Federal Practitioner

It is the neglect of timely repair that makes rebuilding necessary.
Richard Whately, economist and theologian (1787-1863)

US Congressional inquiry and media attention are so frequently directed at the trials and tribulations of the US Department of Veterans Affairs (VA) that we forget the US Department of Defense (DoD) medical system also shares the federal practitioner space. The focus of the government and press recently has shifted to examine the weaknesses and woes of military medicine. This editorial reviews what that examination discovered about the decline of the DoD house of medicine, why it is in disrepair, proposals for its rebuilding, and reflects on what this trajectory can tell us about maintaining the structure of federal practice.

My father never tired of telling me that he and his medical colleagues returned from the Second World War with knowledge and skills gained in combat theaters that, in many respects, surpassed those of the civilian sector. Though he was biased as a career military physician and combat veteran, there is strong evidence backing the assertion that from World War I to Operations Enduring Freedom and Iraqi Freedom, American military medicine has been the glory of the world.¹

A November 2023 report from the DoD Office of the Inspector General (OIG) warned that military medicine was in trouble. The report’s emphasis on access and staffing problems that endanger the availability and quality of health care services will likely strike a chord with VA clinicians. The document is based on data from OIG reports, hotline calls, and audits from the last several years; however, the OIG acknowledges that it did not conduct on-the-ground investigations to confirm the findings.²

When we hear the term military medicine, many immediately think of active duty service members. However, the patient population of DoD is far larger and more diverse. The Military Health System (MHS) provides care to > 9.5 million beneficiaries, including dependents and retirees, veterans, civilian DoD employees, and even contractors. Those who most heavily rely on the MHS are individuals in uniform and their families are experiencing the greatest difficulty with accessing care.³ This includes crucial mental health treatment at a time when rates of military suicide continue to climb.⁴

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

As with both the VA and civilian health care spheres, rural areas are the most impacted. Resource shortfalls adversely affect all aspects of care, especially the highly paid specialties like gastroenterology and urology, as well as primary care practitioners essential to ensure the health of military families. The deficits are widespread—all branches report similar obstacles to providing responsive, appropriate care. As if this was not enough to complete the mirror image of the VA’s struggles, there is a rising tide of complaints about the military’s electronic health record system.⁵ How did the preeminent MHS so rapidly decay? Experts in and out of uniform offer several explanations.

As with most forms of managed care, the need to cut costs drove the Pentagon to send military members and dependents to civilian health care systems to have their medical needs addressed. However, this outsourcing strategy was based on a false assumption that the community had enough capacity to deliver services to the many beneficiaries needing them. Nearly every sector of contemporary American medicine is experiencing a drastic shortage of HCPs. Though the resource allocation problems began before the pandemic, COVID-19 only exacerbated and accelerated them.⁶

This downsizing of military hospitals and clinics led to another predictable and seemingly unheeded consequence. A decrease in complex cases (particularly surgical cases) led to a reduction in the skills of military HCPs and a further flight of highly trained specialists who require a reasonable volume of complicated cases to retain and sharpen their expertise. The losses of those experienced clinicians further drain the pool of specialists the military can muster to sustain the readiness of troops for war and the health of their families in peace.⁷

The OIG recommended that the Defense Health Agency address MHS staffing and access deficiencies noted in its report, including identifying poorly performing TRICARE specialty networks and requiring them to meet their access obligation.² As is customary, the OIG asked for DoD comment. It is unclear whether the DoD responded to that formal request; however, it is more certain it heard the message the OIG and beneficiaries conveyed. In December 2023, the Deputy Secretary of the DoD published a memorandum ordering the stabilization of the MHS. It instructs the MHS to address each of the 3 problem areas outlined in this article: (1) to reclaim patients and beneficiaries who had been outsourced or whose resources were constrained to seek care in the community; (2) to improve access to and staffing for military hospitals and clinics for active duty members and families; and (3) to restore and maintain the military readiness of the clinical forces.⁸ Several other documents have been issued that emphasize the crucial need to recruit and retain qualified HCPs and support staff if these aims are to be actualized, including the 2024 to 2029 MHS strategic plan.⁹ As the VA and US Public Health Service know, the current health care environment may be a near impossible mission.¹⁰ Although what we know from the history of military medicine is that they have a track record of achieving the impossible.

It is the neglect of timely repair that makes rebuilding necessary.
Richard Whately, economist and theologian (1787-1863)

US Congressional inquiry and media attention are so frequently directed at the trials and tribulations of the US Department of Veterans Affairs (VA) that we forget the US Department of Defense (DoD) medical system also shares the federal practitioner space. The focus of the government and press recently has shifted to examine the weaknesses and woes of military medicine. This editorial reviews what that examination discovered about the decline of the DoD house of medicine, why it is in disrepair, proposals for its rebuilding, and reflects on what this trajectory can tell us about maintaining the structure of federal practice.

My father never tired of telling me that he and his medical colleagues returned from the Second World War with knowledge and skills gained in combat theaters that, in many respects, surpassed those of the civilian sector. Though he was biased as a career military physician and combat veteran, there is strong evidence backing the assertion that from World War I to Operations Enduring Freedom and Iraqi Freedom, American military medicine has been the glory of the world.¹

A November 2023 report from the DoD Office of the Inspector General (OIG) warned that military medicine was in trouble. The report’s emphasis on access and staffing problems that endanger the availability and quality of health care services will likely strike a chord with VA clinicians. The document is based on data from OIG reports, hotline calls, and audits from the last several years; however, the OIG acknowledges that it did not conduct on-the-ground investigations to confirm the findings.²

When we hear the term military medicine, many immediately think of active duty service members. However, the patient population of DoD is far larger and more diverse. The Military Health System (MHS) provides care to > 9.5 million beneficiaries, including dependents and retirees, veterans, civilian DoD employees, and even contractors. Those who most heavily rely on the MHS are individuals in uniform and their families are experiencing the greatest difficulty with accessing care.³ This includes crucial mental health treatment at a time when rates of military suicide continue to climb.⁴

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

As with both the VA and civilian health care spheres, rural areas are the most impacted. Resource shortfalls adversely affect all aspects of care, especially the highly paid specialties like gastroenterology and urology, as well as primary care practitioners essential to ensure the health of military families. The deficits are widespread—all branches report similar obstacles to providing responsive, appropriate care. As if this was not enough to complete the mirror image of the VA’s struggles, there is a rising tide of complaints about the military’s electronic health record system.⁵ How did the preeminent MHS so rapidly decay? Experts in and out of uniform offer several explanations.

As with most forms of managed care, the need to cut costs drove the Pentagon to send military members and dependents to civilian health care systems to have their medical needs addressed. However, this outsourcing strategy was based on a false assumption that the community had enough capacity to deliver services to the many beneficiaries needing them. Nearly every sector of contemporary American medicine is experiencing a drastic shortage of HCPs. Though the resource allocation problems began before the pandemic, COVID-19 only exacerbated and accelerated them.⁶

This downsizing of military hospitals and clinics led to another predictable and seemingly unheeded consequence. A decrease in complex cases (particularly surgical cases) led to a reduction in the skills of military HCPs and a further flight of highly trained specialists who require a reasonable volume of complicated cases to retain and sharpen their expertise. The losses of those experienced clinicians further drain the pool of specialists the military can muster to sustain the readiness of troops for war and the health of their families in peace.⁷

The OIG recommended that the Defense Health Agency address MHS staffing and access deficiencies noted in its report, including identifying poorly performing TRICARE specialty networks and requiring them to meet their access obligation.² As is customary, the OIG asked for DoD comment. It is unclear whether the DoD responded to that formal request; however, it is more certain it heard the message the OIG and beneficiaries conveyed. In December 2023, the Deputy Secretary of the DoD published a memorandum ordering the stabilization of the MHS. It instructs the MHS to address each of the 3 problem areas outlined in this article: (1) to reclaim patients and beneficiaries who had been outsourced or whose resources were constrained to seek care in the community; (2) to improve access to and staffing for military hospitals and clinics for active duty members and families; and (3) to restore and maintain the military readiness of the clinical forces.⁸ Several other documents have been issued that emphasize the crucial need to recruit and retain qualified HCPs and support staff if these aims are to be actualized, including the 2024 to 2029 MHS strategic plan.⁹ As the VA and US Public Health Service know, the current health care environment may be a near impossible mission.¹⁰ Although what we know from the history of military medicine is that they have a track record of achieving the impossible.

It is the neglect of timely repair that makes rebuilding necessary.
Richard Whately, economist and theologian (1787-1863)

US Congressional inquiry and media attention are so frequently directed at the trials and tribulations of the US Department of Veterans Affairs (VA) that we forget the US Department of Defense (DoD) medical system also shares the federal practitioner space. The focus of the government and press recently has shifted to examine the weaknesses and woes of military medicine. This editorial reviews what that examination discovered about the decline of the DoD house of medicine, why it is in disrepair, proposals for its rebuilding, and reflects on what this trajectory can tell us about maintaining the structure of federal practice.

My father never tired of telling me that he and his medical colleagues returned from the Second World War with knowledge and skills gained in combat theaters that, in many respects, surpassed those of the civilian sector. Though he was biased as a career military physician and combat veteran, there is strong evidence backing the assertion that from World War I to Operations Enduring Freedom and Iraqi Freedom, American military medicine has been the glory of the world.¹

A November 2023 report from the DoD Office of the Inspector General (OIG) warned that military medicine was in trouble. The report’s emphasis on access and staffing problems that endanger the availability and quality of health care services will likely strike a chord with VA clinicians. The document is based on data from OIG reports, hotline calls, and audits from the last several years; however, the OIG acknowledges that it did not conduct on-the-ground investigations to confirm the findings.²

When we hear the term military medicine, many immediately think of active duty service members. However, the patient population of DoD is far larger and more diverse. The Military Health System (MHS) provides care to > 9.5 million beneficiaries, including dependents and retirees, veterans, civilian DoD employees, and even contractors. Those who most heavily rely on the MHS are individuals in uniform and their families are experiencing the greatest difficulty with accessing care.³ This includes crucial mental health treatment at a time when rates of military suicide continue to climb.⁴

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

The lack of access and dearth of health care practitioners (HCPs) spans both military facilities and the civilian clinics and hospitals where current and former service members and their dependents use the TRICARE beneficiary insurance. Reminiscent of recent challenges at the VA, DoD members are encountering long wait times and the frustrating bureaucracy of inefficient and, at times, inept referral networks. Additionally, many institutions and HCPs will not accept TRICARE because it pays less and has more paperwork than other insurance plans. What is worse, there is currently no governmental leverage to compel them to participate.

As with both the VA and civilian health care spheres, rural areas are the most impacted. Resource shortfalls adversely affect all aspects of care, especially the highly paid specialties like gastroenterology and urology, as well as primary care practitioners essential to ensure the health of military families. The deficits are widespread—all branches report similar obstacles to providing responsive, appropriate care. As if this was not enough to complete the mirror image of the VA’s struggles, there is a rising tide of complaints about the military’s electronic health record system.⁵ How did the preeminent MHS so rapidly decay? Experts in and out of uniform offer several explanations.

As with most forms of managed care, the need to cut costs drove the Pentagon to send military members and dependents to civilian health care systems to have their medical needs addressed. However, this outsourcing strategy was based on a false assumption that the community had enough capacity to deliver services to the many beneficiaries needing them. Nearly every sector of contemporary American medicine is experiencing a drastic shortage of HCPs. Though the resource allocation problems began before the pandemic, COVID-19 only exacerbated and accelerated them.⁶

This downsizing of military hospitals and clinics led to another predictable and seemingly unheeded consequence. A decrease in complex cases (particularly surgical cases) led to a reduction in the skills of military HCPs and a further flight of highly trained specialists who require a reasonable volume of complicated cases to retain and sharpen their expertise. The losses of those experienced clinicians further drain the pool of specialists the military can muster to sustain the readiness of troops for war and the health of their families in peace.⁷

The OIG recommended that the Defense Health Agency address MHS staffing and access deficiencies noted in its report, including identifying poorly performing TRICARE specialty networks and requiring them to meet their access obligation.² As is customary, the OIG asked for DoD comment. It is unclear whether the DoD responded to that formal request; however, it is more certain it heard the message the OIG and beneficiaries conveyed. In December 2023, the Deputy Secretary of the DoD published a memorandum ordering the stabilization of the MHS. It instructs the MHS to address each of the 3 problem areas outlined in this article: (1) to reclaim patients and beneficiaries who had been outsourced or whose resources were constrained to seek care in the community; (2) to improve access to and staffing for military hospitals and clinics for active duty members and families; and (3) to restore and maintain the military readiness of the clinical forces.⁸ Several other documents have been issued that emphasize the crucial need to recruit and retain qualified HCPs and support staff if these aims are to be actualized, including the 2024 to 2029 MHS strategic plan.⁹ As the VA and US Public Health Service know, the current health care environment may be a near impossible mission.¹⁰ Although what we know from the history of military medicine is that they have a track record of achieving the impossible.

TOPLINE:

Patients with chronic neck pain who received acupuncture experienced an alleviation of their symptoms, but not at clinically meaningful levels, compared with those who received sham treatment.

METHODOLOGY:

• A 24-week randomized trial was conducted at four clinical centers in China over a 2-year period starting in 2018.
• A total of 659 patients with chronic neck pain were randomly assigned to one of the four groups: Higher sensitive acupoints (mean age, 38.63 years; 70.41% women; n = 169), lower sensitive acupoints (mean age, 40.21 years; 74.4% women; n = 168), sham acupuncture (mean age, 40.16 years; 75.29% women; n = 170), and a waiting list (mean age, 38.63 years; 69.89% women; n = 176).
• Participants in the acupuncture groups had 10 sessions over 4 weeks and were followed up for 20 weeks. Those in the waiting list group received no treatment.
• The primary outcome was the change in neck pain at 4 weeks, measured on a 0-100 scale. A change of 10 points was considered clinically significant.
• The secondary outcomes were neck pain and movement, quality of life, and use of pain medication over 24 weeks.

TAKEAWAY:

• Acupuncture targeted at higher sensitive points led to a pain score reduction of 12.16 (95% CI, −14.45 to −9.87), while lower sensitive points reduced it by 10.19 (95% CI, −12.43 to −7.95).
• Sham acupuncture reduced the score by 6.11 (95% CI, −8.31 to −3.91), and no treatment reduced it by 2.24 (95% CI, −4.10 to −0.38).
• The higher and lower sensitive acupoint groups showed no clinically significant net differences in pain reduction and secondary outcomes compared with the sham and waiting list groups.
• Differences in reductions in pain between groups all decreased by week 24.

IN PRACTICE:

“The clinical importance of this improvement is unclear. Our results suggest that the selection of pressure pain, sensory-based objective acupoints could be considered as a treatment of CNP [chronic neck pain],” the authors wrote.

SOURCE:

This study, led by Ling Zhao, PhD, of Acupuncture and Tuina School at Chengdu University of Traditional Chinese Medicine in Chengdu, China, was published online in the Annals of Internal Medicine.

LIMITATIONS:

Blinding was not done in the waiting list group. Individuals in the higher and lower sensitive acupoint groups experienced a specific sensation after needle manipulation, which could have influenced the analysis. Additionally, the participants were middle-aged adults with moderate pain, which limited the generalizability to older individuals or those with severe pain.

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Central Guidance on Local Science and Technology Development Fund of Sichuan Province, among others. The authors declared no conflicts of interest outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with chronic neck pain who received acupuncture experienced an alleviation of their symptoms, but not at clinically meaningful levels, compared with those who received sham treatment.

METHODOLOGY:

• A 24-week randomized trial was conducted at four clinical centers in China over a 2-year period starting in 2018.
• A total of 659 patients with chronic neck pain were randomly assigned to one of the four groups: Higher sensitive acupoints (mean age, 38.63 years; 70.41% women; n = 169), lower sensitive acupoints (mean age, 40.21 years; 74.4% women; n = 168), sham acupuncture (mean age, 40.16 years; 75.29% women; n = 170), and a waiting list (mean age, 38.63 years; 69.89% women; n = 176).
• Participants in the acupuncture groups had 10 sessions over 4 weeks and were followed up for 20 weeks. Those in the waiting list group received no treatment.
• The primary outcome was the change in neck pain at 4 weeks, measured on a 0-100 scale. A change of 10 points was considered clinically significant.
• The secondary outcomes were neck pain and movement, quality of life, and use of pain medication over 24 weeks.

TAKEAWAY:

• Acupuncture targeted at higher sensitive points led to a pain score reduction of 12.16 (95% CI, −14.45 to −9.87), while lower sensitive points reduced it by 10.19 (95% CI, −12.43 to −7.95).
• Sham acupuncture reduced the score by 6.11 (95% CI, −8.31 to −3.91), and no treatment reduced it by 2.24 (95% CI, −4.10 to −0.38).
• The higher and lower sensitive acupoint groups showed no clinically significant net differences in pain reduction and secondary outcomes compared with the sham and waiting list groups.
• Differences in reductions in pain between groups all decreased by week 24.

IN PRACTICE:

“The clinical importance of this improvement is unclear. Our results suggest that the selection of pressure pain, sensory-based objective acupoints could be considered as a treatment of CNP [chronic neck pain],” the authors wrote.

SOURCE:

This study, led by Ling Zhao, PhD, of Acupuncture and Tuina School at Chengdu University of Traditional Chinese Medicine in Chengdu, China, was published online in the Annals of Internal Medicine.

LIMITATIONS:

Blinding was not done in the waiting list group. Individuals in the higher and lower sensitive acupoint groups experienced a specific sensation after needle manipulation, which could have influenced the analysis. Additionally, the participants were middle-aged adults with moderate pain, which limited the generalizability to older individuals or those with severe pain.

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Central Guidance on Local Science and Technology Development Fund of Sichuan Province, among others. The authors declared no conflicts of interest outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with chronic neck pain who received acupuncture experienced an alleviation of their symptoms, but not at clinically meaningful levels, compared with those who received sham treatment.

METHODOLOGY:

• A 24-week randomized trial was conducted at four clinical centers in China over a 2-year period starting in 2018.
• A total of 659 patients with chronic neck pain were randomly assigned to one of the four groups: Higher sensitive acupoints (mean age, 38.63 years; 70.41% women; n = 169), lower sensitive acupoints (mean age, 40.21 years; 74.4% women; n = 168), sham acupuncture (mean age, 40.16 years; 75.29% women; n = 170), and a waiting list (mean age, 38.63 years; 69.89% women; n = 176).
• Participants in the acupuncture groups had 10 sessions over 4 weeks and were followed up for 20 weeks. Those in the waiting list group received no treatment.
• The primary outcome was the change in neck pain at 4 weeks, measured on a 0-100 scale. A change of 10 points was considered clinically significant.
• The secondary outcomes were neck pain and movement, quality of life, and use of pain medication over 24 weeks.

TAKEAWAY:

• Acupuncture targeted at higher sensitive points led to a pain score reduction of 12.16 (95% CI, −14.45 to −9.87), while lower sensitive points reduced it by 10.19 (95% CI, −12.43 to −7.95).
• Sham acupuncture reduced the score by 6.11 (95% CI, −8.31 to −3.91), and no treatment reduced it by 2.24 (95% CI, −4.10 to −0.38).
• The higher and lower sensitive acupoint groups showed no clinically significant net differences in pain reduction and secondary outcomes compared with the sham and waiting list groups.
• Differences in reductions in pain between groups all decreased by week 24.

IN PRACTICE:

“The clinical importance of this improvement is unclear. Our results suggest that the selection of pressure pain, sensory-based objective acupoints could be considered as a treatment of CNP [chronic neck pain],” the authors wrote.

SOURCE:

This study, led by Ling Zhao, PhD, of Acupuncture and Tuina School at Chengdu University of Traditional Chinese Medicine in Chengdu, China, was published online in the Annals of Internal Medicine.

LIMITATIONS:

Blinding was not done in the waiting list group. Individuals in the higher and lower sensitive acupoint groups experienced a specific sensation after needle manipulation, which could have influenced the analysis. Additionally, the participants were middle-aged adults with moderate pain, which limited the generalizability to older individuals or those with severe pain.

DISCLOSURES:

The study was supported by grants from the National Natural Science Foundation of China, Central Guidance on Local Science and Technology Development Fund of Sichuan Province, among others. The authors declared no conflicts of interest outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, is known to inhibit angiogenesis and prevent carcinogenesis. Recent evidence from the IMbrave050 trial indicates that combining bevacizumab with atezolizumab enhances recurrence-free survival (RFS) in high-risk HCC patients undergoing curative treatments. Bevacizumab is notorious for causing endothelial dysfunction that may provoke vasospasm, leading to central hypoperfusion, hypertension, and, albeit rarely, PRES. Similarly, immunotherapy, including atezolizumab, has been implicated in PRES, underscoring a potential risk when these therapies are administered concurrently.

Case Presentation

A 64-year-old woman with a history of hepatitis C and alcoholic cirrhosis was diagnosed with stage II (T2 N0 M0) HCC. Following partial hepatectomy, we proceeded with adjuvant systemic therapy with atezolizumab and bevacizumab (per the IMbrave050 trial). After her 2nd treatment, she developed altered mental status, seizures, and severe hypertension. Labs revealed acute kidney injury and elevated creatinine kinase levels suggesting rhabdomyolysis. Computed tomography head showed no acute findings, but magnetic resonance imaging of the brain identified increased flair attenuated inversion recovery (FLAIR) signal in the brain’s posterior regions, indicating PRES. Symptomatic management with anti-hypertensives and intravenous fluids led to the recovery of mental status to baseline. Further therapy with bevacizumab and atezolizumab was then held off.

Discussion

Therapeutic advances in HCC management through the IMbrave050 trial demonstrate the efficacy of bevacizumab and atezolizumab in reducing RFS, without highlighting the serious side effects like PRES. To our knowledge, this is the first case reported where PRES occurred with the simultaneous use of atezolizumab and bevacizumab. Since both drugs can individually cause PRES, there might be a heightened risk with the co-administration, signaling a critical need for vigilant monitoring and further research into this treatment modality’s long-term safety profile.

Background

Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.

Methods

PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.

Results

Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.

Conclusions

Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.

Background

Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.

Methods

PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.

Results

Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.

Conclusions

Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.

Background

Biliary tract cancers (BTC) represent an important rare cancer type in Veterans. The heterogeneity of BTC has revealed distinct molecular subtypes, however a majority of patients remain without precision-based targeted therapeutics. Epigenomic remodeling has been considered as a shared mechanism of therapeutic resistance. Cyclin dependant kinase 7 (CDK7) is an emerging therapeutic target that functions by phosphorylation of RNA polymerase II and cell cycle progression. Here, we investigate CDK7 inhibition using small molecule inhibition (SY-5609) across a panel of BTC organoid models.

Methods

PCOs were expanded from patient-derived tissues and shared models provided from the NCI. Organoid response was tracked from growth using Z-stacked high content imaging (Cytation5) to track individual organoid growth and established viability markers of Caspase-3/7 (C3/7) and ToPro3, for induced apoptosis and necrosis for phenotypic screening. Treatment groups included media control, positive control (cycloheximide) 200uM continuous, gemcitabine (gem) 10uM 24h, cisplatin (cis) 5uM 48h, combination gem+cis, and SY-5609 10nM 144h. Glass’s delta was used to standardize effect size relative to media control.

Results

Patient-derived cancer organoids were generated across four unique models including pathogenic (A-B) IDH1 p.R132G, (C) FGFR2-HPGDS fusion and (D) non-targetable molecular profile (CCNE1 amplified, BRCA1 splice variant). In the non-targeted model, CDK7 inhibition achieved growth arrest +2.0% (SY-5607) v. +43.0% (media control) with effect size >1.1. This response was similar to standard of care gem+cis with growth of +1.5% and augmented using the combination of gem+SY-5609 -3.1% with effect size of >1.3. When treated with CDK7 inhibition, persistent growth was seen across models of IDH1 mutant and FGFR2-HPGDS2 fusion cancers. High content imaging revealed subclonal populations with failed induction of apoptosis and necrosis at 144h, suggestive of the critical need to address intrinsic resistant populations to both SOC chemotherapy and novel targeted strategies.

Conclusions

Across a diversity of BTC cancer models, CDK7 inhibition was found to achieve growth arrest in a CCNE1 amplified cancer model. High content imaging of organoids can identify subclonal resistant populations as a critical unmet need in future therapeutic development. Ongoing work is adapting these techniques to multiple small molecule inhibitors that target transcription including EZH1/2 and CDK9.

Background

Many Veterans with cancer experience substantial side effects related to their chemotherapy treatments resulting in impaired quality of life. Prompt management of such symptoms can improve adherence to therapy and potentially clinical outcomes. Previous studies in cancer patients have shown that mobile apps can improve symptom management and quality of life, though there are limited studies using oncology-focused apps in the VA population. The VA Annie App is an optimal platform for Veterans since it relies primarily on SMS-based texting and not on internet capabilities. This would address several well-known barriers to Veterans’ care access (limited internet connectivity, transportation) and enhance symptom reporting between infrequent provider visits. Providers can securely collect app responses within the VA system and there is already considerable VA developer experience with designing complex protocols. The OCTAGON project (Optimizing Cancer Care with Telehealth Assessment for Goal-Oriented Needs) will have the following goals: 1) To develop Annie App protocols to assist in management of cancer and/or chemotherapy-related symptoms (OCTAGON intervention), 2) To examine initial acceptability, feasibility, and Veteran-reported outcomes, 3) To explore short term effects on the utilization of VA encounters.

Methods

All patients who are primarily being managed at the VA Ann Arbor for their cancer therapy and are receiving one of the following therapies are considered eligible: EGFR inhibitors (lung cancer), antiandrogen therapies (prostate cancer), BTK inhibitors (lymphoma).

Discussion

Drug-specific protocols will be developed in conjunction with clinical pharmacists with experience in outpatient oral chemotherapy toxicity monitoring. Questions will have either a Yes/No, or numerical response. Interventions will be administered weekly for the first 3 months after enrollment, then decrease to monthly for a total of 6 months on protocol. Patients will be directed to contact their providers with any significant changes in tolerability. Planned data collected will include intervention question responses, adverse events, demographics, diagnosis, disease response, hospitalizations, treatment dose reductions or interruptions, provider and staff utilization. Survey responses to assess treatment acceptability (Treatment Acceptability/Adherence Scale), usability (System Usability Scale), general health (PROMIS-GH), and patient satisfaction will also be collected. Funding: VA Telehealth Research and Innovation for Veterans with Cancer (THRIVE).

Background

Many Veterans with cancer experience substantial side effects related to their chemotherapy treatments resulting in impaired quality of life. Prompt management of such symptoms can improve adherence to therapy and potentially clinical outcomes. Previous studies in cancer patients have shown that mobile apps can improve symptom management and quality of life, though there are limited studies using oncology-focused apps in the VA population. The VA Annie App is an optimal platform for Veterans since it relies primarily on SMS-based texting and not on internet capabilities. This would address several well-known barriers to Veterans’ care access (limited internet connectivity, transportation) and enhance symptom reporting between infrequent provider visits. Providers can securely collect app responses within the VA system and there is already considerable VA developer experience with designing complex protocols. The OCTAGON project (Optimizing Cancer Care with Telehealth Assessment for Goal-Oriented Needs) will have the following goals: 1) To develop Annie App protocols to assist in management of cancer and/or chemotherapy-related symptoms (OCTAGON intervention), 2) To examine initial acceptability, feasibility, and Veteran-reported outcomes, 3) To explore short term effects on the utilization of VA encounters.

Methods

All patients who are primarily being managed at the VA Ann Arbor for their cancer therapy and are receiving one of the following therapies are considered eligible: EGFR inhibitors (lung cancer), antiandrogen therapies (prostate cancer), BTK inhibitors (lymphoma).

Discussion

Drug-specific protocols will be developed in conjunction with clinical pharmacists with experience in outpatient oral chemotherapy toxicity monitoring. Questions will have either a Yes/No, or numerical response. Interventions will be administered weekly for the first 3 months after enrollment, then decrease to monthly for a total of 6 months on protocol. Patients will be directed to contact their providers with any significant changes in tolerability. Planned data collected will include intervention question responses, adverse events, demographics, diagnosis, disease response, hospitalizations, treatment dose reductions or interruptions, provider and staff utilization. Survey responses to assess treatment acceptability (Treatment Acceptability/Adherence Scale), usability (System Usability Scale), general health (PROMIS-GH), and patient satisfaction will also be collected. Funding: VA Telehealth Research and Innovation for Veterans with Cancer (THRIVE).

Background

Many Veterans with cancer experience substantial side effects related to their chemotherapy treatments resulting in impaired quality of life. Prompt management of such symptoms can improve adherence to therapy and potentially clinical outcomes. Previous studies in cancer patients have shown that mobile apps can improve symptom management and quality of life, though there are limited studies using oncology-focused apps in the VA population. The VA Annie App is an optimal platform for Veterans since it relies primarily on SMS-based texting and not on internet capabilities. This would address several well-known barriers to Veterans’ care access (limited internet connectivity, transportation) and enhance symptom reporting between infrequent provider visits. Providers can securely collect app responses within the VA system and there is already considerable VA developer experience with designing complex protocols. The OCTAGON project (Optimizing Cancer Care with Telehealth Assessment for Goal-Oriented Needs) will have the following goals: 1) To develop Annie App protocols to assist in management of cancer and/or chemotherapy-related symptoms (OCTAGON intervention), 2) To examine initial acceptability, feasibility, and Veteran-reported outcomes, 3) To explore short term effects on the utilization of VA encounters.

Methods

All patients who are primarily being managed at the VA Ann Arbor for their cancer therapy and are receiving one of the following therapies are considered eligible: EGFR inhibitors (lung cancer), antiandrogen therapies (prostate cancer), BTK inhibitors (lymphoma).

Discussion

Drug-specific protocols will be developed in conjunction with clinical pharmacists with experience in outpatient oral chemotherapy toxicity monitoring. Questions will have either a Yes/No, or numerical response. Interventions will be administered weekly for the first 3 months after enrollment, then decrease to monthly for a total of 6 months on protocol. Patients will be directed to contact their providers with any significant changes in tolerability. Planned data collected will include intervention question responses, adverse events, demographics, diagnosis, disease response, hospitalizations, treatment dose reductions or interruptions, provider and staff utilization. Survey responses to assess treatment acceptability (Treatment Acceptability/Adherence Scale), usability (System Usability Scale), general health (PROMIS-GH), and patient satisfaction will also be collected. Funding: VA Telehealth Research and Innovation for Veterans with Cancer (THRIVE).

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.

Background

The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is combination chemoradiotherapy. Platinum-based chemotherapy is used for radiosensitization and significantly improves locoregional control and survival. Cisplatin is the standard of care; however, many patients are cisplatin-ineligible due to underlying comorbidities. Carboplatin is an alternative chemotherapy in these patients, but efficacy data are lacking. Purpose: To evaluate the efficacy and tolerability of weekly carboplatin concurrent with radiation in veterans with locally advanced HNSCC.

Methods

Our tumor registry was used to identify patients who received platinum-based chemoradiotherapy for stage III-IVB HNSCC at a single center between 2007 to 2017. Patients who received carboplatin were identified. Data including dosing, toxicities, and disease response was collected and analyzed.

Results

A total of 26 patients who received weekly carboplatin were analyzed. All patients were male with an average age of 65. A usual dose of carboplatin AUC 2 was utilized. The average cumulative dose for weekly carboplatin was AUC 12, with most patients (65%) receiving 6 doses or more. The mean number of weekly carboplatin doses held was 0.3. 7 patients (27%) had at least one dose held. 21 (81%) patients showed treatment benefit: 19 (73%) had complete response and 2 (8%) had partial response on first scan following treatment. The four most common toxicities were mucositis (69%), nausea/vomiting (23%), oral thrush (19%), and dermatologic toxicities (19%). The most common toxicities causing dose interruption were fatigue (12%), neutropenia (8%), and thrombocytopenia (8%). Grade 3/4 mucositis was experienced in 6 patients (23%). Other grade 3/4 toxicities included neutropenia (8%), anemia (8%), thrombocytopenia (1%), nephrotoxicity (1%) and nausea (1%).

Conclusions

Carboplatin was both efficacious and well tolerated in our older veteran population. These findings add to the limited body of evidence examining weekly carboplatin in patients with advanced head and neck cancer. While cisplatin remains standard of care, carboplatin may be a reasonable alternative as evidenced in a real-world veteran population.