthy volunteers. On starting PPIs, however, eosinophil counts in these two groups moved in opposite directions: FD-starters’ counts dropped from a mean of 331 to 183 eosinophils/mm², whereas healthy volunteers’ counts rose from a mean of 115 to 229 eosinophils/mm² (P < .0001). Changes in mast cells and paracellular passage followed the same pattern, falling in FD-starters and rising in healthy volunteers. On the other hand, symptoms actually improved in the FD-stoppers after they went off PPIs, although they did not reach symptom levels of the healthy volunteers.

“Differential effects of PPIs in healthy volunteers point to the role of luminal changes in determining low-grade mucosal immune activation in the duodenum, which can also occur in FD after long-term use and provide arguments against continued use in refractory patients,” the investigators wrote.

Dr. Wauters and colleagues suggested that their findings could guide future approaches to FD management.

“Our results suggest that quantification of duodenal eosinophils has the potential to become part of diagnostic workup and guide therapeutic decisions in FD,” they wrote. “Additional study of the underlying mediators might lead to the discovery of new potential biomarkers or novel therapeutic targets, potentially allowing the identification of subgroups responding to biologically targeted rather than symptom-based treatments.”

The study was supported by the clinical research fund of the University Hospitals Leuven. The investigators reported no conflicts of interest.

CASE Young woman with family history of breast cancer detects lump

Two weeks after noting a lump on her breast when her cat happened to jump on her in that spot, a 28-year-old woman (G0) went to her primary care provider. She was referred to her gynecologist; breast imaging, ultrasonography, and mammography were obtained, with microcalcifications noted. A fine needle aspiration diagnosed intraductal malignancy. The surgical breast tissue specimen was estrogen receptor (ER)- and progestogen receptor (PR)-positive and HER2-negative. Other tumor markers were obtained, including carcinoembryonic antigen, and tissue polypeptide specific antigen, p53, cathepsin D, cyclin E, and nestin, but results were not available.

With regard to family history, the woman’s mother and maternal grandmother had a history of breast cancer. The patient and her family underwent gene testing. The patient was found to be BRCA1- and BRCA2-positive; her mother was BRCA1-positive, an older sister was BRCA2-positive, and her grandmother was not tested.

The question arose in light of her family history as to why she was not tested for BRCA and appropriately counseled by her gynecologist prior to the cancer diagnosis. Litigation was initiated. While the case did not go forward regarding litigation, it is indeed a case in point. (Please note that this is a hypothetical case. It is based on a composite of several cases.)
 

Medical considerations

Breast cancer is the most common type of cancer affecting women in the Western world.¹ Advances in clinical testing for gene mutations have escalated and allowed for identification of patients at increased risk for breast and ovarian cancer. Along with these advances come professional liability risk. After looking at the medical considerations for BRCA1 and 2 testing, we will consider a number of important legal issues. In the view of some commentators, the failure to diagnose genetic mutations in patients predisposed to cancer is “poised to become the next wave of medical professional liability lawsuits.”²

BRCA1 and BRCA2 genes provide tumor suppressor proteins, and assessment for mutations is recommended for individuals at high risk for breast and/or ovarian cancer; mutations in BRCA genes cause DNA damage, which increases the chance of developing cancer. The other way to look at it is, BRCA1 and 2 are tumor suppressor genes that are integrally involved with DNA damage control. Once there is a mutation, it adversely affects the beneficial effects of the gene. Mutations in these genes account for 5% to 10% of all hereditary breast cancers.³ Of note, men with BRCA2 are at increased risk for prostate cancer.

A patient who presents to her gynecologist stating that there is a family history of breast cancer, without knowledge of genetic components, presents a challenge (and a medicolegal risk) for the provider to assess. Prediction models have been used to determine specific patient risk for carrying a genetic mutation with resultant breast cancer development.⁴ Risk prediction models do not appear to be a good answer to predicting who is more likely to develop breast or ovarian cancer, however. A Mayo model may assist (FIGURE).⁵ Clinicians should also be aware of other models of risk assessment, including the Gail Model (TABLE 1).⁶

Continue to: Guidelines for genetic testing...

Guidelines for genetic testing

The American College of Obstetricians and Gynecologists states that patient medical history and family history are paramount in obtaining information regarding risk for breast and ovarian cancer. First- and second-degree relatives are allocated to this category. Information regarding age of diagnosis, maternal and paternal lineage, and ethnic background can imply a need for genetic testing (TABLE 2).^7,8 A number of genetics national organizations have participated in recommendations and include the American College of Medical Genetics and Genomics, the National Society for Genetic Counselors, and the Society of Gynecologic Oncology.⁷

The question always surfaces, could the clinical outcome of the cancer when diagnosed have been changed if screening were undertaken, with earlier diagnosis, or prevented with prophylactic mastectomy, and changed the end result. In addition, it is well known that breast augmentation mammoplasty alters the ability to accurately evaluate mammograms. Patients considering this type of plastic surgery, ideally, should be counselled accordingly.⁹

Bottom line, we as clinicians must be cognizant of both ACOG and United States Preventive Services Task Force (USPSTF) recommendations regarding screening and gene testing for women considered high risk for breast cancer based on family history.⁷

Legal considerations

The case presented demonstrates that the discovery of the BRCA1 and BRCA2 genes, and reliable tests for determining the existence of the genes, brought with them legal issues as well as medical advantages. We look at professional liability (malpractice) questions this technology raises, and then consider the outcome of the hypothetical case. (BRCA is used here to apply broadly—not only to BRCA1 and 2 but also to PALB2, CHEK2, and similar genetic abnormalities.)

To date, the most visible BRCA legal issues covered in cases and law reviews have focused more on patent law than malpractice. The most important of these was a decision of the US Supreme Court in Association for Molecular Pathology v Myriad Genetics.¹⁰ The US Patent Office was granting patents to companies finding useful, naturally occurring segments of human DNA, and had granted Myriad several patents on BRCA1 and BRCA2 genes. This patent policy had the potential to seriously interfere with broad scientific use of these genes.¹¹ Fortunately, the Supreme Court stepped in and unanimously invalidated such patents. It held that a “naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.” The Court noted, “Finding the location of the BRCA1 and BRCA2 genes does not render the genes patent eligible ‘new . . . composition[s] of matter.’”⁸ The Court did allow the patenting of tests for specific gene structures, and artificial changes in naturally occurring genes.

Malpractice and BRCA

While the BRCA patent wars have lingered, the potential for a significant increase in BRCA-related malpractice cases is of increasing concern. Like most malpractice liability, these new claims are based on very old principles of negligence.¹² To prevail, the plaintiff (ordinarily, an injured patient) must demonstrate 4 things:

• A duty. That is, the physician owed a duty to the injured party. Usually (but not always) that requires a professional relationship between the physician and the person injured.
• A breach of that duty. Malpractice liability is based on the fact that the physician did something that a reasonably careful physician (generally, of the same specialty) would not have done, or that the physician failed to do something that a reasonable physician would have done. This usually means that the profession itself sees what the physician did (or did not do) as medically inappropriate. In medical malpractice cases, that is ordinarily measured by what the usual or common practice is among prudent physicians. In rare circumstances, courts have found the standard practice of a profession to be negligent. Where, for example, it was custom for a professional not to give an eye pressure test to anyone under age 40, a court found that common standard to be inappropriate.¹³ In the words of Judge Learned Hand (speaking about a different case), “a whole calling may have unduly lagged in the adoption of new and available devices. It never may set its own tests.”¹⁴ Underlying negligence is a cost-benefit analysis (discussed below).
• Damages. There must have been some damage that courts recognize, usually loss of money or opportunity to work, the cost of care, pain and suffering, or loss of enjoyment/quality of life. In malpractice, many states now recognize the “loss of chance” or the “loss of a chance.” That means, if a “physician negligently fails to diagnose a curable disease, and the patient is harmed by the disease, the physician should be liable for causing the ‘loss of a chance of a cure.’”¹⁵ (Delay in diagnosis is the most common reason for claims in breast cancer care.)¹⁶
• Causation. The breach of duty (negligence) must have caused the damages. The causation must have been reasonably close. If a driver drives through a stop sign, or a physician misreads a test, and someone is injured but there is no connection between the negligence and the injury, there is not tort liability.

The 4 elements of malpractice just described are raised in some way in the possible liability associated with BRCA testing. We next look at the ways in which liability may arise from that testing (or lack of it).

Underlying much of the following discussion is the “cost-benefit” consideration noted above. This concept is that the total cost (financial and health) of testing should be compared with the value of the benefits of testing, taking into account the probabilities that the testing will result in better health outcomes. BRCA testing, for example, is essentially cost-free in terms of physical risk. Its financial cost, while not trivial, is not great, and it is commonly covered by health insurance.¹⁷ In terms of benefits, the testing has the potential for providing critical information in making treatment decisions for a meaningful percentage of patients and their families. There are many ways of analyzing the liability risks of genetic malpractice,^7,18 and the following is intended to discuss some of the greatest risks related to BRCA testing.

Continue to: Areas of liability...

The failure to recommend a test. The circumstances in which BRCA testing should be undertaken are set out by professional organizations (noted above). These recommendations are not static, however. They change from time to time. Given the potential harm caused by the failure to test in relevant circumstances, malpractice liability is certainly a possibility when the failure to recommend a test to a patient results in a cancer that might have been prevented had the genetic problem been identified in a timely manner. The circumstances in which testing should be considered continue to change, placing an obligation on clinicians to stay well informed of changing genetic understandings. Another risk is that one specialist may assume that it is the job of another specialist to order the test. Whatever the cause of the failure to test, or unnecessary delay in testing, it appears to be the primary basis for BRCA liability.

The failure to properly interpret a test. Any test that is misinterpreted may lead to harm for the patient. A false negative, of course, may mean that preventive treatment that could have been undertaken will be foregone, as a “loss of a chance.” On the other hand, a false positive can lead to radical, unnecessary surgery or treatment. If a misinterpretation occurred because of carelessness by the testing organization, or confusion by a practitioner, there is a likelihood of negligence.¹⁹

A different form of “misinterpretation” could be reasonable—and not negligent. Advances in scientific-medical understanding may result in the outcome of tests being reconsidered and changed. That has been the case with genetic testing and breast cancer. The availability of multiple breast cancer SNPs (single nucleotide polymorphisms), and combining this information with other risk factors for example, results in a polygenic risk score that may be at odds with the level of risk from earlier testing.^20,21 This naturally leads to the question of when later, updated testing should be recommended to look for a better current interpretation.^22,23

The failure to act on BRCA test results. Testing is of no value, of course, if the results are not used properly. Test results or analyses that are not sent to the proper physicians, or are somehow ignored when properly directed, is a “never” event—it should never happen. It almost always would be considered negligence, and if the patient were injured, could lead to liability. Amazingly, one study found that, in genetic testing liability cases, nearly 20% of the claims arose from failure to return test results to patients.²⁴ In addition, when a patient is found to be BRCA-positive, there is an obligation to discuss the options for dealing with the increased risk associated with the gene mutation(s), as well as to recommend the prudent course of action or to refer the patient to someone who will have that discussion.

Informed consent to the patient. BRCA testing requires informed consent. The physical risks of the testing process are minimal, of course, but it carries a number of other emotional and family risks. The informed consent process is an invitation to an honest discussion between clinicians and patients. It should be an opportunity to discuss what the testing is, and is not, and what the test may mean for treatment. It may also be an opportunity to discuss the implications for other members of the patient’s family (noted below).

One element of informed consent is a discussion of the consequences of failure to consent, or to undertake one of the alternatives. In the case of BRCA testing, this is especially important in cases in which a patient expresses a hesitancy to be tested with an “I’d rather not know philosophy.” Although clinicians should not practice law, some patient concerns about discrimination may be addressed by the protection that the federal Genetic Information Nondiscrimination Act (GINA) and other laws provide (which prohibit insurance and employment discrimination based on genetic information). A good source of information about GINA and related nondiscrimination laws is provided by the National Human Genome Research Institute.²⁵ In addition, the National Institutes of Health has a website that may be helpful to many patients²⁶ (and a much more complex site for health professionals).²⁷ At the same time, courts have resisted plaintiffs/patients who have tried to use informed consent as a way of suing for failure to offer genetic testing.^28,29

The failure to refer. In some cases, a patient should be formally referred for genetics consultation. The considerations here are similar to other circumstances in modern, fast developing medical practice that require special sensitivity to those occasions in which a patient will benefit from additional expertise. It is a principle that the AMA Council on Ethical and Judicial Affairs has expressed this way: “In the absence of adequate expertise in pretest and posttest counseling, a physician should refer the patient to an appropriate specialist.”³⁰ The failure to refer, when that deviates from acceptable practice, may result in liability.

Informing others. BRCA testing is an area of medicine in which results may be of great significance not only to the patient but also to the patient’s family.³¹ Physicians should counsel patients on the importance of informing relatives about relevant results and “should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.”³⁰ The question may arise, however, of whether in some circumstances physicians should go a step further in ensuring relatives receive important information regarding their loved one’s health.³² The law has been reluctant to impose liability to “third parties” (someone not a patient). Duties usually arise through the physician-patient relationship. There are exceptions. Perhaps the best known has been the obligation of mental health professionals to take action to protect third parties from patients who have made believable threats against identifiable victims.³³ There are indications that some courts could find, in extreme circumstances, a “duty to warn” nonpatients in some instances where it is essential to inform third parties that they should receive a specific form of genetic testing.^34,35 Such a duty would, of course, have to protect the privacy rights of the patient to the maximum extent possible. A general duty of this type has not been established widely, but may be part of the future.

Continue to: Was there liability in our example case?...

Was there liability in our example case?

The hypothetical case provided above suggests that there could be liability. Routine medical history by the primary care physician would have produced the fact that the patient’s mother, sister, and maternal grandmother had breast cancer. That would clearly have put her in a category of those who should have received genetic testing. Yet, she was not tested until after her cancer was found. From the limited facts we have, it appears that this timeline of events would have been outside accepted practice—and negligent. The case was not pursued by the patient, however, and this may represent the current state of liability for BRCA issues.

The extent of liability seems to be significant

Our discussion of liability suggests that there is significant potential for BRCA testing negligence within practice, and that the damages in these cases could be substantial. Yet the predicted “tsunami” of malpractice lawsuits related to genetic testing has not appeared.^36,37 One study of cases in the United States (through 2016) found a “slowly rising tide” of liability cases instead of a tsunami,²⁴ as the number of claims made was low. On the other hand, the payments where damages were awarded were an order of magnitude larger than other malpractice cases—a mean of $5.3 million and median of $2 million. This is compared with mean values in the range of $275,000 to $600,000 in other areas of malpractice.

The majority of the genetic malpractice cases involve prenatal and newborn testing, and diagnosis/susceptibility/pharmacogenomic accounting for about 25% of cases. In terms of type of errors claimed, approximately 50% were diagnostic-interpretation errors, 30% failure to offer testing, nearly 20% failure to return test results to the patients, and a few remaining cases of failure to properly treat in light of genetic testing.²⁴

Despite a few very large payments, however, the fact remains that there is a surprisingly low number of genetics malpractice cases. Gary Marchant and colleagues suggest that several reasons may account for this:

• the clinical implementation of genetic science has been slower than expected
• the lack of expertise of many physicians in genetic science
• expert witnesses have sometimes been hard to find
• the lack of understanding by plaintiffs’ attorneys of genetic malpractice
• potential plaintiffs’ lack of understanding of the nature of genetic testing and the harms resulting from genetic negligence.^17,24,37

The tide is slowly coming in

By all appearances, there is every reason to think that genetic malpractice will be increasing, and that the recent past of much higher damages per claim paid in the genetics area will be part of that tide. The National Human Genome Research LawSeq project has suggested a number of useful ways of dealing with the liability issues.¹⁸ In addition to the BRCA issues that we have considered in this article for ObGyns, there are other critical issues of prenatal and newborn genetic testing.³⁸ But those are topics for another day. ●

CASE Young woman with family history of breast cancer detects lump

Two weeks after noting a lump on her breast when her cat happened to jump on her in that spot, a 28-year-old woman (G0) went to her primary care provider. She was referred to her gynecologist; breast imaging, ultrasonography, and mammography were obtained, with microcalcifications noted. A fine needle aspiration diagnosed intraductal malignancy. The surgical breast tissue specimen was estrogen receptor (ER)- and progestogen receptor (PR)-positive and HER2-negative. Other tumor markers were obtained, including carcinoembryonic antigen, and tissue polypeptide specific antigen, p53, cathepsin D, cyclin E, and nestin, but results were not available.

With regard to family history, the woman’s mother and maternal grandmother had a history of breast cancer. The patient and her family underwent gene testing. The patient was found to be BRCA1- and BRCA2-positive; her mother was BRCA1-positive, an older sister was BRCA2-positive, and her grandmother was not tested.

The question arose in light of her family history as to why she was not tested for BRCA and appropriately counseled by her gynecologist prior to the cancer diagnosis. Litigation was initiated. While the case did not go forward regarding litigation, it is indeed a case in point. (Please note that this is a hypothetical case. It is based on a composite of several cases.)
 

Medical considerations

Breast cancer is the most common type of cancer affecting women in the Western world.¹ Advances in clinical testing for gene mutations have escalated and allowed for identification of patients at increased risk for breast and ovarian cancer. Along with these advances come professional liability risk. After looking at the medical considerations for BRCA1 and 2 testing, we will consider a number of important legal issues. In the view of some commentators, the failure to diagnose genetic mutations in patients predisposed to cancer is “poised to become the next wave of medical professional liability lawsuits.”²

BRCA1 and BRCA2 genes provide tumor suppressor proteins, and assessment for mutations is recommended for individuals at high risk for breast and/or ovarian cancer; mutations in BRCA genes cause DNA damage, which increases the chance of developing cancer. The other way to look at it is, BRCA1 and 2 are tumor suppressor genes that are integrally involved with DNA damage control. Once there is a mutation, it adversely affects the beneficial effects of the gene. Mutations in these genes account for 5% to 10% of all hereditary breast cancers.³ Of note, men with BRCA2 are at increased risk for prostate cancer.

A patient who presents to her gynecologist stating that there is a family history of breast cancer, without knowledge of genetic components, presents a challenge (and a medicolegal risk) for the provider to assess. Prediction models have been used to determine specific patient risk for carrying a genetic mutation with resultant breast cancer development.⁴ Risk prediction models do not appear to be a good answer to predicting who is more likely to develop breast or ovarian cancer, however. A Mayo model may assist (FIGURE).⁵ Clinicians should also be aware of other models of risk assessment, including the Gail Model (TABLE 1).⁶

Continue to: Guidelines for genetic testing...

Guidelines for genetic testing

The American College of Obstetricians and Gynecologists states that patient medical history and family history are paramount in obtaining information regarding risk for breast and ovarian cancer. First- and second-degree relatives are allocated to this category. Information regarding age of diagnosis, maternal and paternal lineage, and ethnic background can imply a need for genetic testing (TABLE 2).^7,8 A number of genetics national organizations have participated in recommendations and include the American College of Medical Genetics and Genomics, the National Society for Genetic Counselors, and the Society of Gynecologic Oncology.⁷

The question always surfaces, could the clinical outcome of the cancer when diagnosed have been changed if screening were undertaken, with earlier diagnosis, or prevented with prophylactic mastectomy, and changed the end result. In addition, it is well known that breast augmentation mammoplasty alters the ability to accurately evaluate mammograms. Patients considering this type of plastic surgery, ideally, should be counselled accordingly.⁹

Bottom line, we as clinicians must be cognizant of both ACOG and United States Preventive Services Task Force (USPSTF) recommendations regarding screening and gene testing for women considered high risk for breast cancer based on family history.⁷

Legal considerations

The case presented demonstrates that the discovery of the BRCA1 and BRCA2 genes, and reliable tests for determining the existence of the genes, brought with them legal issues as well as medical advantages. We look at professional liability (malpractice) questions this technology raises, and then consider the outcome of the hypothetical case. (BRCA is used here to apply broadly—not only to BRCA1 and 2 but also to PALB2, CHEK2, and similar genetic abnormalities.)

To date, the most visible BRCA legal issues covered in cases and law reviews have focused more on patent law than malpractice. The most important of these was a decision of the US Supreme Court in Association for Molecular Pathology v Myriad Genetics.¹⁰ The US Patent Office was granting patents to companies finding useful, naturally occurring segments of human DNA, and had granted Myriad several patents on BRCA1 and BRCA2 genes. This patent policy had the potential to seriously interfere with broad scientific use of these genes.¹¹ Fortunately, the Supreme Court stepped in and unanimously invalidated such patents. It held that a “naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.” The Court noted, “Finding the location of the BRCA1 and BRCA2 genes does not render the genes patent eligible ‘new . . . composition[s] of matter.’”⁸ The Court did allow the patenting of tests for specific gene structures, and artificial changes in naturally occurring genes.

Malpractice and BRCA

While the BRCA patent wars have lingered, the potential for a significant increase in BRCA-related malpractice cases is of increasing concern. Like most malpractice liability, these new claims are based on very old principles of negligence.¹² To prevail, the plaintiff (ordinarily, an injured patient) must demonstrate 4 things:

• A duty. That is, the physician owed a duty to the injured party. Usually (but not always) that requires a professional relationship between the physician and the person injured.
• A breach of that duty. Malpractice liability is based on the fact that the physician did something that a reasonably careful physician (generally, of the same specialty) would not have done, or that the physician failed to do something that a reasonable physician would have done. This usually means that the profession itself sees what the physician did (or did not do) as medically inappropriate. In medical malpractice cases, that is ordinarily measured by what the usual or common practice is among prudent physicians. In rare circumstances, courts have found the standard practice of a profession to be negligent. Where, for example, it was custom for a professional not to give an eye pressure test to anyone under age 40, a court found that common standard to be inappropriate.¹³ In the words of Judge Learned Hand (speaking about a different case), “a whole calling may have unduly lagged in the adoption of new and available devices. It never may set its own tests.”¹⁴ Underlying negligence is a cost-benefit analysis (discussed below).
• Damages. There must have been some damage that courts recognize, usually loss of money or opportunity to work, the cost of care, pain and suffering, or loss of enjoyment/quality of life. In malpractice, many states now recognize the “loss of chance” or the “loss of a chance.” That means, if a “physician negligently fails to diagnose a curable disease, and the patient is harmed by the disease, the physician should be liable for causing the ‘loss of a chance of a cure.’”¹⁵ (Delay in diagnosis is the most common reason for claims in breast cancer care.)¹⁶
• Causation. The breach of duty (negligence) must have caused the damages. The causation must have been reasonably close. If a driver drives through a stop sign, or a physician misreads a test, and someone is injured but there is no connection between the negligence and the injury, there is not tort liability.

The 4 elements of malpractice just described are raised in some way in the possible liability associated with BRCA testing. We next look at the ways in which liability may arise from that testing (or lack of it).

Underlying much of the following discussion is the “cost-benefit” consideration noted above. This concept is that the total cost (financial and health) of testing should be compared with the value of the benefits of testing, taking into account the probabilities that the testing will result in better health outcomes. BRCA testing, for example, is essentially cost-free in terms of physical risk. Its financial cost, while not trivial, is not great, and it is commonly covered by health insurance.¹⁷ In terms of benefits, the testing has the potential for providing critical information in making treatment decisions for a meaningful percentage of patients and their families. There are many ways of analyzing the liability risks of genetic malpractice,^7,18 and the following is intended to discuss some of the greatest risks related to BRCA testing.

Continue to: Areas of liability...

The failure to recommend a test. The circumstances in which BRCA testing should be undertaken are set out by professional organizations (noted above). These recommendations are not static, however. They change from time to time. Given the potential harm caused by the failure to test in relevant circumstances, malpractice liability is certainly a possibility when the failure to recommend a test to a patient results in a cancer that might have been prevented had the genetic problem been identified in a timely manner. The circumstances in which testing should be considered continue to change, placing an obligation on clinicians to stay well informed of changing genetic understandings. Another risk is that one specialist may assume that it is the job of another specialist to order the test. Whatever the cause of the failure to test, or unnecessary delay in testing, it appears to be the primary basis for BRCA liability.

The failure to properly interpret a test. Any test that is misinterpreted may lead to harm for the patient. A false negative, of course, may mean that preventive treatment that could have been undertaken will be foregone, as a “loss of a chance.” On the other hand, a false positive can lead to radical, unnecessary surgery or treatment. If a misinterpretation occurred because of carelessness by the testing organization, or confusion by a practitioner, there is a likelihood of negligence.¹⁹

A different form of “misinterpretation” could be reasonable—and not negligent. Advances in scientific-medical understanding may result in the outcome of tests being reconsidered and changed. That has been the case with genetic testing and breast cancer. The availability of multiple breast cancer SNPs (single nucleotide polymorphisms), and combining this information with other risk factors for example, results in a polygenic risk score that may be at odds with the level of risk from earlier testing.^20,21 This naturally leads to the question of when later, updated testing should be recommended to look for a better current interpretation.^22,23

The failure to act on BRCA test results. Testing is of no value, of course, if the results are not used properly. Test results or analyses that are not sent to the proper physicians, or are somehow ignored when properly directed, is a “never” event—it should never happen. It almost always would be considered negligence, and if the patient were injured, could lead to liability. Amazingly, one study found that, in genetic testing liability cases, nearly 20% of the claims arose from failure to return test results to patients.²⁴ In addition, when a patient is found to be BRCA-positive, there is an obligation to discuss the options for dealing with the increased risk associated with the gene mutation(s), as well as to recommend the prudent course of action or to refer the patient to someone who will have that discussion.

Informed consent to the patient. BRCA testing requires informed consent. The physical risks of the testing process are minimal, of course, but it carries a number of other emotional and family risks. The informed consent process is an invitation to an honest discussion between clinicians and patients. It should be an opportunity to discuss what the testing is, and is not, and what the test may mean for treatment. It may also be an opportunity to discuss the implications for other members of the patient’s family (noted below).

One element of informed consent is a discussion of the consequences of failure to consent, or to undertake one of the alternatives. In the case of BRCA testing, this is especially important in cases in which a patient expresses a hesitancy to be tested with an “I’d rather not know philosophy.” Although clinicians should not practice law, some patient concerns about discrimination may be addressed by the protection that the federal Genetic Information Nondiscrimination Act (GINA) and other laws provide (which prohibit insurance and employment discrimination based on genetic information). A good source of information about GINA and related nondiscrimination laws is provided by the National Human Genome Research Institute.²⁵ In addition, the National Institutes of Health has a website that may be helpful to many patients²⁶ (and a much more complex site for health professionals).²⁷ At the same time, courts have resisted plaintiffs/patients who have tried to use informed consent as a way of suing for failure to offer genetic testing.^28,29

The failure to refer. In some cases, a patient should be formally referred for genetics consultation. The considerations here are similar to other circumstances in modern, fast developing medical practice that require special sensitivity to those occasions in which a patient will benefit from additional expertise. It is a principle that the AMA Council on Ethical and Judicial Affairs has expressed this way: “In the absence of adequate expertise in pretest and posttest counseling, a physician should refer the patient to an appropriate specialist.”³⁰ The failure to refer, when that deviates from acceptable practice, may result in liability.

Informing others. BRCA testing is an area of medicine in which results may be of great significance not only to the patient but also to the patient’s family.³¹ Physicians should counsel patients on the importance of informing relatives about relevant results and “should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.”³⁰ The question may arise, however, of whether in some circumstances physicians should go a step further in ensuring relatives receive important information regarding their loved one’s health.³² The law has been reluctant to impose liability to “third parties” (someone not a patient). Duties usually arise through the physician-patient relationship. There are exceptions. Perhaps the best known has been the obligation of mental health professionals to take action to protect third parties from patients who have made believable threats against identifiable victims.³³ There are indications that some courts could find, in extreme circumstances, a “duty to warn” nonpatients in some instances where it is essential to inform third parties that they should receive a specific form of genetic testing.^34,35 Such a duty would, of course, have to protect the privacy rights of the patient to the maximum extent possible. A general duty of this type has not been established widely, but may be part of the future.

Continue to: Was there liability in our example case?...

Was there liability in our example case?

The hypothetical case provided above suggests that there could be liability. Routine medical history by the primary care physician would have produced the fact that the patient’s mother, sister, and maternal grandmother had breast cancer. That would clearly have put her in a category of those who should have received genetic testing. Yet, she was not tested until after her cancer was found. From the limited facts we have, it appears that this timeline of events would have been outside accepted practice—and negligent. The case was not pursued by the patient, however, and this may represent the current state of liability for BRCA issues.

The extent of liability seems to be significant

Our discussion of liability suggests that there is significant potential for BRCA testing negligence within practice, and that the damages in these cases could be substantial. Yet the predicted “tsunami” of malpractice lawsuits related to genetic testing has not appeared.^36,37 One study of cases in the United States (through 2016) found a “slowly rising tide” of liability cases instead of a tsunami,²⁴ as the number of claims made was low. On the other hand, the payments where damages were awarded were an order of magnitude larger than other malpractice cases—a mean of $5.3 million and median of $2 million. This is compared with mean values in the range of $275,000 to $600,000 in other areas of malpractice.

The majority of the genetic malpractice cases involve prenatal and newborn testing, and diagnosis/susceptibility/pharmacogenomic accounting for about 25% of cases. In terms of type of errors claimed, approximately 50% were diagnostic-interpretation errors, 30% failure to offer testing, nearly 20% failure to return test results to the patients, and a few remaining cases of failure to properly treat in light of genetic testing.²⁴

Despite a few very large payments, however, the fact remains that there is a surprisingly low number of genetics malpractice cases. Gary Marchant and colleagues suggest that several reasons may account for this:

• the clinical implementation of genetic science has been slower than expected
• the lack of expertise of many physicians in genetic science
• expert witnesses have sometimes been hard to find
• the lack of understanding by plaintiffs’ attorneys of genetic malpractice
• potential plaintiffs’ lack of understanding of the nature of genetic testing and the harms resulting from genetic negligence.^17,24,37

The tide is slowly coming in

By all appearances, there is every reason to think that genetic malpractice will be increasing, and that the recent past of much higher damages per claim paid in the genetics area will be part of that tide. The National Human Genome Research LawSeq project has suggested a number of useful ways of dealing with the liability issues.¹⁸ In addition to the BRCA issues that we have considered in this article for ObGyns, there are other critical issues of prenatal and newborn genetic testing.³⁸ But those are topics for another day. ●

CASE Young woman with family history of breast cancer detects lump

Two weeks after noting a lump on her breast when her cat happened to jump on her in that spot, a 28-year-old woman (G0) went to her primary care provider. She was referred to her gynecologist; breast imaging, ultrasonography, and mammography were obtained, with microcalcifications noted. A fine needle aspiration diagnosed intraductal malignancy. The surgical breast tissue specimen was estrogen receptor (ER)- and progestogen receptor (PR)-positive and HER2-negative. Other tumor markers were obtained, including carcinoembryonic antigen, and tissue polypeptide specific antigen, p53, cathepsin D, cyclin E, and nestin, but results were not available.

With regard to family history, the woman’s mother and maternal grandmother had a history of breast cancer. The patient and her family underwent gene testing. The patient was found to be BRCA1- and BRCA2-positive; her mother was BRCA1-positive, an older sister was BRCA2-positive, and her grandmother was not tested.

The question arose in light of her family history as to why she was not tested for BRCA and appropriately counseled by her gynecologist prior to the cancer diagnosis. Litigation was initiated. While the case did not go forward regarding litigation, it is indeed a case in point. (Please note that this is a hypothetical case. It is based on a composite of several cases.)
 

Medical considerations

Breast cancer is the most common type of cancer affecting women in the Western world.¹ Advances in clinical testing for gene mutations have escalated and allowed for identification of patients at increased risk for breast and ovarian cancer. Along with these advances come professional liability risk. After looking at the medical considerations for BRCA1 and 2 testing, we will consider a number of important legal issues. In the view of some commentators, the failure to diagnose genetic mutations in patients predisposed to cancer is “poised to become the next wave of medical professional liability lawsuits.”²

BRCA1 and BRCA2 genes provide tumor suppressor proteins, and assessment for mutations is recommended for individuals at high risk for breast and/or ovarian cancer; mutations in BRCA genes cause DNA damage, which increases the chance of developing cancer. The other way to look at it is, BRCA1 and 2 are tumor suppressor genes that are integrally involved with DNA damage control. Once there is a mutation, it adversely affects the beneficial effects of the gene. Mutations in these genes account for 5% to 10% of all hereditary breast cancers.³ Of note, men with BRCA2 are at increased risk for prostate cancer.

A patient who presents to her gynecologist stating that there is a family history of breast cancer, without knowledge of genetic components, presents a challenge (and a medicolegal risk) for the provider to assess. Prediction models have been used to determine specific patient risk for carrying a genetic mutation with resultant breast cancer development.⁴ Risk prediction models do not appear to be a good answer to predicting who is more likely to develop breast or ovarian cancer, however. A Mayo model may assist (FIGURE).⁵ Clinicians should also be aware of other models of risk assessment, including the Gail Model (TABLE 1).⁶

Continue to: Guidelines for genetic testing...

Guidelines for genetic testing

The American College of Obstetricians and Gynecologists states that patient medical history and family history are paramount in obtaining information regarding risk for breast and ovarian cancer. First- and second-degree relatives are allocated to this category. Information regarding age of diagnosis, maternal and paternal lineage, and ethnic background can imply a need for genetic testing (TABLE 2).^7,8 A number of genetics national organizations have participated in recommendations and include the American College of Medical Genetics and Genomics, the National Society for Genetic Counselors, and the Society of Gynecologic Oncology.⁷

The question always surfaces, could the clinical outcome of the cancer when diagnosed have been changed if screening were undertaken, with earlier diagnosis, or prevented with prophylactic mastectomy, and changed the end result. In addition, it is well known that breast augmentation mammoplasty alters the ability to accurately evaluate mammograms. Patients considering this type of plastic surgery, ideally, should be counselled accordingly.⁹

Bottom line, we as clinicians must be cognizant of both ACOG and United States Preventive Services Task Force (USPSTF) recommendations regarding screening and gene testing for women considered high risk for breast cancer based on family history.⁷

Legal considerations

The case presented demonstrates that the discovery of the BRCA1 and BRCA2 genes, and reliable tests for determining the existence of the genes, brought with them legal issues as well as medical advantages. We look at professional liability (malpractice) questions this technology raises, and then consider the outcome of the hypothetical case. (BRCA is used here to apply broadly—not only to BRCA1 and 2 but also to PALB2, CHEK2, and similar genetic abnormalities.)

To date, the most visible BRCA legal issues covered in cases and law reviews have focused more on patent law than malpractice. The most important of these was a decision of the US Supreme Court in Association for Molecular Pathology v Myriad Genetics.¹⁰ The US Patent Office was granting patents to companies finding useful, naturally occurring segments of human DNA, and had granted Myriad several patents on BRCA1 and BRCA2 genes. This patent policy had the potential to seriously interfere with broad scientific use of these genes.¹¹ Fortunately, the Supreme Court stepped in and unanimously invalidated such patents. It held that a “naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated.” The Court noted, “Finding the location of the BRCA1 and BRCA2 genes does not render the genes patent eligible ‘new . . . composition[s] of matter.’”⁸ The Court did allow the patenting of tests for specific gene structures, and artificial changes in naturally occurring genes.

Malpractice and BRCA

While the BRCA patent wars have lingered, the potential for a significant increase in BRCA-related malpractice cases is of increasing concern. Like most malpractice liability, these new claims are based on very old principles of negligence.¹² To prevail, the plaintiff (ordinarily, an injured patient) must demonstrate 4 things:

• A duty. That is, the physician owed a duty to the injured party. Usually (but not always) that requires a professional relationship between the physician and the person injured.
• A breach of that duty. Malpractice liability is based on the fact that the physician did something that a reasonably careful physician (generally, of the same specialty) would not have done, or that the physician failed to do something that a reasonable physician would have done. This usually means that the profession itself sees what the physician did (or did not do) as medically inappropriate. In medical malpractice cases, that is ordinarily measured by what the usual or common practice is among prudent physicians. In rare circumstances, courts have found the standard practice of a profession to be negligent. Where, for example, it was custom for a professional not to give an eye pressure test to anyone under age 40, a court found that common standard to be inappropriate.¹³ In the words of Judge Learned Hand (speaking about a different case), “a whole calling may have unduly lagged in the adoption of new and available devices. It never may set its own tests.”¹⁴ Underlying negligence is a cost-benefit analysis (discussed below).
• Damages. There must have been some damage that courts recognize, usually loss of money or opportunity to work, the cost of care, pain and suffering, or loss of enjoyment/quality of life. In malpractice, many states now recognize the “loss of chance” or the “loss of a chance.” That means, if a “physician negligently fails to diagnose a curable disease, and the patient is harmed by the disease, the physician should be liable for causing the ‘loss of a chance of a cure.’”¹⁵ (Delay in diagnosis is the most common reason for claims in breast cancer care.)¹⁶
• Causation. The breach of duty (negligence) must have caused the damages. The causation must have been reasonably close. If a driver drives through a stop sign, or a physician misreads a test, and someone is injured but there is no connection between the negligence and the injury, there is not tort liability.

The 4 elements of malpractice just described are raised in some way in the possible liability associated with BRCA testing. We next look at the ways in which liability may arise from that testing (or lack of it).

Underlying much of the following discussion is the “cost-benefit” consideration noted above. This concept is that the total cost (financial and health) of testing should be compared with the value of the benefits of testing, taking into account the probabilities that the testing will result in better health outcomes. BRCA testing, for example, is essentially cost-free in terms of physical risk. Its financial cost, while not trivial, is not great, and it is commonly covered by health insurance.¹⁷ In terms of benefits, the testing has the potential for providing critical information in making treatment decisions for a meaningful percentage of patients and their families. There are many ways of analyzing the liability risks of genetic malpractice,^7,18 and the following is intended to discuss some of the greatest risks related to BRCA testing.

Continue to: Areas of liability...

The failure to recommend a test. The circumstances in which BRCA testing should be undertaken are set out by professional organizations (noted above). These recommendations are not static, however. They change from time to time. Given the potential harm caused by the failure to test in relevant circumstances, malpractice liability is certainly a possibility when the failure to recommend a test to a patient results in a cancer that might have been prevented had the genetic problem been identified in a timely manner. The circumstances in which testing should be considered continue to change, placing an obligation on clinicians to stay well informed of changing genetic understandings. Another risk is that one specialist may assume that it is the job of another specialist to order the test. Whatever the cause of the failure to test, or unnecessary delay in testing, it appears to be the primary basis for BRCA liability.

The failure to properly interpret a test. Any test that is misinterpreted may lead to harm for the patient. A false negative, of course, may mean that preventive treatment that could have been undertaken will be foregone, as a “loss of a chance.” On the other hand, a false positive can lead to radical, unnecessary surgery or treatment. If a misinterpretation occurred because of carelessness by the testing organization, or confusion by a practitioner, there is a likelihood of negligence.¹⁹

A different form of “misinterpretation” could be reasonable—and not negligent. Advances in scientific-medical understanding may result in the outcome of tests being reconsidered and changed. That has been the case with genetic testing and breast cancer. The availability of multiple breast cancer SNPs (single nucleotide polymorphisms), and combining this information with other risk factors for example, results in a polygenic risk score that may be at odds with the level of risk from earlier testing.^20,21 This naturally leads to the question of when later, updated testing should be recommended to look for a better current interpretation.^22,23

The failure to act on BRCA test results. Testing is of no value, of course, if the results are not used properly. Test results or analyses that are not sent to the proper physicians, or are somehow ignored when properly directed, is a “never” event—it should never happen. It almost always would be considered negligence, and if the patient were injured, could lead to liability. Amazingly, one study found that, in genetic testing liability cases, nearly 20% of the claims arose from failure to return test results to patients.²⁴ In addition, when a patient is found to be BRCA-positive, there is an obligation to discuss the options for dealing with the increased risk associated with the gene mutation(s), as well as to recommend the prudent course of action or to refer the patient to someone who will have that discussion.

Informed consent to the patient. BRCA testing requires informed consent. The physical risks of the testing process are minimal, of course, but it carries a number of other emotional and family risks. The informed consent process is an invitation to an honest discussion between clinicians and patients. It should be an opportunity to discuss what the testing is, and is not, and what the test may mean for treatment. It may also be an opportunity to discuss the implications for other members of the patient’s family (noted below).

One element of informed consent is a discussion of the consequences of failure to consent, or to undertake one of the alternatives. In the case of BRCA testing, this is especially important in cases in which a patient expresses a hesitancy to be tested with an “I’d rather not know philosophy.” Although clinicians should not practice law, some patient concerns about discrimination may be addressed by the protection that the federal Genetic Information Nondiscrimination Act (GINA) and other laws provide (which prohibit insurance and employment discrimination based on genetic information). A good source of information about GINA and related nondiscrimination laws is provided by the National Human Genome Research Institute.²⁵ In addition, the National Institutes of Health has a website that may be helpful to many patients²⁶ (and a much more complex site for health professionals).²⁷ At the same time, courts have resisted plaintiffs/patients who have tried to use informed consent as a way of suing for failure to offer genetic testing.^28,29

The failure to refer. In some cases, a patient should be formally referred for genetics consultation. The considerations here are similar to other circumstances in modern, fast developing medical practice that require special sensitivity to those occasions in which a patient will benefit from additional expertise. It is a principle that the AMA Council on Ethical and Judicial Affairs has expressed this way: “In the absence of adequate expertise in pretest and posttest counseling, a physician should refer the patient to an appropriate specialist.”³⁰ The failure to refer, when that deviates from acceptable practice, may result in liability.

Informing others. BRCA testing is an area of medicine in which results may be of great significance not only to the patient but also to the patient’s family.³¹ Physicians should counsel patients on the importance of informing relatives about relevant results and “should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.”³⁰ The question may arise, however, of whether in some circumstances physicians should go a step further in ensuring relatives receive important information regarding their loved one’s health.³² The law has been reluctant to impose liability to “third parties” (someone not a patient). Duties usually arise through the physician-patient relationship. There are exceptions. Perhaps the best known has been the obligation of mental health professionals to take action to protect third parties from patients who have made believable threats against identifiable victims.³³ There are indications that some courts could find, in extreme circumstances, a “duty to warn” nonpatients in some instances where it is essential to inform third parties that they should receive a specific form of genetic testing.^34,35 Such a duty would, of course, have to protect the privacy rights of the patient to the maximum extent possible. A general duty of this type has not been established widely, but may be part of the future.

Continue to: Was there liability in our example case?...

Was there liability in our example case?

The hypothetical case provided above suggests that there could be liability. Routine medical history by the primary care physician would have produced the fact that the patient’s mother, sister, and maternal grandmother had breast cancer. That would clearly have put her in a category of those who should have received genetic testing. Yet, she was not tested until after her cancer was found. From the limited facts we have, it appears that this timeline of events would have been outside accepted practice—and negligent. The case was not pursued by the patient, however, and this may represent the current state of liability for BRCA issues.

The extent of liability seems to be significant

Our discussion of liability suggests that there is significant potential for BRCA testing negligence within practice, and that the damages in these cases could be substantial. Yet the predicted “tsunami” of malpractice lawsuits related to genetic testing has not appeared.^36,37 One study of cases in the United States (through 2016) found a “slowly rising tide” of liability cases instead of a tsunami,²⁴ as the number of claims made was low. On the other hand, the payments where damages were awarded were an order of magnitude larger than other malpractice cases—a mean of $5.3 million and median of $2 million. This is compared with mean values in the range of $275,000 to $600,000 in other areas of malpractice.

The majority of the genetic malpractice cases involve prenatal and newborn testing, and diagnosis/susceptibility/pharmacogenomic accounting for about 25% of cases. In terms of type of errors claimed, approximately 50% were diagnostic-interpretation errors, 30% failure to offer testing, nearly 20% failure to return test results to the patients, and a few remaining cases of failure to properly treat in light of genetic testing.²⁴

Despite a few very large payments, however, the fact remains that there is a surprisingly low number of genetics malpractice cases. Gary Marchant and colleagues suggest that several reasons may account for this:

• the clinical implementation of genetic science has been slower than expected
• the lack of expertise of many physicians in genetic science
• expert witnesses have sometimes been hard to find
• the lack of understanding by plaintiffs’ attorneys of genetic malpractice
• potential plaintiffs’ lack of understanding of the nature of genetic testing and the harms resulting from genetic negligence.^17,24,37

The tide is slowly coming in

By all appearances, there is every reason to think that genetic malpractice will be increasing, and that the recent past of much higher damages per claim paid in the genetics area will be part of that tide. The National Human Genome Research LawSeq project has suggested a number of useful ways of dealing with the liability issues.¹⁸ In addition to the BRCA issues that we have considered in this article for ObGyns, there are other critical issues of prenatal and newborn genetic testing.³⁸ But those are topics for another day. ●

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●

Gynecologic malignancies continue to be a major cause of cancer-related mortality in women. In 2020, a number of developments changed practice in gynecologic oncology. In this Update, we highlight 3 important articles. The first showed that human papillomavirus (HPV) vaccination reduced the rate of cervical cancer. The next evaluated a novel targeted therapeutic approach using the combination of pembrolizumab and lenvatinib in women with recurrent endometrial carcinoma that progressed after prior systemic therapy. Finally, the third article showed that talcum powder was not associated with an increased risk of ovarian cancer. We provide here a brief overview of the major findings of these studies and how these results are influencing practice.

Evidence establishes that HPV vaccination cuts risk of invasive cervical cancer

Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med. 2020;383:1340-1348.

HPV infection is associated with 99% of cervical cancers, and approximately 65% to 75% of cases involve HPV 16 or 18.^1,2 The quadrivalent HPV (6, 11, 16, 18) vaccine was approved by the US Food and Drug Administration in 2006 for the prevention of cervical intraepithelial lesions and genital warts associated with HPV.^3-5 Previous studies of the HPV vaccine showed it to be effective in preventing HPV infection, genital warts, and high-grade precancerous cervical lesions, such as cervical intraepithelial neoplasia grade 2 (CIN2) and grade 3 (CIN3).^6-8 While the vaccine offers a number of advantages, the long-term goal of the vaccine—to reduce the incidence of invasive cervical cancer—was not shown until recently.

Large study followed HPV vaccinated and unvaccinated women

Lei and colleagues conducted a registry based cohort study from 2006 through 2017 of women aged 10 to 30 years who were living in Sweden.⁹ They followed the women from their 10th birthday until they were diagnosed with cervical cancer, died, emigrated from Sweden, were lost to follow-up, or turned 31 years of age. In the study, the unique personal identity numbers assigned to all Swedish residents were linked to a number of large national administrative databases. Beginning in 2007 in Sweden, the quadrivalent vaccine was subsidized for use in girls aged 13 to 17, and a subsequent catch-up period that started in 2012 incorporated women who had not been vaccinated.

Continue to: Cervical cancer rates were lowest in women vaccinated before age 17...

Cervical cancer rates were lowest in women vaccinated before age 17

A total of 1,672,983 women were included in the study; 527,871 received at least one dose of the HPV vaccine. During the study period, cervical cancer was diagnosed in 19 women who had received the quadrivalent HPV vaccine and in 538 women who had not received the vaccine. Women who initiated vaccination before age 17 had the lowest rates of cervical cancer (4 cases per 100,000 persons), followed by women vaccinated after age 17 (54 cases per 100,000 persons) and then those who were not vaccinated (94 cases per 100,000 persons).

After adjusting for confounders, the incidence rate ratio (RR) of cervical cancer was significantly lower among vaccinated women compared with unvaccinated women (RR, 0.37; 95% confidence interval [CI], 0.21– 0.57) (FIGURE 1).⁹ In addition, women who were vaccinated before age 17 demonstrated the greatest benefit. For those vaccinated before age 17 versus those who were unvaccinated, the RR was 0.12 (95% CI, 0.00–0.34). For women vaccinated between age 17 and 30 versus unvaccinated women, the RR was 0.47 (95% CI, 0.27–0.75).

Promising option for patients with advanced endometrial cancer: Lenvatinib plus pembrolizumab

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:2981-2992.

Advanced stage endometrial cancer is associated with a 17% 5-year survival rate.¹⁰ Paclitaxel with carboplatin is the standard first-line treatment for advanced, recurrent, and metastatic endometrial cancer; for women who do not respond to this regimen, effective treatment options are limited.^11,12

The immunotherapy approach

Immunotherapy is a more recently developed treatment, an approach in which the immune system is activated to target cancer cells. Pembrolizumab is a commonly used agent for many solid tumors.¹³ This drug binds to the programmed cell death receptor 1 (PD-1) or PD-ligand 1 (PD-L1), a component of the immune checkpoint, which then allows the immune system to target and destroy cancer cells.¹⁴

Prembrolizumab is FDA approved for use in the treatment of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors that have progressed after prior therapy and for which there are no satisfactory alternative treatment options.¹⁵ Endometrial cancers frequently display microsatellite instability and mismatch repair defects.¹⁶

Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors 1, 2, 3, and 4; and platelet derived growth factor receptor alpha, RET, and KIT.^17-19 In a phase 2 study of lenvatinib monotherapy for advanced previously treated endometrial cancer, the response rate was 14.3%.²⁰

While some preclinical studies have examined the combination of immune checkpoint inhibitors with lenvatinib,^21-23 a recent study is the first to evaluate this combination in patients with advanced tumors.²⁴

Continue to: Prembrolizumab-lenvatinib combination therapy...

Prembrolizumab-lenvatinib combination therapy

Makker and colleagues conducted an ongoing multinational, open-label, phase 1B/2 study of lenvatinib 20 mg daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks in patients with select solid tumors.²⁴ Women with previously treated endometrial carcinoma (N = 125) were included. Of the study participants, 49% were PD-L1 positive and 10% were MSI-H/dMMR. The primary end point was objective response rate (ORR) at 24 weeks, which was 38.0% (95% CI, 28.8%–47.8%).

The median duration of response was 21.2 months (95% CI, 7.6 months to not estimable). The ORR was similar in patients with PD-L1 expressing tumors (35.8%; 95% CI, 23.1%–50.2%), who are more likely to respond to immunotherapy, compared with those without PD-L1 expression (39.5%; 95% CI, 25.0%–55.6%). For patients with MSI-H/dMMR, there was a higher ORR (63.6%; 95% CI, 30.8%–89.1%, versus 36.2%; 95% CI, 26.5%–46.7%).

Median progression-free survival was 7.4 months (95% CI, 5.3–8.7 months) and median overall survival was 16.7 months (15 months to not estimable). Moderate to severe treatment-related adverse events occurred in 83 patients (66.9%), and 22 patients (17.7%) discontinued 1 or both study drugs because of adverse effects. Two deaths were judged to be treatment related.

What is the risk of ovarian cancer in women who use powder in the genital area?

O’Brien KM, Tworoger SS, Harris HR, et al. Association of powder use in the genital area with risk of ovarian cancer. JAMA. 2020;323:49-59.

Women apply talcum powder to their genital area to keep skin dry and to prevent rashes. Powder can be applied by direct application, sanitary napkins, diaphragms, or tampons. Most powder products contain the mineral talc. Because it often is found in nature with asbestos, a known carcinogen, talc’s carcinogenic effects have been investigated.^26,27

Talc also might ascend through the genital tract and irritate the epithelial lining of the fallopian tubes or ovaries, possibly triggering an inflammatory response that may promote carcinogenesis.^28,29 Case-control studies have reported a possible association between genital powder use and ovarian cancer.^30,31 Since these studies, talc-related lawsuits and media coverage have increased.^32,33

Large prospective cohorts provide data for analysis

In a pooled analysis of 4 large US-based observational cohorts between 1976 and 2017, O’Brien and colleagues noted that 38% of the 252,745 women included in the study self-reported the use of powder in the genital area.³⁴ With a median of 11.2 years of follow-up, 2,168 women developed ovarian cancer (58 cases/100,000 person-years). Among women who reported using genital powder, the incidence of ovarian cancer was 61 cases/100,000 person-years, while for women who reported never using genital powder, the incidence was 55 cases/100,000 person-years. This corresponded to an estimated hazard ratio (HR) of 1.08 (95% CI, 0.99–1.17).

Frequent powder use, long-term use, and never use. Similar findings were seen for those with frequent use versus never use (HR, 1.09; 95% CI, 0.97–1.23) and long-term use versus never use (HR, 1.01; 95% CI, 0.82– 1.25). When restricting the group to women with a patent reproductive tract at baseline, the HR was 1.13 (95% CI, 1.01–1.26), but the P value for interaction comparing women with versus women without a patent reproductive tract was 0.15 (FIGURE 2).³⁴

Bottom line. In contrast to a prior meta-analysis, in this study there was no statistically significant association between the self-reported use of powder in the genital area and the incidence of ovarian cancer. ●