Photo by Bill Branson

The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).

CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.

The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.

The EC’s approval is supported by data from 5 studies, including a phase 3 trial.

Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.

The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).

About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).

The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).

Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.

The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).

Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.

Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).

Photo by Bill Branson

The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).

CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.

The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.

The EC’s approval is supported by data from 5 studies, including a phase 3 trial.

Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.

The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).

About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).

The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).

Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.

The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).

Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.

Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).

Photo by Bill Branson

The European Commission (EC) has approved CPX-351 (Vyxeos), a liposomal formulation that delivers a fixed ratio of daunorubicin and cytarabine (44 mg/100 mg).

CPX-351 is approved to treat adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes.

The approval extends to all European Union member states as well as Iceland, Norway, and Liechtenstein.

The EC’s approval is supported by data from 5 studies, including a phase 3 trial.

Data from the phase 3 trial were published in the Journal of Clinical Oncology in July.

The trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

Patients received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The overall remission rate—the rate of complete response (CR) plus CR with incomplete count recovery—was 47.7% in the CPX-351 arm and 33.3% in the 7+3 arm (P=0.016). The CR rate was 37.3% and 25.6%, respectively (P=0.040).

About 30% of patients went on to allogeneic hematopoietic stem cell transplant—34% in the CPX-351 arm and 25% in the 7+3 arm (P=0.098).

The median overall survival was 9.56 months in the CPX-351 arm and 5.95 months in the 7+3 arm (P=0.003). The median event-free survival was 2.53 months and 1.31 months, respectively (P=0.021).

Adverse events (AEs) that led to treatment discontinuation in the CPX-351 arm were cardiac failure (n=1), cardiomyopathy (n=1), and acute renal failure (n=1). AEs that led to treatment discontinuation in the 7+3 arm were decreased ejection fraction in 2 patients.

The most common grade 3 to 5 AEs (in the CPX-351 and 7+3 arms, respectively) were infection-related events (83.7% and 86.1%), febrile neutropenia (68.0% and 70.9%), pneumonia (19.6% and 14.6%), hypoxia (13.1% and 15.2%), and bleeding events (11.8% and 8.6%).

Ultimately, 69.3% of patients in the CPX-351 arm and 84.8% of those in the 7+3 arm died.

Deaths (in the CPX-351 and 7+3 cohorts, respectively) were due to progressive disease (n=65 and 67), AEs (n=15 and 19), cancer-related organ failure in the absence of progressive disease (n=0 and 5), and unknown/other causes (n=26 and 37).

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).

CX-01 also has orphan drug designation from the FDA.

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.

The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

CX-01 research

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were published in Blood Advances in February.

The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.

They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).

Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.

At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.

The median disease-free survival was 14.8 months, and the median overall survival was not reached.

There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.

Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.

The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).

CX-01 also has orphan drug designation from the FDA.

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.

The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

CX-01 research

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were published in Blood Advances in February.

The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.

They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).

Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.

At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.

The median disease-free survival was 14.8 months, and the median overall survival was not reached.

There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.

Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.

The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to CX-01 as a treatment for patients older than 60 receiving induction therapy for newly diagnosed acute myeloid leukemia (AML).

CX-01 also has orphan drug designation from the FDA.

CX-01 is a polysaccharide derived from heparin that is thought to enhance chemotherapy by disrupting the adhesion of leukemia cells in the bone marrow.

CX-01 inhibits the activity of HMGB1, disrupts the CXCL12/CXCR4 axis, and neutralizes the activity of platelet factor 4. HMGB1 has been implicated in autophagy, a mechanism by which cells withstand the effects of chemotherapy.

The CXCL12/CXCR4 axis is thought to be involved in protecting leukemia cells from chemotherapy. And platelet factor 4 inhibits bone marrow recovery after chemotherapy.

CX-01 research

Cantex Pharmaceuticals, Inc., is conducting a randomized, phase 2b study to determine whether CX-01 can improve the efficacy of frontline chemotherapy in patients with AML.

This study builds upon results of a pilot study, which were published in Blood Advances in February.

The study enrolled 12 adults with newly diagnosed AML. Patients had good-risk (n=3), intermediate-risk (n=5), and poor-risk (n=4) disease.

They received CX-01 as a 7-day continuous infusion, along with standard induction chemotherapy (cytarabine and idarubicin).

Eleven patients (92%) achieved morphologic complete remission after one cycle of induction. This includes two patients who did not complete induction. All patients received subsequent therapy—consolidation, salvage, or transplant—on- or off-study.

At a median follow-up of 24 months, 8 patients were still alive. Two patients died of transplant-related complications, one died of infectious complications, and one died of cerebral hemorrhage.

The median disease-free survival was 14.8 months, and the median overall survival was not reached.

There were five serious adverse events (AEs) in five patients. Most of these AEs were considered unrelated to CX-01, but a case of grade 4 sepsis was considered possibly related to CX-01.

Transient, asymptomatic, low-grade elevations of liver transaminases observed during induction were considered possibly related to CX-01. There were also transient, asymptomatic, grade 3-4 liver transaminase elevations observed during consolidation that were considered possibly related to CX-01.

The researchers said the most frequent nonserious AEs were hematologic toxicities, infectious complications, and organ toxicity complications resulting from treatment and/or the underlying leukemia.

About fast track, orphan designations

The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.

Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

 A negative chest radiograph can be used to rule out the possibility of pneumonia in children suspected of having the disease, and therefore reduce antibiotic use, researchers say.

In a paper published in the September issue of Pediatrics, researchers report the results of a prospective cohort study in 683 children – with a median age of 3.1 years – presenting to emergency departments with suspected pneumonia.

Dr. Susan C. Lipsett, from the division of emergency medicine at Boston Children’s Hospital, and co-authors, wrote that the use of chest radiograph to diagnose pneumonia is thought to have limitations such as its inability to distinguish between bacteria and viral infection, and the possible absence of radiographic presentations early in the disease in patients with dehydration.

In this study, 457 (72.8%) of the children had negative chest radiographs. Of these, 44 were clinically diagnosed with pneumonia, despite the radiograph results, and prescribed antibiotics. These children were more likely to have rales or respiratory distress and less likely to have wheezing compared with the children with negative radiographs who were not initially diagnosed with pneumonia.

Among the remaining 411 children with negative radiographs – who were not prescribed antibiotics – five (1.2%) were subsequently diagnosed with pneumonia within 2 weeks of the radiograph. These five children were all under 3 years of age, but none had been treated with intravenous fluids for dehydration. Only one had radiographic findings of pneumonia on a follow-up visit.

Counting the 44 children diagnosed with pneumonia despite the negative x-ray, chest radiography showed a negative predictive value of 89.2% (95% confidence interval, 85.9%-91.9%). Without those children, the negative predictive value was 98.8% (95% CI, 97%-99.6%).

There were also 113 children (16.5%) with positive chest radiographs, and 72 (10.7%) with equivocal radiographs.

The authors said their results showed that most children with negative chest radiograph would recover fully without needing antibiotics, and argued there was a place for chest radiography in the diagnostic process, to rule out bacterial pneumonia.

“Most clinicians caring for children in the outpatient setting rely on clinical signs and symptoms to determine whether to prescribe an antibiotic for the treatment of pneumonia,” they wrote. “However, given recent literature in which the poor reliability and validity of physical examination findings are cited, reliance on physical examination alone may lead to the overdiagnosis of pneumonia.”

They acknowledged that the lack of a universally accepted gold standard for the diagnosis of pneumonia in children was a significant limitation of the research. In addition, the lack of systematic radiographs meant some children who initially had a negative result and recovered without antibiotics may have shown a positive result on a second scan.

No conflicts of interest were declared.

SOURCE: Lipsett S et al. Pediatrics 2018 142(3):e20180236.

 

 A negative chest radiograph can be used to rule out the possibility of pneumonia in children suspected of having the disease, and therefore reduce antibiotic use, researchers say.

In a paper published in the September issue of Pediatrics, researchers report the results of a prospective cohort study in 683 children – with a median age of 3.1 years – presenting to emergency departments with suspected pneumonia.

Dr. Susan C. Lipsett, from the division of emergency medicine at Boston Children’s Hospital, and co-authors, wrote that the use of chest radiograph to diagnose pneumonia is thought to have limitations such as its inability to distinguish between bacteria and viral infection, and the possible absence of radiographic presentations early in the disease in patients with dehydration.

In this study, 457 (72.8%) of the children had negative chest radiographs. Of these, 44 were clinically diagnosed with pneumonia, despite the radiograph results, and prescribed antibiotics. These children were more likely to have rales or respiratory distress and less likely to have wheezing compared with the children with negative radiographs who were not initially diagnosed with pneumonia.

Among the remaining 411 children with negative radiographs – who were not prescribed antibiotics – five (1.2%) were subsequently diagnosed with pneumonia within 2 weeks of the radiograph. These five children were all under 3 years of age, but none had been treated with intravenous fluids for dehydration. Only one had radiographic findings of pneumonia on a follow-up visit.

Counting the 44 children diagnosed with pneumonia despite the negative x-ray, chest radiography showed a negative predictive value of 89.2% (95% confidence interval, 85.9%-91.9%). Without those children, the negative predictive value was 98.8% (95% CI, 97%-99.6%).

There were also 113 children (16.5%) with positive chest radiographs, and 72 (10.7%) with equivocal radiographs.

The authors said their results showed that most children with negative chest radiograph would recover fully without needing antibiotics, and argued there was a place for chest radiography in the diagnostic process, to rule out bacterial pneumonia.

“Most clinicians caring for children in the outpatient setting rely on clinical signs and symptoms to determine whether to prescribe an antibiotic for the treatment of pneumonia,” they wrote. “However, given recent literature in which the poor reliability and validity of physical examination findings are cited, reliance on physical examination alone may lead to the overdiagnosis of pneumonia.”

They acknowledged that the lack of a universally accepted gold standard for the diagnosis of pneumonia in children was a significant limitation of the research. In addition, the lack of systematic radiographs meant some children who initially had a negative result and recovered without antibiotics may have shown a positive result on a second scan.

No conflicts of interest were declared.

SOURCE: Lipsett S et al. Pediatrics 2018 142(3):e20180236.

 

 A negative chest radiograph can be used to rule out the possibility of pneumonia in children suspected of having the disease, and therefore reduce antibiotic use, researchers say.

In a paper published in the September issue of Pediatrics, researchers report the results of a prospective cohort study in 683 children – with a median age of 3.1 years – presenting to emergency departments with suspected pneumonia.

Dr. Susan C. Lipsett, from the division of emergency medicine at Boston Children’s Hospital, and co-authors, wrote that the use of chest radiograph to diagnose pneumonia is thought to have limitations such as its inability to distinguish between bacteria and viral infection, and the possible absence of radiographic presentations early in the disease in patients with dehydration.

In this study, 457 (72.8%) of the children had negative chest radiographs. Of these, 44 were clinically diagnosed with pneumonia, despite the radiograph results, and prescribed antibiotics. These children were more likely to have rales or respiratory distress and less likely to have wheezing compared with the children with negative radiographs who were not initially diagnosed with pneumonia.

Among the remaining 411 children with negative radiographs – who were not prescribed antibiotics – five (1.2%) were subsequently diagnosed with pneumonia within 2 weeks of the radiograph. These five children were all under 3 years of age, but none had been treated with intravenous fluids for dehydration. Only one had radiographic findings of pneumonia on a follow-up visit.

Counting the 44 children diagnosed with pneumonia despite the negative x-ray, chest radiography showed a negative predictive value of 89.2% (95% confidence interval, 85.9%-91.9%). Without those children, the negative predictive value was 98.8% (95% CI, 97%-99.6%).

There were also 113 children (16.5%) with positive chest radiographs, and 72 (10.7%) with equivocal radiographs.

The authors said their results showed that most children with negative chest radiograph would recover fully without needing antibiotics, and argued there was a place for chest radiography in the diagnostic process, to rule out bacterial pneumonia.

“Most clinicians caring for children in the outpatient setting rely on clinical signs and symptoms to determine whether to prescribe an antibiotic for the treatment of pneumonia,” they wrote. “However, given recent literature in which the poor reliability and validity of physical examination findings are cited, reliance on physical examination alone may lead to the overdiagnosis of pneumonia.”

They acknowledged that the lack of a universally accepted gold standard for the diagnosis of pneumonia in children was a significant limitation of the research. In addition, the lack of systematic radiographs meant some children who initially had a negative result and recovered without antibiotics may have shown a positive result on a second scan.

No conflicts of interest were declared.

SOURCE: Lipsett S et al. Pediatrics 2018 142(3):e20180236.

 

I just finished reading Dr. Nasrallah’s editorial “The DNA of psychiatric practice: A covenant with our patients” (From the Editor, Current Psychiatry. May 2018, p. 20, 22). It offered very good messages. I can add a few more: “Make a commitment to life-long professional education. Understand how to critique research findings and their clinical applicability. Distinguish fad from science.”

David W. Goodman, MD, FAPA
Assistant Professor
Department of Psychiatry and Behavioral Sciences
Johns Hopkins School of Medicine
Baltimore, Maryland

Unfortunately, there is no way a physician who uses an electronic medical record can “Maintain total and unimpeachable confidentiality” as the “The medical record is a clinical, billing, legal, and research document.” Since 2003, patients no longer need to give consent for their medical records to be seen by the many staff members who work in treatment, payment, and health care operations, as long as these individuals follow the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Even de-identified data is no longer safe because re-identification is still possible with all the databases available for cross-referencing (ie, Facebook and hospitals as one instance).

So, when a patient finally tells you about a history of sexual abuse, do you make it clear to him or her that although this information is no longer private, it can be expected to be kept confidential by all the business associates, covered entities, government agencies, etc., who see their records?

Maybe there also would be fewer physician suicides if they could be assured of receiving truly private, off-the-grid psychiatric treatment.

Susan Israel, MD
Private psychiatric practice (retired)
Woodbridge, Connecticut

I just read your excellent and exhaustive May editorial, which offered advice for new psychiatrists. I was surprised to see that nowhere on the list was “Please remember to practice what you preach and be vigilant about self-care. We have become increasingly aware of the high rates of burnout among physicians. Know your own limitations so that you can appreciate the work that you do.”

Hal D. Cash, MD
Private psychiatric practice (retired)
Mica Collaborative
Wellesley, Massachusetts

Continue to: Dr. Nasrallah's editorial should have...

Dr. Nasrallah’s editorial should have listed something about the terms of payment for the psychiatrist who “provides” his or her clinical services to patients. This is an ethical issue. As you know, usually a corporation, rather than a patient, pays the psychiatrist. This payment may come from a health insurance company, government program, or (increasingly) a large clinic. When an organization pays the psychiatrist, it calls the tune for both the doctor’s employment and the patient’s access to quality care. Contracts between the hiring organization and psychiatrists are crucial, and therefore, most young doctors must join a hiring organization for financial reasons after completing their psychiatric residency. The young psychiatrists with whom I speak tell me they have no alternative but to be a “corporate dependent” in the world of 2018 psychiatric practice. They are aware of your (and my) noble principles, which should govern their relationships with patients. But the boss often does not agree with such principles.

In my book Passion for Patients¹ and as President of the 501(c)3 Minnesota Physician-Patient Alliance think tank (www.physician-patient.org), I argue for empowering patients with the means to direct payments to their physicians. Allowing patients this option is especially important for forming and maintaining strong relationship-based psychiatric and other medical treatments. In 1996, I was fed up with being a psychiatric medical director for 5 years at a large Minnesota Preferred Provider Organization. For me, the saving grace was being able to have an independent, private psychiatric practice. Most of my patients agreed.Therefore, I suggest another principle: “Build and maintain an independent psychiatric practice as an escape option no matter what you do should you decide the ethical practice of psychiatry is not possible if you are employed by a given organization.”

Lee Beecher, MD
Member
Editorial Advisory Board
Clinical Psychiatry News
Adjunct Professor of Psychiatry
University of Minnesota
Minneapolis, Minnesota

Reference

1. Beecher L, Racer D. Passion for patients. St. Paul, MN: Alethos Press; 2017.

I agree with Dr. Nasrallah’s guiding principles of psychiatry, which he proposes to govern the relationships of psychiatrists with their patients. However, there is one glaring omission. The first principle should be “to appropriately diagnose the patient’s condition,” which may or may not be based in psychiatry. Misdiagnoses and inappropriate pharmacologic therapy have ruined the lives of some very good friends of mine, and the need to first do no harm by misdiagnosing the patient, especially in psychiatric emergency rooms and on inpatient units, cannot be overemphasized.

These situations may not rear their head in the everyday practice of psychiatry. However, medical malpractice, especially in the field of psychiatry, is a constant caution that all new physicians need to watch for.

I would like to thank Dr. Nasrallah for his efforts to strengthen the patient–psychiatrist contract.

Rama Kasturi, PhD
Associate Professor (retired)
Department of Pharmacology and Cell Biophysics
Director (1999 to 2013)
Medical Pharmacology Tutorial Program University of Cincinnati, College of Medicine
Cincinnati, Ohio

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

I thank my 5 colleagues for their perspectives on my editorial. You all made cogent points.

I agree with Dr. Israel that our patients’ records are now accessible by many entities due to the drastic changes in our health care delivery system. However, while I regard the basic psychiatric signs and symptoms as medical data, like heart disease or cancer, there are personal details that emerge during psychotherapy that should remain confidential and not be included in the written record, and thus are not accessible to billers, health insurance companies, or malpractice lawyers. As for physicians who consider suicide because of fear of the consequences of receiving psychiatric treatment that becomes a matter of record, that is a matter of the unfortunate stigma and ignorance about mental illness and how treatable it can be.

Regarding Dr. Cash’s comments, I agree that psychiatrists should be (and are almost always are) introspective about their vulnerabilities and limitations, and should act accordingly, which includes taking care of their needs to stay healthy and avoid burnout.

As Dr. Beecher pointed out, the employment model for psychiatrists does have many implications and constraints for patient care. I concur that having a small direct-care practice, sometimes called a “cash practice,” provides patients who can afford it the complete privacy they desire, with no one having access to their medical records except for their psychiatrist. Your book is a useful resource in that regard.

Dr. Kasturi is right about the importance of arriving at an accurate diagnosis before embarking on treatment; otherwise, patients will suffer from “therapeutic misadventures.” I have observed this being experienced by some of the patients referred to me because of “treatment resistance.”

Thanks again to my colleagues for their comments and suggestions to the newly minted psychiatrists for whom my editorial was intended.

Henry A. Nasrallah, MD
The Sydney W. Souers Endowed ChairProfessor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

I just finished reading Dr. Nasrallah’s editorial “The DNA of psychiatric practice: A covenant with our patients” (From the Editor, Current Psychiatry. May 2018, p. 20, 22). It offered very good messages. I can add a few more: “Make a commitment to life-long professional education. Understand how to critique research findings and their clinical applicability. Distinguish fad from science.”

David W. Goodman, MD, FAPA
Assistant Professor
Department of Psychiatry and Behavioral Sciences
Johns Hopkins School of Medicine
Baltimore, Maryland

Unfortunately, there is no way a physician who uses an electronic medical record can “Maintain total and unimpeachable confidentiality” as the “The medical record is a clinical, billing, legal, and research document.” Since 2003, patients no longer need to give consent for their medical records to be seen by the many staff members who work in treatment, payment, and health care operations, as long as these individuals follow the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Even de-identified data is no longer safe because re-identification is still possible with all the databases available for cross-referencing (ie, Facebook and hospitals as one instance).

So, when a patient finally tells you about a history of sexual abuse, do you make it clear to him or her that although this information is no longer private, it can be expected to be kept confidential by all the business associates, covered entities, government agencies, etc., who see their records?

Maybe there also would be fewer physician suicides if they could be assured of receiving truly private, off-the-grid psychiatric treatment.

Susan Israel, MD
Private psychiatric practice (retired)
Woodbridge, Connecticut

I just read your excellent and exhaustive May editorial, which offered advice for new psychiatrists. I was surprised to see that nowhere on the list was “Please remember to practice what you preach and be vigilant about self-care. We have become increasingly aware of the high rates of burnout among physicians. Know your own limitations so that you can appreciate the work that you do.”

Hal D. Cash, MD
Private psychiatric practice (retired)
Mica Collaborative
Wellesley, Massachusetts

Continue to: Dr. Nasrallah's editorial should have...

Dr. Nasrallah’s editorial should have listed something about the terms of payment for the psychiatrist who “provides” his or her clinical services to patients. This is an ethical issue. As you know, usually a corporation, rather than a patient, pays the psychiatrist. This payment may come from a health insurance company, government program, or (increasingly) a large clinic. When an organization pays the psychiatrist, it calls the tune for both the doctor’s employment and the patient’s access to quality care. Contracts between the hiring organization and psychiatrists are crucial, and therefore, most young doctors must join a hiring organization for financial reasons after completing their psychiatric residency. The young psychiatrists with whom I speak tell me they have no alternative but to be a “corporate dependent” in the world of 2018 psychiatric practice. They are aware of your (and my) noble principles, which should govern their relationships with patients. But the boss often does not agree with such principles.

In my book Passion for Patients¹ and as President of the 501(c)3 Minnesota Physician-Patient Alliance think tank (www.physician-patient.org), I argue for empowering patients with the means to direct payments to their physicians. Allowing patients this option is especially important for forming and maintaining strong relationship-based psychiatric and other medical treatments. In 1996, I was fed up with being a psychiatric medical director for 5 years at a large Minnesota Preferred Provider Organization. For me, the saving grace was being able to have an independent, private psychiatric practice. Most of my patients agreed.Therefore, I suggest another principle: “Build and maintain an independent psychiatric practice as an escape option no matter what you do should you decide the ethical practice of psychiatry is not possible if you are employed by a given organization.”

Lee Beecher, MD
Member
Editorial Advisory Board
Clinical Psychiatry News
Adjunct Professor of Psychiatry
University of Minnesota
Minneapolis, Minnesota

Reference

1. Beecher L, Racer D. Passion for patients. St. Paul, MN: Alethos Press; 2017.

I agree with Dr. Nasrallah’s guiding principles of psychiatry, which he proposes to govern the relationships of psychiatrists with their patients. However, there is one glaring omission. The first principle should be “to appropriately diagnose the patient’s condition,” which may or may not be based in psychiatry. Misdiagnoses and inappropriate pharmacologic therapy have ruined the lives of some very good friends of mine, and the need to first do no harm by misdiagnosing the patient, especially in psychiatric emergency rooms and on inpatient units, cannot be overemphasized.

These situations may not rear their head in the everyday practice of psychiatry. However, medical malpractice, especially in the field of psychiatry, is a constant caution that all new physicians need to watch for.

I would like to thank Dr. Nasrallah for his efforts to strengthen the patient–psychiatrist contract.

Rama Kasturi, PhD
Associate Professor (retired)
Department of Pharmacology and Cell Biophysics
Director (1999 to 2013)
Medical Pharmacology Tutorial Program University of Cincinnati, College of Medicine
Cincinnati, Ohio

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

I thank my 5 colleagues for their perspectives on my editorial. You all made cogent points.

I agree with Dr. Israel that our patients’ records are now accessible by many entities due to the drastic changes in our health care delivery system. However, while I regard the basic psychiatric signs and symptoms as medical data, like heart disease or cancer, there are personal details that emerge during psychotherapy that should remain confidential and not be included in the written record, and thus are not accessible to billers, health insurance companies, or malpractice lawyers. As for physicians who consider suicide because of fear of the consequences of receiving psychiatric treatment that becomes a matter of record, that is a matter of the unfortunate stigma and ignorance about mental illness and how treatable it can be.

Regarding Dr. Cash’s comments, I agree that psychiatrists should be (and are almost always are) introspective about their vulnerabilities and limitations, and should act accordingly, which includes taking care of their needs to stay healthy and avoid burnout.

As Dr. Beecher pointed out, the employment model for psychiatrists does have many implications and constraints for patient care. I concur that having a small direct-care practice, sometimes called a “cash practice,” provides patients who can afford it the complete privacy they desire, with no one having access to their medical records except for their psychiatrist. Your book is a useful resource in that regard.

Dr. Kasturi is right about the importance of arriving at an accurate diagnosis before embarking on treatment; otherwise, patients will suffer from “therapeutic misadventures.” I have observed this being experienced by some of the patients referred to me because of “treatment resistance.”

Thanks again to my colleagues for their comments and suggestions to the newly minted psychiatrists for whom my editorial was intended.

Henry A. Nasrallah, MD
The Sydney W. Souers Endowed ChairProfessor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

I just finished reading Dr. Nasrallah’s editorial “The DNA of psychiatric practice: A covenant with our patients” (From the Editor, Current Psychiatry. May 2018, p. 20, 22). It offered very good messages. I can add a few more: “Make a commitment to life-long professional education. Understand how to critique research findings and their clinical applicability. Distinguish fad from science.”

David W. Goodman, MD, FAPA
Assistant Professor
Department of Psychiatry and Behavioral Sciences
Johns Hopkins School of Medicine
Baltimore, Maryland

Unfortunately, there is no way a physician who uses an electronic medical record can “Maintain total and unimpeachable confidentiality” as the “The medical record is a clinical, billing, legal, and research document.” Since 2003, patients no longer need to give consent for their medical records to be seen by the many staff members who work in treatment, payment, and health care operations, as long as these individuals follow the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Even de-identified data is no longer safe because re-identification is still possible with all the databases available for cross-referencing (ie, Facebook and hospitals as one instance).

So, when a patient finally tells you about a history of sexual abuse, do you make it clear to him or her that although this information is no longer private, it can be expected to be kept confidential by all the business associates, covered entities, government agencies, etc., who see their records?

Maybe there also would be fewer physician suicides if they could be assured of receiving truly private, off-the-grid psychiatric treatment.

Susan Israel, MD
Private psychiatric practice (retired)
Woodbridge, Connecticut

I just read your excellent and exhaustive May editorial, which offered advice for new psychiatrists. I was surprised to see that nowhere on the list was “Please remember to practice what you preach and be vigilant about self-care. We have become increasingly aware of the high rates of burnout among physicians. Know your own limitations so that you can appreciate the work that you do.”

Hal D. Cash, MD
Private psychiatric practice (retired)
Mica Collaborative
Wellesley, Massachusetts

Continue to: Dr. Nasrallah's editorial should have...

Dr. Nasrallah’s editorial should have listed something about the terms of payment for the psychiatrist who “provides” his or her clinical services to patients. This is an ethical issue. As you know, usually a corporation, rather than a patient, pays the psychiatrist. This payment may come from a health insurance company, government program, or (increasingly) a large clinic. When an organization pays the psychiatrist, it calls the tune for both the doctor’s employment and the patient’s access to quality care. Contracts between the hiring organization and psychiatrists are crucial, and therefore, most young doctors must join a hiring organization for financial reasons after completing their psychiatric residency. The young psychiatrists with whom I speak tell me they have no alternative but to be a “corporate dependent” in the world of 2018 psychiatric practice. They are aware of your (and my) noble principles, which should govern their relationships with patients. But the boss often does not agree with such principles.

In my book Passion for Patients¹ and as President of the 501(c)3 Minnesota Physician-Patient Alliance think tank (www.physician-patient.org), I argue for empowering patients with the means to direct payments to their physicians. Allowing patients this option is especially important for forming and maintaining strong relationship-based psychiatric and other medical treatments. In 1996, I was fed up with being a psychiatric medical director for 5 years at a large Minnesota Preferred Provider Organization. For me, the saving grace was being able to have an independent, private psychiatric practice. Most of my patients agreed.Therefore, I suggest another principle: “Build and maintain an independent psychiatric practice as an escape option no matter what you do should you decide the ethical practice of psychiatry is not possible if you are employed by a given organization.”

Lee Beecher, MD
Member
Editorial Advisory Board
Clinical Psychiatry News
Adjunct Professor of Psychiatry
University of Minnesota
Minneapolis, Minnesota

Reference

1. Beecher L, Racer D. Passion for patients. St. Paul, MN: Alethos Press; 2017.

I agree with Dr. Nasrallah’s guiding principles of psychiatry, which he proposes to govern the relationships of psychiatrists with their patients. However, there is one glaring omission. The first principle should be “to appropriately diagnose the patient’s condition,” which may or may not be based in psychiatry. Misdiagnoses and inappropriate pharmacologic therapy have ruined the lives of some very good friends of mine, and the need to first do no harm by misdiagnosing the patient, especially in psychiatric emergency rooms and on inpatient units, cannot be overemphasized.

These situations may not rear their head in the everyday practice of psychiatry. However, medical malpractice, especially in the field of psychiatry, is a constant caution that all new physicians need to watch for.

I would like to thank Dr. Nasrallah for his efforts to strengthen the patient–psychiatrist contract.

Rama Kasturi, PhD
Associate Professor (retired)
Department of Pharmacology and Cell Biophysics
Director (1999 to 2013)
Medical Pharmacology Tutorial Program University of Cincinnati, College of Medicine
Cincinnati, Ohio

Continue to: Dr. Nasrallah responds

 

 

Dr. Nasrallah responds

I thank my 5 colleagues for their perspectives on my editorial. You all made cogent points.

I agree with Dr. Israel that our patients’ records are now accessible by many entities due to the drastic changes in our health care delivery system. However, while I regard the basic psychiatric signs and symptoms as medical data, like heart disease or cancer, there are personal details that emerge during psychotherapy that should remain confidential and not be included in the written record, and thus are not accessible to billers, health insurance companies, or malpractice lawyers. As for physicians who consider suicide because of fear of the consequences of receiving psychiatric treatment that becomes a matter of record, that is a matter of the unfortunate stigma and ignorance about mental illness and how treatable it can be.

Regarding Dr. Cash’s comments, I agree that psychiatrists should be (and are almost always are) introspective about their vulnerabilities and limitations, and should act accordingly, which includes taking care of their needs to stay healthy and avoid burnout.

As Dr. Beecher pointed out, the employment model for psychiatrists does have many implications and constraints for patient care. I concur that having a small direct-care practice, sometimes called a “cash practice,” provides patients who can afford it the complete privacy they desire, with no one having access to their medical records except for their psychiatrist. Your book is a useful resource in that regard.

Dr. Kasturi is right about the importance of arriving at an accurate diagnosis before embarking on treatment; otherwise, patients will suffer from “therapeutic misadventures.” I have observed this being experienced by some of the patients referred to me because of “treatment resistance.”

Thanks again to my colleagues for their comments and suggestions to the newly minted psychiatrists for whom my editorial was intended.

Henry A. Nasrallah, MD
The Sydney W. Souers Endowed ChairProfessor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to authors of a recent prospective study.

Nephron/Wikimedia Commons/CC BY-SA 3.0

Pretreatment ctDNA levels predicted 24-month event-free survival – an important disease milestone in DLBCL – as well as overall survival in the study, which included more than 200 patients at six institutions in North America and Europe.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy, according to corresponding author Ash A. Alizadeh, MD, PhD, of Stanford (Calif.) University and his coinvestigators.

“Our data suggest that both pretreatment and dynamic assessments of ctDNA are feasible and can add to established risk factors,” Dr. Alizadeh and his coauthors reported in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, they wrote in the report.

In an evaluation of pretreatment ctDNA levels, investigators found a 2.5 log haploid genome equivalents per milliliter (hGE/mL) threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P = .007) for frontline treatment and 2.9 (P = 0.01) for salvage.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy, according to investigators. An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P = .0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P less than .001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival, according to investigators.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index (IPI) and interim PET/CT studies, results of multivariable analysis showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, and conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

SOURCE: Kurtz DM et al. J Clin Oncol. 2018 Aug 20. doi: 10.1200/JCO.2018.78.5246.

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to authors of a recent prospective study.

Nephron/Wikimedia Commons/CC BY-SA 3.0

Pretreatment ctDNA levels predicted 24-month event-free survival – an important disease milestone in DLBCL – as well as overall survival in the study, which included more than 200 patients at six institutions in North America and Europe.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy, according to corresponding author Ash A. Alizadeh, MD, PhD, of Stanford (Calif.) University and his coinvestigators.

“Our data suggest that both pretreatment and dynamic assessments of ctDNA are feasible and can add to established risk factors,” Dr. Alizadeh and his coauthors reported in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, they wrote in the report.

In an evaluation of pretreatment ctDNA levels, investigators found a 2.5 log haploid genome equivalents per milliliter (hGE/mL) threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P = .007) for frontline treatment and 2.9 (P = 0.01) for salvage.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy, according to investigators. An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P = .0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P less than .001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival, according to investigators.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index (IPI) and interim PET/CT studies, results of multivariable analysis showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, and conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

SOURCE: Kurtz DM et al. J Clin Oncol. 2018 Aug 20. doi: 10.1200/JCO.2018.78.5246.

Measurement of circulating tumor DNA (ctDNA) could be a new and useful tool for predicting survival outcomes and response to therapy in patients with diffuse large B-cell lymphoma (DLBCL), according to authors of a recent prospective study.

Nephron/Wikimedia Commons/CC BY-SA 3.0

Pretreatment ctDNA levels predicted 24-month event-free survival – an important disease milestone in DLBCL – as well as overall survival in the study, which included more than 200 patients at six institutions in North America and Europe.

Changes in ctDNA during treatment were prognostic for outcomes as early as 21 days into therapy, according to corresponding author Ash A. Alizadeh, MD, PhD, of Stanford (Calif.) University and his coinvestigators.

“Our data suggest that both pretreatment and dynamic assessments of ctDNA are feasible and can add to established risk factors,” Dr. Alizadeh and his coauthors reported in the Journal of Clinical Oncology.

ctDNA was detected in 98% of the 217 patients evaluated, which demonstrated the “potentially universal applicability” of this approach, they wrote in the report.

In an evaluation of pretreatment ctDNA levels, investigators found a 2.5 log haploid genome equivalents per milliliter (hGE/mL) threshold stratified patient outcomes. Event-free survival was significantly inferior at 24 months in patients with ctDNA above that threshold, with hazard ratios of 2.6 (P = .007) for frontline treatment and 2.9 (P = 0.01) for salvage.

On-treatment ctDNA levels were favorably prognostic for outcomes in patients receiving frontline therapy, according to investigators. An early molecular response (EMR), defined as a 2-log decrease in ctDNA levels after one cycle of treatment, was associated with a 24-month event-free survival of 83% versus 50% for no EMR (P = .0015).

Major molecular response (MMR), defined as a 2.5-log drop in ctDNA after two cycles of treatment, was associated with a 24-month event-free survival of 82% versus 46% for no MMR in patients on frontline therapy (P less than .001).

In one cohort of patients receiving salvage therapy, EMR also predicted superior 24-month event-free survival, according to investigators.

The EMR measure was also favorably prognostic for overall survival in both the frontline and salvage settings.

The prognostic value of measuring ctDNA was independent of International Prognostic Index (IPI) and interim PET/CT studies, results of multivariable analysis showed.

Patients had “excellent outcomes” if they had both molecular response and favorable interim PET results, and conversely, patients were at “extremely high risk” for treatment failure if they had no molecular response and a positive PET scan.

“The identification of patients at exceptionally high risk (i.e., interim PET/CT positive and not achieving EMR/MMR) could provide an opportunity for early intervention with alternative treatments, including autologous bone marrow transplantation or chimeric antigen receptor T cells,” the researchers wrote.

Patients in the study were all treated with combination immunochemotherapy according to local standards.

Dr. Alizadeh reported disclosures related to CiberMed, Forty Seven, Janssen Oncology, Celgene, Roche/Genentech, and Gilead, as well as patent filings on ctDNA detection assigned to Stanford University.

SOURCE: Kurtz DM et al. J Clin Oncol. 2018 Aug 20. doi: 10.1200/JCO.2018.78.5246.

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

[email protected]

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

[email protected]

The Food and Drug Administration has approved ibrutinib (Imbruvica) for use in combination with rituximab to treat adults with Waldenström’s macroglobulinemia (WM).

Ibrutinib was approved for use as a single agent in adults with WM in January 2015.

[email protected]

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Hand, foot, and mouth disease (HFMD) has become a global challenge since its first description in 1957 in New Zealand and Canada. Clinicians readily recognize the characteristic syndrome in young children: fever associated with a papulovesicular rash affecting the palms or soles, or both, usually in spring, summer, or fall. In most cases the disease is self-limited, and brief. However, aseptic meningitis, brainstem encephalitis, acute flaccid paralysis or autonomic nervous system deregulation or cardiorespiratory failure may complicate the clinical course.

Copyright MidgleyDJ/Wikimedia Commons

HFMD is caused by enterovirus A (formerly called human enterovirus A) which consists of 25 serotypes including multiple coxsackie A viruses, multiple enteroviruses, simian enteroviruses, and baboon enterovirus A13. The clinical spectrum spans from herpangina, characterized by fever and painful mouth ulcers most prominent in the posterior oral cavity (uvula, tonsils, soft plates, and anterior pharyngeal folds), to HFMD with papulovesicular rash on palms and soles with or without mouth ulcers/vesicles.¹ In atypical cases, the rash may be maculopapular and may include the buttocks, knees or elbows.

In the United States, the predominant cause is coxsackie A16. However, coxsackie A6 appears to be emerging; often more than one HFMD causing virus is circulating concurrently and clinically indistinguishable. Globally, especially, in Asia, enterovirus 1 is a major cause of HFMD and more often associated with prominent central nervous system involvement. Disease can be sporadic or epidemic. An outbreak is usually defined as two or more cases within a defined geographic area; global epidemics as large as 1.5 million cases (Taiwan, 1998) have been reported, and outbreaks in China involving tens of thousands with multiple deaths have been reported.

In 2015, an outbreak of HFMD occurred during basic military training at Lackland Air Force Base, Bexar County, Texas, due to coxsackie A6.² The illness was characterized by prodromal symptoms of fever and malaise followed by erosive stomatitis and a rash that began on the palms and soles. The rate of infection among trainees was 4.7% (50 of 1,054 persons).

The differential diagnosis includes aphthous ulcers and herpetic gingivostomatitis.³ Aphthous ulcers are seen more commonly in older children and adolescents, are often recurrent, are not seasonal, and are not associated with rash. Herpes simplex virus gingivostomatitis usually has a febrile prodrome, perioral lesions are frequent in addition to gum and tongue involvement, and gingival bleeding is common. HFMD usually has an incubation period of 3-5 days and fever, malaise, and myalgia prodrome followed by onset of oral and dermatologic manifestations in sequence. The skin rash has features that may overlap with varicella, erythema multiforme (EM) or drug eruption. Varicella usually involves the face before spreading to the extremities, and the lesions are characterized by umbilication and subsequent crusting. EM is characterized by target lesions and drug eruptions are morbilliform or maculopapular. The majority of cases of HFMD are diagnosed clinically; polymerase chain reaction testing is available and best performed on throat or vesicle specimens. Serologic testing for A16 and enterovirus 71 (IgM) is available. Infected patients shed virus for 2-4 weeks and virus is stable in the environment resulting in fecal-oral or oral-oral transmission.

Atypical features of HFMD include occurrence in the winter (outbreak in Alabama in 2011/2012) or an atypical distribution of rash involving the antecubital and popliteal fossae distribution of rash, or “eczema coxsackium” – the accentuation of rash in areas previously affected by atopic dermatitis. Additional features may include nail dystrophies that manifest as Beau lines (deep grooved lines that run from side to side on the fingernail or the toenail) and nail shedding.

A spectrum of neurologic complications has been observed, more frequently with EV71 and more frequently in Asia. The spectrum includes aseptic meningitis and brainstem encephalitis. Progressive cardiopulmonary failure also can be observed in severe cases. The hallmark of severe disease is often presentation with high fever, sweating, mottled skin, and tachycardia. Early signs of CNS involvement include myoclonic jerks, ataxia, and “wandering eyes.”³ Elevated white blood count and/or hyperglycemia may distinguish children with severe disease from benign disease. Anecdotal reports of response to treatment with high-dose methylprednisolone and intravenous immune globulin suggest that the neurologic disease may be an autoimmune phenomenon.

The clinician’s primary role is to accurately diagnose HFMD, provide supportive care for fever and dehydration, and identify those with early signs or laboratory features heralding a more severe course of disease.³ The Centers for Disease Control and Prevention recommends frequent hand washing after toileting and changing diapers, disinfecting surfaces such as toys, avoiding close contact with infected individuals or sharing of personal items for all affected patients. No antiviral treatment is available although improvement following early treatment with acyclovir has been reported anecdotally. Intravenous immunoglobulin has been used in severe cases in Asia with retrospective data analysis suggesting a potential for improvement when administered prior to cardiopulmonary arrest.¹

Dr. Pelton is professor of pediatrics and epidemiology at Boston University. Dr. Pelton said he had no relevant financial disclosures. Email him at [email protected].

References

1. Cleveland Clinic Journal of Medicine 2014;81(9):537-43.

2. Morbidity and Mortality Weekly Report MMWR. 2016 Jul 8;65(26);678-80.

3. A Guide to clinical management and public health response for hand, foot and mouth disease (HFMD).

Hand, foot, and mouth disease (HFMD) has become a global challenge since its first description in 1957 in New Zealand and Canada. Clinicians readily recognize the characteristic syndrome in young children: fever associated with a papulovesicular rash affecting the palms or soles, or both, usually in spring, summer, or fall. In most cases the disease is self-limited, and brief. However, aseptic meningitis, brainstem encephalitis, acute flaccid paralysis or autonomic nervous system deregulation or cardiorespiratory failure may complicate the clinical course.

Copyright MidgleyDJ/Wikimedia Commons

HFMD is caused by enterovirus A (formerly called human enterovirus A) which consists of 25 serotypes including multiple coxsackie A viruses, multiple enteroviruses, simian enteroviruses, and baboon enterovirus A13. The clinical spectrum spans from herpangina, characterized by fever and painful mouth ulcers most prominent in the posterior oral cavity (uvula, tonsils, soft plates, and anterior pharyngeal folds), to HFMD with papulovesicular rash on palms and soles with or without mouth ulcers/vesicles.¹ In atypical cases, the rash may be maculopapular and may include the buttocks, knees or elbows.

In the United States, the predominant cause is coxsackie A16. However, coxsackie A6 appears to be emerging; often more than one HFMD causing virus is circulating concurrently and clinically indistinguishable. Globally, especially, in Asia, enterovirus 1 is a major cause of HFMD and more often associated with prominent central nervous system involvement. Disease can be sporadic or epidemic. An outbreak is usually defined as two or more cases within a defined geographic area; global epidemics as large as 1.5 million cases (Taiwan, 1998) have been reported, and outbreaks in China involving tens of thousands with multiple deaths have been reported.

In 2015, an outbreak of HFMD occurred during basic military training at Lackland Air Force Base, Bexar County, Texas, due to coxsackie A6.² The illness was characterized by prodromal symptoms of fever and malaise followed by erosive stomatitis and a rash that began on the palms and soles. The rate of infection among trainees was 4.7% (50 of 1,054 persons).

The differential diagnosis includes aphthous ulcers and herpetic gingivostomatitis.³ Aphthous ulcers are seen more commonly in older children and adolescents, are often recurrent, are not seasonal, and are not associated with rash. Herpes simplex virus gingivostomatitis usually has a febrile prodrome, perioral lesions are frequent in addition to gum and tongue involvement, and gingival bleeding is common. HFMD usually has an incubation period of 3-5 days and fever, malaise, and myalgia prodrome followed by onset of oral and dermatologic manifestations in sequence. The skin rash has features that may overlap with varicella, erythema multiforme (EM) or drug eruption. Varicella usually involves the face before spreading to the extremities, and the lesions are characterized by umbilication and subsequent crusting. EM is characterized by target lesions and drug eruptions are morbilliform or maculopapular. The majority of cases of HFMD are diagnosed clinically; polymerase chain reaction testing is available and best performed on throat or vesicle specimens. Serologic testing for A16 and enterovirus 71 (IgM) is available. Infected patients shed virus for 2-4 weeks and virus is stable in the environment resulting in fecal-oral or oral-oral transmission.

Atypical features of HFMD include occurrence in the winter (outbreak in Alabama in 2011/2012) or an atypical distribution of rash involving the antecubital and popliteal fossae distribution of rash, or “eczema coxsackium” – the accentuation of rash in areas previously affected by atopic dermatitis. Additional features may include nail dystrophies that manifest as Beau lines (deep grooved lines that run from side to side on the fingernail or the toenail) and nail shedding.

A spectrum of neurologic complications has been observed, more frequently with EV71 and more frequently in Asia. The spectrum includes aseptic meningitis and brainstem encephalitis. Progressive cardiopulmonary failure also can be observed in severe cases. The hallmark of severe disease is often presentation with high fever, sweating, mottled skin, and tachycardia. Early signs of CNS involvement include myoclonic jerks, ataxia, and “wandering eyes.”³ Elevated white blood count and/or hyperglycemia may distinguish children with severe disease from benign disease. Anecdotal reports of response to treatment with high-dose methylprednisolone and intravenous immune globulin suggest that the neurologic disease may be an autoimmune phenomenon.

The clinician’s primary role is to accurately diagnose HFMD, provide supportive care for fever and dehydration, and identify those with early signs or laboratory features heralding a more severe course of disease.³ The Centers for Disease Control and Prevention recommends frequent hand washing after toileting and changing diapers, disinfecting surfaces such as toys, avoiding close contact with infected individuals or sharing of personal items for all affected patients. No antiviral treatment is available although improvement following early treatment with acyclovir has been reported anecdotally. Intravenous immunoglobulin has been used in severe cases in Asia with retrospective data analysis suggesting a potential for improvement when administered prior to cardiopulmonary arrest.¹

Dr. Pelton is professor of pediatrics and epidemiology at Boston University. Dr. Pelton said he had no relevant financial disclosures. Email him at [email protected].

References

1. Cleveland Clinic Journal of Medicine 2014;81(9):537-43.

2. Morbidity and Mortality Weekly Report MMWR. 2016 Jul 8;65(26);678-80.

3. A Guide to clinical management and public health response for hand, foot and mouth disease (HFMD).

Hand, foot, and mouth disease (HFMD) has become a global challenge since its first description in 1957 in New Zealand and Canada. Clinicians readily recognize the characteristic syndrome in young children: fever associated with a papulovesicular rash affecting the palms or soles, or both, usually in spring, summer, or fall. In most cases the disease is self-limited, and brief. However, aseptic meningitis, brainstem encephalitis, acute flaccid paralysis or autonomic nervous system deregulation or cardiorespiratory failure may complicate the clinical course.

Copyright MidgleyDJ/Wikimedia Commons

HFMD is caused by enterovirus A (formerly called human enterovirus A) which consists of 25 serotypes including multiple coxsackie A viruses, multiple enteroviruses, simian enteroviruses, and baboon enterovirus A13. The clinical spectrum spans from herpangina, characterized by fever and painful mouth ulcers most prominent in the posterior oral cavity (uvula, tonsils, soft plates, and anterior pharyngeal folds), to HFMD with papulovesicular rash on palms and soles with or without mouth ulcers/vesicles.¹ In atypical cases, the rash may be maculopapular and may include the buttocks, knees or elbows.

In the United States, the predominant cause is coxsackie A16. However, coxsackie A6 appears to be emerging; often more than one HFMD causing virus is circulating concurrently and clinically indistinguishable. Globally, especially, in Asia, enterovirus 1 is a major cause of HFMD and more often associated with prominent central nervous system involvement. Disease can be sporadic or epidemic. An outbreak is usually defined as two or more cases within a defined geographic area; global epidemics as large as 1.5 million cases (Taiwan, 1998) have been reported, and outbreaks in China involving tens of thousands with multiple deaths have been reported.

In 2015, an outbreak of HFMD occurred during basic military training at Lackland Air Force Base, Bexar County, Texas, due to coxsackie A6.² The illness was characterized by prodromal symptoms of fever and malaise followed by erosive stomatitis and a rash that began on the palms and soles. The rate of infection among trainees was 4.7% (50 of 1,054 persons).

The differential diagnosis includes aphthous ulcers and herpetic gingivostomatitis.³ Aphthous ulcers are seen more commonly in older children and adolescents, are often recurrent, are not seasonal, and are not associated with rash. Herpes simplex virus gingivostomatitis usually has a febrile prodrome, perioral lesions are frequent in addition to gum and tongue involvement, and gingival bleeding is common. HFMD usually has an incubation period of 3-5 days and fever, malaise, and myalgia prodrome followed by onset of oral and dermatologic manifestations in sequence. The skin rash has features that may overlap with varicella, erythema multiforme (EM) or drug eruption. Varicella usually involves the face before spreading to the extremities, and the lesions are characterized by umbilication and subsequent crusting. EM is characterized by target lesions and drug eruptions are morbilliform or maculopapular. The majority of cases of HFMD are diagnosed clinically; polymerase chain reaction testing is available and best performed on throat or vesicle specimens. Serologic testing for A16 and enterovirus 71 (IgM) is available. Infected patients shed virus for 2-4 weeks and virus is stable in the environment resulting in fecal-oral or oral-oral transmission.

Atypical features of HFMD include occurrence in the winter (outbreak in Alabama in 2011/2012) or an atypical distribution of rash involving the antecubital and popliteal fossae distribution of rash, or “eczema coxsackium” – the accentuation of rash in areas previously affected by atopic dermatitis. Additional features may include nail dystrophies that manifest as Beau lines (deep grooved lines that run from side to side on the fingernail or the toenail) and nail shedding.

A spectrum of neurologic complications has been observed, more frequently with EV71 and more frequently in Asia. The spectrum includes aseptic meningitis and brainstem encephalitis. Progressive cardiopulmonary failure also can be observed in severe cases. The hallmark of severe disease is often presentation with high fever, sweating, mottled skin, and tachycardia. Early signs of CNS involvement include myoclonic jerks, ataxia, and “wandering eyes.”³ Elevated white blood count and/or hyperglycemia may distinguish children with severe disease from benign disease. Anecdotal reports of response to treatment with high-dose methylprednisolone and intravenous immune globulin suggest that the neurologic disease may be an autoimmune phenomenon.

The clinician’s primary role is to accurately diagnose HFMD, provide supportive care for fever and dehydration, and identify those with early signs or laboratory features heralding a more severe course of disease.³ The Centers for Disease Control and Prevention recommends frequent hand washing after toileting and changing diapers, disinfecting surfaces such as toys, avoiding close contact with infected individuals or sharing of personal items for all affected patients. No antiviral treatment is available although improvement following early treatment with acyclovir has been reported anecdotally. Intravenous immunoglobulin has been used in severe cases in Asia with retrospective data analysis suggesting a potential for improvement when administered prior to cardiopulmonary arrest.¹

Dr. Pelton is professor of pediatrics and epidemiology at Boston University. Dr. Pelton said he had no relevant financial disclosures. Email him at [email protected].

References

1. Cleveland Clinic Journal of Medicine 2014;81(9):537-43.

2. Morbidity and Mortality Weekly Report MMWR. 2016 Jul 8;65(26);678-80.

3. A Guide to clinical management and public health response for hand, foot and mouth disease (HFMD).

Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic, clear cell renal cell carcinoma (RCC), according to results of the randomized, phase 3 CARMENA trial.

Overall survival was not inferior in the sunitinib arm of the trial, which comprised 450 patients who were suitable candidates for nephrectomy and had MSKCC intermediate or poor risk disease.

These findings contrast with those of previous retrospective studies suggesting patients undergoing nephrectomy who were treated with targeted therapies had an overall survival benefit, according to Bernard Escudier, MD, of Gustave Roussy Institute, Villejuif, France, and his coauthors.

“Given the many approved options for systemic targeted therapy that are now available, the reassessment of the role of surgery in disease management is important,” Dr. Escudier and his colleagues noted. The report is in the New England Journal of Medicine.

The CARMENA trial enrolled 450 out of a planned 576 patients in 79 European centers between September 2009 and September 2017. A total of 226 were randomized to sunitinib alone and 224 to nephrectomy and sunitinib.

With a median follow-up of 50.9 months and 326 deaths, the hazard ratio for death was 0.89 (95% confidence interval, 0.71-1.10). The upper boundary of the 95% CI for noninferiority was 1.20, according to the report.

Median overall survival was 18.4 months for the sunitinib alone arm, and 13.9 months for the nephrectomy-plus-sunitinib arm. While the study was statistically underpowered because of incomplete enrollment, that “trend in longer overall survival” supports the findings favoring sunitinib alone in this noninferiority trial, the authors noted.

Safety results were as expected based on previous trial results, according to the investigators. Grade 3/4 adverse events occurred in 91 patients (42.7%) in the sunitinib group, and 61 (32.8%) in the nephrectomy-sunitinib group, they reported. Nine patients in the sunitinib group had grade 3/4 renal or urinary tract disorders, versus 1 in the nephrectomy-sunitinib group (P = .051).

These findings confirm current clinical practice guidelines on the use of systemic targeted therapy in patients with poor-risk metastatic RCC, according to the authors.

However, targeted therapy in this setting has evolved considerably since the CARMENA trial was designed.

Sunitinib remains one of the most commonly used treatments in patients with good or intermediate prognosis metastatic RCC; however, recent randomized trials show the superiority of the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor combination of nivolumab plus ipilimumab over sunitinib.

Those newer agents will likely become initial treatment options for intermediate- and poor-risk groups, according to the authors.

Both cabozantinib and nivolumab plus ipilimumab are listed as first-line treatment options for intermediate- and poor-risk patients in the most recent clinical practice guidelines from the National Comprehensive Cancer Network.

Nephrectomy may have a role for symptom control in some patients with metastatic RCC, based on results of previous retrospective studies suggesting benefit.

“There is no ‘one size fits all’ approach,” Dr. Escudier and his coauthors wrote. “The multimodal approach of individualized treatment provides appropriate management of metastatic renal-cell carcinoma.”

Dr. Escudier reported personal fees from Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, and Roche outside the submitted work. Coauthors reported disclosures with Bayer, MSD, Janssen, Astellas, Bouchara, Ferring, and others.

SOURCE: Méjean A et al. N Engl J Med. 2018 Aug 2. doi: 10.1056/NEJMoa1803675.

Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic, clear cell renal cell carcinoma (RCC), according to results of the randomized, phase 3 CARMENA trial.

Overall survival was not inferior in the sunitinib arm of the trial, which comprised 450 patients who were suitable candidates for nephrectomy and had MSKCC intermediate or poor risk disease.

These findings contrast with those of previous retrospective studies suggesting patients undergoing nephrectomy who were treated with targeted therapies had an overall survival benefit, according to Bernard Escudier, MD, of Gustave Roussy Institute, Villejuif, France, and his coauthors.

“Given the many approved options for systemic targeted therapy that are now available, the reassessment of the role of surgery in disease management is important,” Dr. Escudier and his colleagues noted. The report is in the New England Journal of Medicine.

The CARMENA trial enrolled 450 out of a planned 576 patients in 79 European centers between September 2009 and September 2017. A total of 226 were randomized to sunitinib alone and 224 to nephrectomy and sunitinib.

With a median follow-up of 50.9 months and 326 deaths, the hazard ratio for death was 0.89 (95% confidence interval, 0.71-1.10). The upper boundary of the 95% CI for noninferiority was 1.20, according to the report.

Median overall survival was 18.4 months for the sunitinib alone arm, and 13.9 months for the nephrectomy-plus-sunitinib arm. While the study was statistically underpowered because of incomplete enrollment, that “trend in longer overall survival” supports the findings favoring sunitinib alone in this noninferiority trial, the authors noted.

Safety results were as expected based on previous trial results, according to the investigators. Grade 3/4 adverse events occurred in 91 patients (42.7%) in the sunitinib group, and 61 (32.8%) in the nephrectomy-sunitinib group, they reported. Nine patients in the sunitinib group had grade 3/4 renal or urinary tract disorders, versus 1 in the nephrectomy-sunitinib group (P = .051).

These findings confirm current clinical practice guidelines on the use of systemic targeted therapy in patients with poor-risk metastatic RCC, according to the authors.

However, targeted therapy in this setting has evolved considerably since the CARMENA trial was designed.

Sunitinib remains one of the most commonly used treatments in patients with good or intermediate prognosis metastatic RCC; however, recent randomized trials show the superiority of the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor combination of nivolumab plus ipilimumab over sunitinib.

Those newer agents will likely become initial treatment options for intermediate- and poor-risk groups, according to the authors.

Both cabozantinib and nivolumab plus ipilimumab are listed as first-line treatment options for intermediate- and poor-risk patients in the most recent clinical practice guidelines from the National Comprehensive Cancer Network.

Nephrectomy may have a role for symptom control in some patients with metastatic RCC, based on results of previous retrospective studies suggesting benefit.

“There is no ‘one size fits all’ approach,” Dr. Escudier and his coauthors wrote. “The multimodal approach of individualized treatment provides appropriate management of metastatic renal-cell carcinoma.”

Dr. Escudier reported personal fees from Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, and Roche outside the submitted work. Coauthors reported disclosures with Bayer, MSD, Janssen, Astellas, Bouchara, Ferring, and others.

SOURCE: Méjean A et al. N Engl J Med. 2018 Aug 2. doi: 10.1056/NEJMoa1803675.

Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic, clear cell renal cell carcinoma (RCC), according to results of the randomized, phase 3 CARMENA trial.

Overall survival was not inferior in the sunitinib arm of the trial, which comprised 450 patients who were suitable candidates for nephrectomy and had MSKCC intermediate or poor risk disease.

These findings contrast with those of previous retrospective studies suggesting patients undergoing nephrectomy who were treated with targeted therapies had an overall survival benefit, according to Bernard Escudier, MD, of Gustave Roussy Institute, Villejuif, France, and his coauthors.

“Given the many approved options for systemic targeted therapy that are now available, the reassessment of the role of surgery in disease management is important,” Dr. Escudier and his colleagues noted. The report is in the New England Journal of Medicine.

The CARMENA trial enrolled 450 out of a planned 576 patients in 79 European centers between September 2009 and September 2017. A total of 226 were randomized to sunitinib alone and 224 to nephrectomy and sunitinib.

With a median follow-up of 50.9 months and 326 deaths, the hazard ratio for death was 0.89 (95% confidence interval, 0.71-1.10). The upper boundary of the 95% CI for noninferiority was 1.20, according to the report.

Median overall survival was 18.4 months for the sunitinib alone arm, and 13.9 months for the nephrectomy-plus-sunitinib arm. While the study was statistically underpowered because of incomplete enrollment, that “trend in longer overall survival” supports the findings favoring sunitinib alone in this noninferiority trial, the authors noted.

Safety results were as expected based on previous trial results, according to the investigators. Grade 3/4 adverse events occurred in 91 patients (42.7%) in the sunitinib group, and 61 (32.8%) in the nephrectomy-sunitinib group, they reported. Nine patients in the sunitinib group had grade 3/4 renal or urinary tract disorders, versus 1 in the nephrectomy-sunitinib group (P = .051).

These findings confirm current clinical practice guidelines on the use of systemic targeted therapy in patients with poor-risk metastatic RCC, according to the authors.

However, targeted therapy in this setting has evolved considerably since the CARMENA trial was designed.

Sunitinib remains one of the most commonly used treatments in patients with good or intermediate prognosis metastatic RCC; however, recent randomized trials show the superiority of the c-MET inhibitor cabozantinib and the immune checkpoint inhibitor combination of nivolumab plus ipilimumab over sunitinib.

Those newer agents will likely become initial treatment options for intermediate- and poor-risk groups, according to the authors.

Both cabozantinib and nivolumab plus ipilimumab are listed as first-line treatment options for intermediate- and poor-risk patients in the most recent clinical practice guidelines from the National Comprehensive Cancer Network.

Nephrectomy may have a role for symptom control in some patients with metastatic RCC, based on results of previous retrospective studies suggesting benefit.

“There is no ‘one size fits all’ approach,” Dr. Escudier and his coauthors wrote. “The multimodal approach of individualized treatment provides appropriate management of metastatic renal-cell carcinoma.”

Dr. Escudier reported personal fees from Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, and Roche outside the submitted work. Coauthors reported disclosures with Bayer, MSD, Janssen, Astellas, Bouchara, Ferring, and others.

SOURCE: Méjean A et al. N Engl J Med. 2018 Aug 2. doi: 10.1056/NEJMoa1803675.

There are many lawmakers who made their names in health care, seeking to usher through historic changes to a broken system.

Sen. John McCain was not one of them.

And yet, the six-term senator from Arizona and decorated military veteran leaves behind his own health care legacy, seemingly driven less by his interest in health care policy than his disdain for bullies trampling the “little guy.”

He was not always successful. While Sen. McCain was instrumental in the passage of the Americans with Disabilities Act in 1990, most of the health initiatives he undertook failed after running afoul of traditional Republican priorities. His prescriptions often involved more government regulation and increased taxes.

In 2008, as the Republican nominee for president, he ran on a health care platform that dumbfounded many in his party who worried it would raise taxes on top of overhauling the U.S. tradition of workplace insurance.

Many will remember Sen. McCain as the incidental savior of the Affordable Care Act, whose late-night thumbs-down vote halted his party’s most promising effort to overturn a major Democratic achievement – the signature achievement, in fact, of the Democrat who beat him to become president. It was a vote that earned him regular – and biting – admonishments from President Donald Trump.

Sen. McCain died Aug. 25, following a battle with brain cancer. He was 81. Coincidentally, his Senate colleague and good friend Ted Kennedy died on the same date, Aug. 25, 9 years ago, succumbing to the same type of rare brain tumor.

Whether indulging in conspiracy theories or wishful thinking, some have attributed Sen. McCain’s vote on the ACA in July 2017 to a change of heart shortly after his terminal cancer diagnosis.

But Sen. McCain spent much of his 35 years in Congress fighting a never-ending supply of goliaths, among them health insurance companies, the tobacco industry and, in his estimation, the Affordable Care Act, a law that extended insurance coverage to millions of Americans but did not solve the system’s ballooning costs.

His prey were the sort of boogeymen that made for compelling campaign ads in a career stacked with campaigns. But Sen. McCain was “always for the little guy,” said Douglas Holtz-Eakin, the chief domestic policy adviser on Sen. McCain’s 2008 presidential campaign.

“John’s idea of empathy is saying to you, ‘I’ll punch the bully for you,’ ” he said in an interview before Sen. McCain’s death.

Sen. McCain’s distaste for President Barack Obama’s health care law was no secret. While he agreed that the health care system was broken, he did not think more government involvement would fix it. Like most Republicans, he campaigned in his last Senate race on a promise to repeal and replace the law with something better.

After Republicans spent months bickering amongst themselves about what was better, Sen. McCain was disappointed in the option presented to senators hours before their vote: Hobble the ACA, and trust that a handful of lawmakers would be able to craft an alternative behind closed doors, despite failing to accomplish that very thing after years of trying.

What bothered Sen. McCain more, though, was his party’s strategy to pass their so-called skinny repeal measure, skipping committee consideration and delivering it straight to the floor. They also rejected any input from the opposing party, a tactic for which he had slammed Democrats when the ACA passed in 2010 without a single GOP vote. He lamented that Republican leaders had cast aside compromise-nurturing Senate procedures in pursuit of political victory.

In his 2018 memoirs, “The Restless Wave,” Sen. McCain said even President Obama called to express gratitude for Sen. McCain’s vote against the Republican repeal bill.

“I was thanked for my vote by Democratic friends more profusely than I should have been for helping save Obamacare,” Sen. McCain wrote. “That had not been my goal.”

Better known for his work on campaign finance reform and the military, Sen. McCain did have a hand in one landmark health bill – the Americans with Disabilities Act of 1990, the country’s first comprehensive civil rights law that addressed the needs of those with disabilities. An early cosponsor of the legislation, he championed the rights of the disabled, speaking of the service members and civilians he met in his travels who had become disabled during military conflict.

Sen. McCain himself had limited use of his arms due to injuries inflicted while he was a prisoner of war in Vietnam, though he was quicker to talk about the troubles of others than his own when advocating policy.

Yet two of his biggest bills on health care ended in defeat.

In 1998, Sen. McCain introduced a sweeping bill that would regulate the tobacco industry and increase taxes on cigarettes, hoping to discourage teenagers from smoking and raise money for research and related health care costs. It faltered under opposition from his fellow Republicans.

Sen. McCain also joined an effort with two Democratic senators, Sen. Kennedy of Massachusetts and Sen. John Edwards of North Carolina, to pass a patients’ bill of rights in 2001. He resisted at first, concerned in particular about the right it gave patients to sue health care companies, said Sonya Elling, who served as a health care aide in Sen. McCain’s office for about a decade. But he came around.

“It was the human, the personal aspect of it, basically,” said Ms. Elling, now senior director of federal affairs at Eli Lilly. “It was providing him some of the real stories about how people were being hurt and some of the barriers that existed for people in the current system.”

The legislation would have granted patients with private insurance the right to emergency and specialist care in addition to the right to seek redress for being wrongly denied care. But President George W. Bush threatened to veto the measure, claiming it would fuel frivolous lawsuits. The bill failed.

Sen. McCain’s health care efforts bolstered his reputation as a lawmaker willing to work across the aisle. Sen. Chuck Schumer of New York, now the Senate’s Democratic leader, sought his help on legislation in 2001 to expand access to generic drugs. In 2015, Sen. McCain led a bipartisan coalition to pass a law that would strengthen mental health and suicide prevention programs for veterans, among other veterans’ care measures he undertook.

It was Sen. McCain’s relationship with Sen. Kennedy that stood out, inspiring eerie comparisons when Sen. McCain was diagnosed last year with glioblastoma – a form of brain cancer – shortly before his vote saved the Affordable Care Act.

That same aggressive brain cancer killed Sen. Kennedy in 2009, months before the passage of the law that helped realize his work to secure better access for Americans to health care.

“I had strenuously opposed it, but I was very sorry that Ted had not lived to see his long crusade come to a successful end,” Sen. McCain wrote in his 2018 book.

While some of his biggest health care measures failed, the experiences helped burnish Sen. McCain’s résumé for his 2000 and 2008 presidential campaigns.

In 2007, trailing other favored Republicans, such as former New York City mayor Rudy Giuliani in early polling and fundraising, Sen. McCain asked his advisers to craft a health care proposal, said Mr. Holtz-Eakin. It was an unusual move for a Republican presidential primary.

The result was a remarkable plan that would eliminate the tax break employers get for providing health benefits to workers, known as the employer exclusion, and replace it with refundable tax credits to help people – not just those working in firms that supplied coverage – buy insurance individually. He argued employer-provided plans were driving up costs, as well as keeping salaries lower.

The plan was controversial, triggering “a total freak-out” when Sen. McCain gained more prominence and scrutiny, Mr. Holtz-Eakin said. But Sen. McCain stood by it.

“He might not have been a health guy, but he knew how important that was,” he said. “And he was relentless about getting it done.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

There are many lawmakers who made their names in health care, seeking to usher through historic changes to a broken system.

Sen. John McCain was not one of them.

And yet, the six-term senator from Arizona and decorated military veteran leaves behind his own health care legacy, seemingly driven less by his interest in health care policy than his disdain for bullies trampling the “little guy.”

He was not always successful. While Sen. McCain was instrumental in the passage of the Americans with Disabilities Act in 1990, most of the health initiatives he undertook failed after running afoul of traditional Republican priorities. His prescriptions often involved more government regulation and increased taxes.

In 2008, as the Republican nominee for president, he ran on a health care platform that dumbfounded many in his party who worried it would raise taxes on top of overhauling the U.S. tradition of workplace insurance.

Many will remember Sen. McCain as the incidental savior of the Affordable Care Act, whose late-night thumbs-down vote halted his party’s most promising effort to overturn a major Democratic achievement – the signature achievement, in fact, of the Democrat who beat him to become president. It was a vote that earned him regular – and biting – admonishments from President Donald Trump.

Sen. McCain died Aug. 25, following a battle with brain cancer. He was 81. Coincidentally, his Senate colleague and good friend Ted Kennedy died on the same date, Aug. 25, 9 years ago, succumbing to the same type of rare brain tumor.

Whether indulging in conspiracy theories or wishful thinking, some have attributed Sen. McCain’s vote on the ACA in July 2017 to a change of heart shortly after his terminal cancer diagnosis.

But Sen. McCain spent much of his 35 years in Congress fighting a never-ending supply of goliaths, among them health insurance companies, the tobacco industry and, in his estimation, the Affordable Care Act, a law that extended insurance coverage to millions of Americans but did not solve the system’s ballooning costs.

His prey were the sort of boogeymen that made for compelling campaign ads in a career stacked with campaigns. But Sen. McCain was “always for the little guy,” said Douglas Holtz-Eakin, the chief domestic policy adviser on Sen. McCain’s 2008 presidential campaign.

“John’s idea of empathy is saying to you, ‘I’ll punch the bully for you,’ ” he said in an interview before Sen. McCain’s death.

Sen. McCain’s distaste for President Barack Obama’s health care law was no secret. While he agreed that the health care system was broken, he did not think more government involvement would fix it. Like most Republicans, he campaigned in his last Senate race on a promise to repeal and replace the law with something better.

After Republicans spent months bickering amongst themselves about what was better, Sen. McCain was disappointed in the option presented to senators hours before their vote: Hobble the ACA, and trust that a handful of lawmakers would be able to craft an alternative behind closed doors, despite failing to accomplish that very thing after years of trying.

What bothered Sen. McCain more, though, was his party’s strategy to pass their so-called skinny repeal measure, skipping committee consideration and delivering it straight to the floor. They also rejected any input from the opposing party, a tactic for which he had slammed Democrats when the ACA passed in 2010 without a single GOP vote. He lamented that Republican leaders had cast aside compromise-nurturing Senate procedures in pursuit of political victory.

In his 2018 memoirs, “The Restless Wave,” Sen. McCain said even President Obama called to express gratitude for Sen. McCain’s vote against the Republican repeal bill.

“I was thanked for my vote by Democratic friends more profusely than I should have been for helping save Obamacare,” Sen. McCain wrote. “That had not been my goal.”

Better known for his work on campaign finance reform and the military, Sen. McCain did have a hand in one landmark health bill – the Americans with Disabilities Act of 1990, the country’s first comprehensive civil rights law that addressed the needs of those with disabilities. An early cosponsor of the legislation, he championed the rights of the disabled, speaking of the service members and civilians he met in his travels who had become disabled during military conflict.

Sen. McCain himself had limited use of his arms due to injuries inflicted while he was a prisoner of war in Vietnam, though he was quicker to talk about the troubles of others than his own when advocating policy.

Yet two of his biggest bills on health care ended in defeat.

In 1998, Sen. McCain introduced a sweeping bill that would regulate the tobacco industry and increase taxes on cigarettes, hoping to discourage teenagers from smoking and raise money for research and related health care costs. It faltered under opposition from his fellow Republicans.

Sen. McCain also joined an effort with two Democratic senators, Sen. Kennedy of Massachusetts and Sen. John Edwards of North Carolina, to pass a patients’ bill of rights in 2001. He resisted at first, concerned in particular about the right it gave patients to sue health care companies, said Sonya Elling, who served as a health care aide in Sen. McCain’s office for about a decade. But he came around.

“It was the human, the personal aspect of it, basically,” said Ms. Elling, now senior director of federal affairs at Eli Lilly. “It was providing him some of the real stories about how people were being hurt and some of the barriers that existed for people in the current system.”

The legislation would have granted patients with private insurance the right to emergency and specialist care in addition to the right to seek redress for being wrongly denied care. But President George W. Bush threatened to veto the measure, claiming it would fuel frivolous lawsuits. The bill failed.

Sen. McCain’s health care efforts bolstered his reputation as a lawmaker willing to work across the aisle. Sen. Chuck Schumer of New York, now the Senate’s Democratic leader, sought his help on legislation in 2001 to expand access to generic drugs. In 2015, Sen. McCain led a bipartisan coalition to pass a law that would strengthen mental health and suicide prevention programs for veterans, among other veterans’ care measures he undertook.

It was Sen. McCain’s relationship with Sen. Kennedy that stood out, inspiring eerie comparisons when Sen. McCain was diagnosed last year with glioblastoma – a form of brain cancer – shortly before his vote saved the Affordable Care Act.

That same aggressive brain cancer killed Sen. Kennedy in 2009, months before the passage of the law that helped realize his work to secure better access for Americans to health care.

“I had strenuously opposed it, but I was very sorry that Ted had not lived to see his long crusade come to a successful end,” Sen. McCain wrote in his 2018 book.

While some of his biggest health care measures failed, the experiences helped burnish Sen. McCain’s résumé for his 2000 and 2008 presidential campaigns.

In 2007, trailing other favored Republicans, such as former New York City mayor Rudy Giuliani in early polling and fundraising, Sen. McCain asked his advisers to craft a health care proposal, said Mr. Holtz-Eakin. It was an unusual move for a Republican presidential primary.

The result was a remarkable plan that would eliminate the tax break employers get for providing health benefits to workers, known as the employer exclusion, and replace it with refundable tax credits to help people – not just those working in firms that supplied coverage – buy insurance individually. He argued employer-provided plans were driving up costs, as well as keeping salaries lower.

The plan was controversial, triggering “a total freak-out” when Sen. McCain gained more prominence and scrutiny, Mr. Holtz-Eakin said. But Sen. McCain stood by it.

“He might not have been a health guy, but he knew how important that was,” he said. “And he was relentless about getting it done.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

There are many lawmakers who made their names in health care, seeking to usher through historic changes to a broken system.

Sen. John McCain was not one of them.

And yet, the six-term senator from Arizona and decorated military veteran leaves behind his own health care legacy, seemingly driven less by his interest in health care policy than his disdain for bullies trampling the “little guy.”

He was not always successful. While Sen. McCain was instrumental in the passage of the Americans with Disabilities Act in 1990, most of the health initiatives he undertook failed after running afoul of traditional Republican priorities. His prescriptions often involved more government regulation and increased taxes.

In 2008, as the Republican nominee for president, he ran on a health care platform that dumbfounded many in his party who worried it would raise taxes on top of overhauling the U.S. tradition of workplace insurance.

Many will remember Sen. McCain as the incidental savior of the Affordable Care Act, whose late-night thumbs-down vote halted his party’s most promising effort to overturn a major Democratic achievement – the signature achievement, in fact, of the Democrat who beat him to become president. It was a vote that earned him regular – and biting – admonishments from President Donald Trump.

Sen. McCain died Aug. 25, following a battle with brain cancer. He was 81. Coincidentally, his Senate colleague and good friend Ted Kennedy died on the same date, Aug. 25, 9 years ago, succumbing to the same type of rare brain tumor.

Whether indulging in conspiracy theories or wishful thinking, some have attributed Sen. McCain’s vote on the ACA in July 2017 to a change of heart shortly after his terminal cancer diagnosis.

But Sen. McCain spent much of his 35 years in Congress fighting a never-ending supply of goliaths, among them health insurance companies, the tobacco industry and, in his estimation, the Affordable Care Act, a law that extended insurance coverage to millions of Americans but did not solve the system’s ballooning costs.

His prey were the sort of boogeymen that made for compelling campaign ads in a career stacked with campaigns. But Sen. McCain was “always for the little guy,” said Douglas Holtz-Eakin, the chief domestic policy adviser on Sen. McCain’s 2008 presidential campaign.

“John’s idea of empathy is saying to you, ‘I’ll punch the bully for you,’ ” he said in an interview before Sen. McCain’s death.

Sen. McCain’s distaste for President Barack Obama’s health care law was no secret. While he agreed that the health care system was broken, he did not think more government involvement would fix it. Like most Republicans, he campaigned in his last Senate race on a promise to repeal and replace the law with something better.

After Republicans spent months bickering amongst themselves about what was better, Sen. McCain was disappointed in the option presented to senators hours before their vote: Hobble the ACA, and trust that a handful of lawmakers would be able to craft an alternative behind closed doors, despite failing to accomplish that very thing after years of trying.

What bothered Sen. McCain more, though, was his party’s strategy to pass their so-called skinny repeal measure, skipping committee consideration and delivering it straight to the floor. They also rejected any input from the opposing party, a tactic for which he had slammed Democrats when the ACA passed in 2010 without a single GOP vote. He lamented that Republican leaders had cast aside compromise-nurturing Senate procedures in pursuit of political victory.

In his 2018 memoirs, “The Restless Wave,” Sen. McCain said even President Obama called to express gratitude for Sen. McCain’s vote against the Republican repeal bill.

“I was thanked for my vote by Democratic friends more profusely than I should have been for helping save Obamacare,” Sen. McCain wrote. “That had not been my goal.”

Better known for his work on campaign finance reform and the military, Sen. McCain did have a hand in one landmark health bill – the Americans with Disabilities Act of 1990, the country’s first comprehensive civil rights law that addressed the needs of those with disabilities. An early cosponsor of the legislation, he championed the rights of the disabled, speaking of the service members and civilians he met in his travels who had become disabled during military conflict.

Sen. McCain himself had limited use of his arms due to injuries inflicted while he was a prisoner of war in Vietnam, though he was quicker to talk about the troubles of others than his own when advocating policy.

Yet two of his biggest bills on health care ended in defeat.

In 1998, Sen. McCain introduced a sweeping bill that would regulate the tobacco industry and increase taxes on cigarettes, hoping to discourage teenagers from smoking and raise money for research and related health care costs. It faltered under opposition from his fellow Republicans.

Sen. McCain also joined an effort with two Democratic senators, Sen. Kennedy of Massachusetts and Sen. John Edwards of North Carolina, to pass a patients’ bill of rights in 2001. He resisted at first, concerned in particular about the right it gave patients to sue health care companies, said Sonya Elling, who served as a health care aide in Sen. McCain’s office for about a decade. But he came around.

“It was the human, the personal aspect of it, basically,” said Ms. Elling, now senior director of federal affairs at Eli Lilly. “It was providing him some of the real stories about how people were being hurt and some of the barriers that existed for people in the current system.”

The legislation would have granted patients with private insurance the right to emergency and specialist care in addition to the right to seek redress for being wrongly denied care. But President George W. Bush threatened to veto the measure, claiming it would fuel frivolous lawsuits. The bill failed.

Sen. McCain’s health care efforts bolstered his reputation as a lawmaker willing to work across the aisle. Sen. Chuck Schumer of New York, now the Senate’s Democratic leader, sought his help on legislation in 2001 to expand access to generic drugs. In 2015, Sen. McCain led a bipartisan coalition to pass a law that would strengthen mental health and suicide prevention programs for veterans, among other veterans’ care measures he undertook.

It was Sen. McCain’s relationship with Sen. Kennedy that stood out, inspiring eerie comparisons when Sen. McCain was diagnosed last year with glioblastoma – a form of brain cancer – shortly before his vote saved the Affordable Care Act.

That same aggressive brain cancer killed Sen. Kennedy in 2009, months before the passage of the law that helped realize his work to secure better access for Americans to health care.

“I had strenuously opposed it, but I was very sorry that Ted had not lived to see his long crusade come to a successful end,” Sen. McCain wrote in his 2018 book.

While some of his biggest health care measures failed, the experiences helped burnish Sen. McCain’s résumé for his 2000 and 2008 presidential campaigns.

In 2007, trailing other favored Republicans, such as former New York City mayor Rudy Giuliani in early polling and fundraising, Sen. McCain asked his advisers to craft a health care proposal, said Mr. Holtz-Eakin. It was an unusual move for a Republican presidential primary.

The result was a remarkable plan that would eliminate the tax break employers get for providing health benefits to workers, known as the employer exclusion, and replace it with refundable tax credits to help people – not just those working in firms that supplied coverage – buy insurance individually. He argued employer-provided plans were driving up costs, as well as keeping salaries lower.

The plan was controversial, triggering “a total freak-out” when Sen. McCain gained more prominence and scrutiny, Mr. Holtz-Eakin said. But Sen. McCain stood by it.

“He might not have been a health guy, but he knew how important that was,” he said. “And he was relentless about getting it done.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.