Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Photo by Larry Young

LA JOLLA, CA—A 2-drug combination has demonstrated preferential activity in T-cell lymphomas over B-cell lymphomas, according to researchers.

In a small, phase 1/2 study, treatment with oral 5-azacitidine and romidepsin produced a higher overall response rate (ORR) and prolonged progression-free survival (PFS) in patients with T-cell lymphomas.

“In a very limited sample, we’ve definitely observed exquisite activity of the combination in patients with T-cell lymphoma compared to all other subtypes,” said Lorenzo Falchi, MD, of Columbia University Medical Center in New York, New York.

Dr Falchi presented these results at the 10th Annual T-cell Lymphoma Forum.

The research was funded by the Leukemia and Lymphoma Society, the Lymphoma Research Fund at Columbia University, and Celgene.

The phase 1 portion of this study included patients with previously treated non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma. The phase 2 portion included only patients with T-cell lymphomas, newly diagnosed or previously treated.

Thirty-three patients were enrolled—12 with Hodgkin lymphoma, 8 with B-cell NHL, and 13 with T-cell NHL.

The patients’ median age was 54 (range, 23-79). Fifty-seven percent (n=19) were male. Sixty-one percent of patients were non-Hispanic white (n=20), 24% (n=8) were black, and 12% (n=4) were Asian.

“This was a very heavily pretreated patient population,” Dr Falchi noted. “I’d like to emphasize that the median number of prior treatments is 5 [range, 0-15].”

“Over half of patients had had stem cell transplantation [17 autologous and 5 allogeneic]. And, if you look at the subtypes by histology, all patients, pretty much, at some point, received all the standard chemotherapy or treatment approaches that are typically used for that subtype.”

Treatment

Patients were divided into 7 dosing cohorts. Azacitidine doses ranged from 100 mg to 300 mg on days 1-14 or days 1-21 per cycle.

Romidepsin doses ranged from 10 mg/m² to 14 mg/m². The drug was given on days 8 and 15 every 21 or 28 days, or it was given on days 8, 15, and 22 every 35 days.

There were 2 dose-limiting toxicities (DLTs) in cohort 2—grade 3 thrombocytopenia and grade 3 pleural effusion. In this cohort, 3 patients received azacitidine at 200 mg on days 1-14 plus romidepsin at 10 mg/m² on days 8 and 15 every 21 days.

There were 3 DLTs in cohort 7—2 cases of grade 4 neutropenia and 1 case of grade 3 thrombocytopenia. In this cohort, 5 patients received azacitidine at 300 mg on days 1 to 21 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Because of the DLTs in cohort 7, cohort 6 was chosen as the maximum tolerated dose. In cohort 6, 3 patients received azacitidine at 300 mg on days 1-14 plus romidepsin at 14 mg/m² on days 8, 15, and 22 every 35 days.

Patients in the expansion cohort received treatment at the maximum tolerated dose. This cohort included 7 patients with T-cell lymphoma.

Safety

Treatment-emergent adverse events occurring in at least 5% of patients included:

• Anemia—3% grade 3
• Anorexia—9% grade 1
• Back pain—6% grade 2
• Constipation—6% grade 1
• Cough—9% grade 1
• Depression—3% grade 1 and 2
• Diarrhea—15% grade 1 and 6% grade 2
• Dyspnea—3% grade 1 and 2
• Fatigue—21% grade 1, 9% grade 2, and 3% grade 3
• Febrile neutropenia—3% grade 3 and 4
• Fever—6% grade 1 and 3% grade 2
• General disorders and administration site conditions—15% grade 1
• Hyperglycemia—3% grade 3
• Hypokalemia—6% grade 1
• Hypotension—3% grade 3
• Insomnia—6% grade 1
• Oral mucositis—9% grade 1 and 3% grade 2
• Nausea—18% grade 1, 27% grade 2, and 3% grade 3
• Neutrophil count decrease—3% grade 3 and 4
• Pain—3% grade 1 and 6% grade 2
• Pain of skin—3% grade 1 and 2
• Platelet count decrease—6% grade 2, 9% grade 3, and 6% grade 4
• Urinary tract infection—3% grade 3
• Vomiting—18% grade 1 and 21% grade 2.

Efficacy

Twenty-eight patients were evaluable for efficacy. The ORR for these patients was 36% (n=10).

The complete response (CR) rate was 22% (n=6), and the partial response (PR) rate was 14% (n=4). Twenty-five percent of patients (n=7) had stable disease, and 39% (n=11) progressed.

Dr Falchi noted that the ORR was “much higher” in patients with T-cell lymphoma than in those with B-cell lymphoma—80% (n=8) and 11% (n=2), respectively.

The CR rates were 50% (n=5) in T-cell lymphoma patients and 5.5% (n=1) in B-cell patients. PR rates were 30% (n=3) and 5.5% (n=1), respectively. Thirty-nine percent (n=7) of B-cell patients had stable disease, but none of the T-cell patients did.

“Patients with non-T-cell lymphoma were much more likely to progress on treatment,” Dr Falchi noted. “Half of them did so [n=9].”

This is in comparison to the 20% of T-cell lymphoma patients who progressed on treatment (n=2).

Disease subtypes for complete responders included transformed follicular lymphoma (n=1), T-lymphoblastic lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1), extranodal NK/T-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=2).

Partial responders had follicular lymphoma (n=1), cutaneous peripheral T-cell lymphoma (n=1), cutaneous anaplastic large-cell lymphoma (n=1), and angioimmunoblastic T-cell lymphoma (n=1).

The 2 responders with B-cell lymphoma (1 CR and 1 PR) ultimately progressed and died.

Of the 8 responders with T-cell lymphoma, 3 have an ongoing CR, and 2 of these patients proceeded to transplant.

One T-cell patient who achieved a CR and proceeded to transplant was lost to follow-up. Another died after transplant.

Two T-cell patients who achieved a PR progressed and died. And 1 patient has an ongoing PR.

In total, 75% of patients (n=21) progressed. The median PFS for the entire study cohort was 3.6 months (range, 1.5-5.7).

The median PFS was 2.2 months (range, 1.1-3.2) for patients with B-cell lymphomas and was not reached for the T-cell lymphoma patients.

Eighty-nine percent of B-cell patients progressed (n=16), as did 40% of T-cell patients (n=4).

Dr Falchi and his colleagues are now conducting studies to correlate the pharmacokinetics of azacitidine-romidepsin with genome-wide methylation and correlate TET2, IDH2, and DNMT3A mutation status with clinical response.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Red blood cells

The US Food and Drug Administration (FDA) has expanded the approved indication for ferumoxytol injection (Feraheme®).

The drug is now approved to treat adults with iron deficiency anemia (IDA) who cannot tolerate or have had an unsatisfactory response to oral iron.

Ferumoxytol injection was previously approved by the FDA to treat IDA in adults with chronic kidney disease.

“Iron deficiency anemia is a serious and under-treated health condition which negatively impacts quality of life for millions of people, many of whom do not benefit from or cannot tolerate oral iron therapy,” said Michael Auerbach, MD, of Georgetown University School of Medicine in Washington, DC.

“Physicians now have a new option for patients who meet the broader ferumoxytol injection indication that can be administered in 15 minutes, providing a gram of iron in 2 doses as few as 3 days apart.”

The expanded approval for ferumoxytol injection was supported by a trio of phase 3 trials. All 3 trials included IDA patients who could not tolerate or had an unsatisfactory response to oral iron.

In the first trial (NCT01114139), researchers compared ferumoxytol injection to placebo.

The second trial (NCT01114204) was a comparison of ferumoxytol injection and iron sucrose.

In the third trial (NCT02694978), researchers compared ferumoxytol injection to ferric carboxymaltose injection (Injectafer®).

Details on these trials are included in the prescribing information for ferumoxytol injection, which is available at www.feraheme.com.

The prescribing information includes a boxed warning detailing the risk of fatal and serious hypersensitivity reactions, including anaphylaxis, in patients receiving ferumoxytol injection.

Ferumoxytol injection is a product of AMAG Pharmaceuticals, Inc.

The company has a patient access support program called AMAG Assist™. Uninsured or underinsured patients who need help paying for their ferumoxytol injection prescription can call 844-635-2624 to see if they qualify for help.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

Photo by Larry Young

LA JOLLA, CA—Phase 1 results suggest duvelisib combination therapies can be active and well-tolerated in patients with relapsed/refractory T-cell lymphomas.

Researchers said duvelisib had an acceptable safety profile when given in combination with romidepsin or bortezomib to patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL).

Duvelisib plus romidepsin produced a 60% overall response rate (ORR) in these patients, and duvelisib plus bortezomib produced a 35% ORR.

Response rates were higher in PTCL patients than CTCL patients.

Neha Mehta-Shah, MD, of Washington University in St. Louis, Missouri, and her colleagues presented these results in a poster at the 10th Annual T-cell Lymphoma Forum.

The research was supported by the Leukemia & Lymphoma Society, Infinity Pharmaceuticals, and Verastem Inc.

This phase 1 trial consists of parallel arms evaluating duvelisib in combination with romidepsin (arm A) or bortezomib (arm B). The trial enrolled patients with PTCL or CTCL that had progressed after at least 1 prior therapy.

All patients received duvelisib at 25 mg, 50 mg, or 75 mg twice daily for 28-day cycles.

Patients in arm A received romidepsin at 10 mg/m² on days 1, 8, and 15 of each cycle.

Patients in arm B received bortezomib at 1 mg/m² on days 1, 4, 8, and 11 of each cycle.

Romidepsin combination

Sixteen patients received duvelisib plus romidepsin, and 15 of them were evaluable for efficacy. Eleven patients had PTCL, and 4 had CTCL.

The ORR was 60% (9/16), and the complete response (CR) rate was 27% (n=4). The median time to response was 51 days (range, 49-54).

The ORR was 64% in the PTCL patients and 50% in the CTCL patients. All 4 CRs occurred in PTCL patients, 2 in patients with PTCL not otherwise specified (NOS) and 2 in patients with angioimmunoblastic T-cell lymphoma (AITL).

There were 5 responses among patients who received the 75 mg dose of duvelisib (n=8) and 2 responses each in the 50 mg dose group (n=3) and 25 mg dose group (n=4).

There were no dose-limiting toxicities, so the 75 mg dose of duvelisib was considered the maximum tolerated dose.

All 16 patients were evaluable for safety. There were 2 serious adverse events (AEs) considered possibly related to treatment—grade 3 fatigue and grade 2 aspartate aminotransferase (AST) increase.

There were 2 deaths considered unrelated to treatment—diffuse alveolar hemorrhage after allogeneic transplant and sepsis in the setting of disease progression.

Treatment-related AEs (occurring in at least 2 patients) were fatigue (56%), nausea (50%), altered taste (50%), diarrhea (38%), neutropenia (38%), rash (31%), thrombocytopenia (25%), dysphagia (25%), and anorexia (25%).

Grade 3/4 treatment-related AEs included neutropenia (38%) and thrombocytopenia (6%).

One patient discontinued duvelisib-romidepsin due to toxicity, and 7 discontinued due to progressive disease.

Three patients proceeded to bone marrow transplant/donor lymphocyte infusion, and 4 patients are still receiving study treatment.

Bortezomib combination

There were 17 patients who received duvelisib plus bortezomib—10 with PTCL and 7 with CTCL.

The ORR was 35% (6/17), and the CR rate was 18% (n=3). The median time to response was 52 days (range, 47-57).

The ORR was 50% in PTCL patients and 14% among CTCL patients.

All 3 CRs occurred in the PTCL patients—1 in a patient with AITL, 1 in a patient with PTCL-NOS, and 1 in a patient who had intestinal T-cell lymphoma with B-cell lymphoproliferative disorder.

There were 3 responses among patients who received the 25 mg dose of duvelisib (n=8), 2 responses in the 50 mg dose group (n=3), and 1 response in the 75 mg dose group (n=6).

There was 1 dose-limiting toxicity—pneumonia—in a patient treated at the 25 mg dose.

The 25 mg dose was deemed optimal due to grade 3 alanine transaminase (ALT)/AST elevations observed after cycle 1 with the 50 mg dose (n=3) and the 75 mg dose (n=2).

There were 6 serious AEs considered possibly related to treatment:

• Grade 3 pneumonia (n=2)
• Grade 3 infectious colitis (n=1)
• Grade 3 colitis (n=1)
• Grade 4 ALT/AST elevation (n=1)
• Grade 5 Stevens-Johnson syndrome (n=1).

The fatal case of Stevens-Johnson syndrome was considered possibly related to bortezomib, duvelisib, and trimethoprim-sulfamethoxazole, a medication that was started at the beginning of the study.

Treatment-related AEs (occurring in at least 2 patients) included diarrhea/colitis (71%), ALT/AST increase (41%), rash (24%), neutropenia (24%), nausea/vomiting (24%), chills (24%), fatigue (24%), and alkaline phosphatase increase (12%).

Grade 3/4 AEs included ALT/AST increase (35%), rash (12%), neutropenia (12%), diarrhea/colitis (6%), and alkaline phosphatase increase (6%).

Seven patients discontinued duvelisib-bortezomib due to toxicity, and 8 discontinued due to disease progression. Two patients are still on study treatment.

ANSWER

This ECG demonstrates sinus rhythm with premature atrial contractions (PACs), a normal axis, a right bundle branch block, a prolonged QTc interval, and T-wave abnormalities suggestive of lateral ischemia.

Sinus rhythm is indicated by a P wave for every QRS complex and a QRS complex for every P wave with a consistent PR interval.

PACs are seen on the seventh, 10th, and 12th beats on the rhythm strip. Notice that the R-R interval is shortened, the R wave of the PACs is identical to that of sinus rhythm, and there is a compensatory pause following the PAC before the sinus rhythm ensues. The R-wave axis of 26° is within the normal range (–30° to 90°).

A right bundle branch block is identified by a QRS duration > 120 ms (156 ms), an RSR’ “rabbit ear” pattern in the anterior precordial leads (particularly lead V₁), and slurred S waves in leads I and aVL. Although opinions vary, a QTc interval > 460 ms in women (> 440 ms in men) is typically considered prolonged. This patient fits that criteria (529 ms). Finally, the ST depressions in leads V₄ to V₆ suggest lateral ischemia.

A comparison of this ECG to one obtained a year ago showed no difference, with the exception of new-onset PACs. The patient was cleared for surgical repair of her forearm fracture.

ANSWER

This ECG demonstrates sinus rhythm with premature atrial contractions (PACs), a normal axis, a right bundle branch block, a prolonged QTc interval, and T-wave abnormalities suggestive of lateral ischemia.

Sinus rhythm is indicated by a P wave for every QRS complex and a QRS complex for every P wave with a consistent PR interval.

PACs are seen on the seventh, 10th, and 12th beats on the rhythm strip. Notice that the R-R interval is shortened, the R wave of the PACs is identical to that of sinus rhythm, and there is a compensatory pause following the PAC before the sinus rhythm ensues. The R-wave axis of 26° is within the normal range (–30° to 90°).

A right bundle branch block is identified by a QRS duration > 120 ms (156 ms), an RSR’ “rabbit ear” pattern in the anterior precordial leads (particularly lead V₁), and slurred S waves in leads I and aVL. Although opinions vary, a QTc interval > 460 ms in women (> 440 ms in men) is typically considered prolonged. This patient fits that criteria (529 ms). Finally, the ST depressions in leads V₄ to V₆ suggest lateral ischemia.

A comparison of this ECG to one obtained a year ago showed no difference, with the exception of new-onset PACs. The patient was cleared for surgical repair of her forearm fracture.

ANSWER

This ECG demonstrates sinus rhythm with premature atrial contractions (PACs), a normal axis, a right bundle branch block, a prolonged QTc interval, and T-wave abnormalities suggestive of lateral ischemia.

Sinus rhythm is indicated by a P wave for every QRS complex and a QRS complex for every P wave with a consistent PR interval.

PACs are seen on the seventh, 10th, and 12th beats on the rhythm strip. Notice that the R-R interval is shortened, the R wave of the PACs is identical to that of sinus rhythm, and there is a compensatory pause following the PAC before the sinus rhythm ensues. The R-wave axis of 26° is within the normal range (–30° to 90°).

A right bundle branch block is identified by a QRS duration > 120 ms (156 ms), an RSR’ “rabbit ear” pattern in the anterior precordial leads (particularly lead V₁), and slurred S waves in leads I and aVL. Although opinions vary, a QTc interval > 460 ms in women (> 440 ms in men) is typically considered prolonged. This patient fits that criteria (529 ms). Finally, the ST depressions in leads V₄ to V₆ suggest lateral ischemia.

A comparison of this ECG to one obtained a year ago showed no difference, with the exception of new-onset PACs. The patient was cleared for surgical repair of her forearm fracture.

The addition of pomalidomide to bortezomib and low-dose dexamethasone showed a statistically significant improvement in progression-free survival for patients with relapsed/refractory multiple myeloma, compared with just the two agents, according to Celgene.

Celgene, which markets pomalidomide, announced the results from the phase 3 OPTIMISMM trial (NCT01734928) on Feb. 6. The company expects the results to be presented at future medical meetings, they said.

OPTIMISMM is the first phase 3 trial to examine a triple-drug combination for multiple myeloma patients who have all received prior lenalidomide, Celgene noted.

The pomalidomide/bortezomib/low-dose dexamethasone combination is not currently approved, but pomalidomide plus dexamethasone is approved for multiple myeloma patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and have shown disease progression within 60 days of last therapy.

mschneider@frontlinemedcom.com

The addition of pomalidomide to bortezomib and low-dose dexamethasone showed a statistically significant improvement in progression-free survival for patients with relapsed/refractory multiple myeloma, compared with just the two agents, according to Celgene.

Celgene, which markets pomalidomide, announced the results from the phase 3 OPTIMISMM trial (NCT01734928) on Feb. 6. The company expects the results to be presented at future medical meetings, they said.

OPTIMISMM is the first phase 3 trial to examine a triple-drug combination for multiple myeloma patients who have all received prior lenalidomide, Celgene noted.

The pomalidomide/bortezomib/low-dose dexamethasone combination is not currently approved, but pomalidomide plus dexamethasone is approved for multiple myeloma patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and have shown disease progression within 60 days of last therapy.

mschneider@frontlinemedcom.com

The addition of pomalidomide to bortezomib and low-dose dexamethasone showed a statistically significant improvement in progression-free survival for patients with relapsed/refractory multiple myeloma, compared with just the two agents, according to Celgene.

Celgene, which markets pomalidomide, announced the results from the phase 3 OPTIMISMM trial (NCT01734928) on Feb. 6. The company expects the results to be presented at future medical meetings, they said.

OPTIMISMM is the first phase 3 trial to examine a triple-drug combination for multiple myeloma patients who have all received prior lenalidomide, Celgene noted.

The pomalidomide/bortezomib/low-dose dexamethasone combination is not currently approved, but pomalidomide plus dexamethasone is approved for multiple myeloma patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and have shown disease progression within 60 days of last therapy.

mschneider@frontlinemedcom.com

MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

“BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

A meeting attendee suggested that management of a patient with melanoma might not differ based on genetic-testing results. “I agree with you that I don’t need to know the genetic status within these families to help with their cutaneous melanomas,” Dr. Tsao replied. “But the question becomes, are there other internal malignancies you’re not screening for appropriately?”

Another attendee asked about genetic counseling. “I encourage genetic counseling since dermatologists often don’t have time to take at detailed family history of all cancers and ages of onset,” Dr. Tsao said. “Genetic counselors can help sort out the strength of the genetic pedigree in a family. My residents usually ask if someone has a history of melanoma in their family, and that’s it. But there is a big difference between having a cousin with melanoma and three brothers with melanoma.”

MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

“BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

A meeting attendee suggested that management of a patient with melanoma might not differ based on genetic-testing results. “I agree with you that I don’t need to know the genetic status within these families to help with their cutaneous melanomas,” Dr. Tsao replied. “But the question becomes, are there other internal malignancies you’re not screening for appropriately?”

Another attendee asked about genetic counseling. “I encourage genetic counseling since dermatologists often don’t have time to take at detailed family history of all cancers and ages of onset,” Dr. Tsao said. “Genetic counselors can help sort out the strength of the genetic pedigree in a family. My residents usually ask if someone has a history of melanoma in their family, and that’s it. But there is a big difference between having a cousin with melanoma and three brothers with melanoma.”

MIAMI – Although rare, patients who present with one or more skin cancers characteristic of those associated with loss of the BAP1 tumor suppressor protein may be at elevated risk for more aggressive uveal melanomas and other cancers such as kidney cancer and mesothelioma. For this reason, dermatologists who recognize the lesions and telltale pattern of this inherited mutation within families can do a great service, encouraging education, genetic counseling, and referral of patients to a nearby cancer center, according to Hensin Tsao, MD, PhD.

“BAP1 is a mixed-tumor syndrome. These patients are getting melanoma and mesothelioma, kidney cancer and ocular melanoma,” Dr. Tsao said at the 2018 Orlando Dermatology Aesthetic and Clinical Conference.

Courtesy James Dick

No longer ‘condemned proteins’

Under normal circumstances, BAP1 is a tumor suppressor protein involved in cellular process called “ubiquitination.” Often, ubiquitination serves to identify proteins “condemned” for destruction by the proteasome system. The BAP1 protein acts through a molecular relay and removes ubiquitin polypeptide groups on the protein. “In the absence of BAP1, proteins often linger longer because they accumulate ubiquitin groups, or alternatively, the protein’s function is somehow altered by mechanisms we don’t quite understand yet,” Dr. Tsao explained.

Dr. Hensin Tsao

A family history lesson

Ask patients not only about history of melanoma in their family, including if any close relative was diagnosed with eye melanoma, Dr. Tsao suggested. “We had an opportunity to look at cutaneous and ocular melanoma families. Overall, if your family has an ocular melanoma along with cutaneous melanoma, the risk of being a BAP1 mutation–bearing family is greater.” In addition, he and his colleagues did a case control study with Ivana K. Kim, MD, at the Massachusetts Eye and Ear Infirmary in Boston, and found people with metastatic ocular melanoma were more likely to have BAP1 mutations, compared with those with nonmetastatic ocular melanoma.

“The fear is, of course, patient who are BAP1 mutation carriers might be predisposed to more lethal variants of uveal melanoma.”

Although taking a family history is essential, some patients may be unfamiliar with mesothelioma. “So ask about any unusual lung cancers or eye cancers,” Dr. Tsao suggested. “And if it looks like there is an aggregation of rare tumors, get them to a nearby cancer center [for further work-up]. Mesothelioma is difficult to treat and a horrible disease,” he added. “So if there is any chance you can [catch] the mesothelioma early, that’s good.”

He also cautioned against over interpretation of patient reports about family malignancies, in part because lung and breast cancers are relatively common. “Sometimes, when you see a family with lung or breast cancers, it could just be a chance association since these are quite common in the general population.” In other words, determining if a lung cancer in a family with melanoma is an association beyond chance can take some “pretty large numbers to prove.”

In contrast, “the number of kidney cancers among BAP1 families I do believe are out of proportion with normal population expectations,” Dr. Tsao added.
 

Follow-up and genetic counseling

There is no standard protocol for follow-up once a patient is identified with a BAP1 mutation. “I refer them for uveal, kidney, and/or lung cancer evaluation and see them back two to four times a year for skin checks.”

A meeting attendee suggested that management of a patient with melanoma might not differ based on genetic-testing results. “I agree with you that I don’t need to know the genetic status within these families to help with their cutaneous melanomas,” Dr. Tsao replied. “But the question becomes, are there other internal malignancies you’re not screening for appropriately?”

Another attendee asked about genetic counseling. “I encourage genetic counseling since dermatologists often don’t have time to take at detailed family history of all cancers and ages of onset,” Dr. Tsao said. “Genetic counselors can help sort out the strength of the genetic pedigree in a family. My residents usually ask if someone has a history of melanoma in their family, and that’s it. But there is a big difference between having a cousin with melanoma and three brothers with melanoma.”

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

bjancin@frontlinemedcom.com

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

bjancin@frontlinemedcom.com

KAUAI, HAWAII – All psoriasis patients not already known to have psoriatic arthritis should complete the brief Psoriasis Epidemiology Screening Tool (PEST) for the rheumatologic disease once per year, advised Jashin J. Wu, MD. The PEST is a simple, validated, five-question yes/no screening tool. It’s geared towards nonrheumatologists who may not feel competent to diagnose psoriatic arthritis or who just don’t have time to do so. Three or more “yes” answers is deemed a positive result warranting consideration of referral to a rheumatologist, explained Dr. Wu, the director of the psoriasis clinic and director of dermatology research at Kaiser Permanente Los Angeles Medical Center.

Bruce Jancin/Frontline Medical News

• Have you ever had a swollen joint (or joints)?
• Has a doctor ever told you that you have arthritis?
• Do your fingernails or toenails have holes or pits?
• Have you had pain in your heel?
• Have you had a finger or toe that was completely swollen and painful for no apparent reason?

The PEST has been shown to have 92% sensitivity and 78% specificity for diagnosis of psoriatic arthritis (Clin Exp Rheumatol. 2009 May-Jun;27[3]:469-74).

Dr. Wu’s call for regular screening for psoriatic arthritis resonated with another psoriasis expert at the meeting, Craig L. Leonardi, MD.

“It’s our moral obligation to be on the lookout for that disease. Remember that patients who develop psoriatic arthritis usually have their skin disease for 10 years before they develop their first signs and symptoms of psoriatic arthritis. So that means they should be in the dermatologist’s office getting their skin treated as they start to have problems with their joints,” observed Dr. Leonardi, of Saint Louis University.

Dr. Wu reported receiving research funding from AbbVie, Amgen, Eli Lilly, Janssen, Novartis, and Regeneron.

The SDEF and this news organization are owned by the same parent company.
 

bjancin@frontlinemedcom.com

Clinical Research

New guidelines for adult bronchiectasis

Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).

For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.

Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.

Bharat Bajantri, MD
Fellow-in-Training Member

Airways Disorders

ICS/LABA combo therapy: black box warning removed

Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.

In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).

Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.

Aaron Holley, MD, FCCP
Steering Committee Member

Navitha Ramesh, MD, MBBS
Fellow-in-Training Member

Critical Care

Standardized handoffs in the ICU: room for improvement?

Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).

In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.

In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).

Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.

Shruti Gadre, MD
Fellow-in-Training Member

Christopher Carroll, MD, FCCP
Vice-Chair

Home-Based Mechanical Ventilation and Neuromuscular Disease

Update on two recent FDA-approved therapies for ALS and SMA

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.

Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.

Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.

Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.

Ashraf Elsayegh, MD, FCCP
Steering Committee Member

Won Y. Lee, MD
Steering Committee Member

Interstitial and Diffuse Lung Disease

Frailty as a measure of disease activity in ILD

Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.

There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.

Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.

Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member

Clinical Research

New guidelines for adult bronchiectasis

Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).

For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.

Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.

Bharat Bajantri, MD
Fellow-in-Training Member

Airways Disorders

ICS/LABA combo therapy: black box warning removed

Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.

In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).

Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.

Aaron Holley, MD, FCCP
Steering Committee Member

Navitha Ramesh, MD, MBBS
Fellow-in-Training Member

Critical Care

Standardized handoffs in the ICU: room for improvement?

Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).

In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.

In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).

Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.

Shruti Gadre, MD
Fellow-in-Training Member

Christopher Carroll, MD, FCCP
Vice-Chair

Home-Based Mechanical Ventilation and Neuromuscular Disease

Update on two recent FDA-approved therapies for ALS and SMA

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.

Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.

Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.

Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.

Ashraf Elsayegh, MD, FCCP
Steering Committee Member

Won Y. Lee, MD
Steering Committee Member

Interstitial and Diffuse Lung Disease

Frailty as a measure of disease activity in ILD

Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.

There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.

Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.

Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member

Clinical Research

New guidelines for adult bronchiectasis

Clinically significant bronchiectasis is a combination of radiologic bronchial dilatation with clinical symptoms. Guidelines on management of adult bronchiectasis were recently published (Eur Respir J. 2017; Sep 10;50[3]).

For all adult patients with clinically significant bronchiectasis, the guidelines suggest standardized minimum testing with differential blood count, serum immunoglobulins, and testing for allergic bronchopulmonary aspergillosis with any further workup on an individual basis. Annual sputum surveillance is suggested for clinically stable adult patients; however, the evidence for this recommendation came from studies done on patients with cystic fibrosis.

Inhaled bronchodilators are suggested as the first-line treatment in symptomatic patients. Long-term antibiotics (greater than 3 months) are recommended in patients with greater than 3 exacerbations/year after optimizing airway clearance and disease-specific treatment. Pseudomonas aeruginosa infections are to be treated with inhaled antibiotics (colistin or gentamicin) (Charles SH, et al. Am J Respir Crit Care Med. 2014;189[8]975; Murray P, et al. Am J Respir Crit Care Med. 2011;183[4]:491; and nonpseudomonal infections are to be treated with macrolides (Conroy W, et al. Lancet. 2012;380[9842]:660; Altenburg J, et al. JAMA. 2013;309[12];1251), although interchangeable for intolerance. Sputum cultured early will guide therapy among poor responders. Long-term mucolytic agents are suggested in appropriate tolerating patients. Pulmonary rehabilitation for 6-8 weeks is strongly recommended in adult bronchiectasis with impaired exercise capacity. Surgical interventions for bronchiectasis are reserved for a small group of patients who have localized disease and high exacerbation rates despite maximal medical therapy. Inhaled corticosteroids are suggested not to be used in adult bronchiectasis. Guidelines recommend against the use of statins and recombinant human DNase as it increases exacerbations (Chest. 1998;113[5]:1329. The task force acknowledged the low quality of evidence for their recommendations requiring more research in the field of adult bronchiectasis.

Bharat Bajantri, MD
Fellow-in-Training Member

Airways Disorders

ICS/LABA combo therapy: black box warning removed

Publication of the Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 caused panic among asthmatics and the physicians who treat them (Nelson et al. Chest. 2006;129[1]:15). The study suggested that the long-acting beta-2-agonist (LABA) salmeterol leads to an increased risk of asthma/respiratory-related deaths compared with placebo. This finding was more pronounced in the African American subpopulation. The study left many questions unanswered, including whether or not this risk is present when LABA therapy is combined with inhaled corticosteroids (ICS) (O’Byrne. Chest. 2006;129[1]:3). Subsequent meta-analyses confirmed the increased risk with LABA monotherapy but not with LABA/ICS (Salpeter et al. Ann Inter Med. 2006;144[12]: 904; Jaeschke et al. Am J Respir Crit Care Med. 2008;178[10]:1009). Still, a black box warning relating LABA to asthma-related death was applied to LABA/ICS products.

In 2011, the Food and Drug Administration (FDA) mandated large, randomized controlled trials be performed for LABA/ICS products to assess safety. These trials were recently completed, showing no difference in asthma-related deaths between LABA/ICS and ICS alone. There were 41, 297 patients across four trials, three included teenagers and adults (age ≥ 12) and one enrolled children (ages 4-11). These studies prompted the FDA to remove the black box warning from salmeterol/fluticasone, formoterol/budesonide, and formoterol/mometasone (https://wwwfdagov/downloads/Drugs/DrugSafety/UCM589997pdf).

Conclusion: Because LABA/ICS therapy is effective for asthma, most pulmonologists continue to prescribe it despite the SMART study results and FDA warning. In a practical sense, we don’t expect the FDA findings to radically change asthma care. Still, it seems we can finally put this question to rest – LABA/ICS is indeed safe for asthmatics. Most physicians will continue to avoid LABA monotherapy, and now that tiotropium is included in the 2017 GINA guidelines, it’s only matter of time before we’re debating whether LABA/long-acting muscarinic antagonist (LAMA) is safe for asthmatics.

Aaron Holley, MD, FCCP
Steering Committee Member

Navitha Ramesh, MD, MBBS
Fellow-in-Training Member

Critical Care

Standardized handoffs in the ICU: room for improvement?

Transitions in patient care are commonplace in the ICU. But handoffs are particularly susceptible to error given the complexity of the patient population. Impacts of less-than-ideal handoffs likely include adverse events, delays in medical diagnosis and treatment, redundant communications, redundant activities such as additional procedures and tests, lower provider and patient satisfaction, higher costs, longer hospital stays, more hospital admissions, and less effective training for health -care providers. Yet, there is great heterogeneity in handoff practiced, and the impact of standardized handoffs in the ICU is unclear (Cochran A. JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5468. [Epub ahead of print]).

In a survey of over 600 academic intensivists, 55% of the participants stated that attending handoffs in the ICU should be standardized, yet, only 13% of those participating in handoffs reported using a standardized process (Lane-Fall M. Crit Care Med. 2016;44[4]690). Clinician miscommunication contributes to an estimated 250,000 deaths in US hospitals per year (Makary M. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139). Standardized handoffs may improve outcomes in the ICU.

In many ICUs that do use standardized sign-out templates, higher clinician satisfaction and fewer unexpected patient events have been reported (Bavare AC. J Healthc Qual. 2015;37[5]:267; Nanchal R. BMJ Qual Saf. 2017;26[12]:987). In a recent randomized controlled trial, use of a standardized handoff curriculum in the ICU resulted in a significant 3% decrease in communication errors, without any change in the duration of the handoff. There also was a clinician-reported improvement in team communication and patient safety; but no changes in ICU length of stay, duration of mechanical ventilation, or number of re-intubations were noted (JAMA Surg. 2018 Jan 3. doi: 10.1001/jamasurg.2017.5440. [Epub ahead of print]).

Unfortunately, despite interest in improving patient handoffs, there are few tools to evaluate the effectiveness of different handoff strategies. Most studies report clinician perceptions rather than patient-centered outcomes. Further research is required to examine the optimal approach to handover communication. However, based on the available evidence, a standardized approach to handoffs is likely better than a nonstandardized format.

Shruti Gadre, MD
Fellow-in-Training Member

Christopher Carroll, MD, FCCP
Vice-Chair

Home-Based Mechanical Ventilation and Neuromuscular Disease

Update on two recent FDA-approved therapies for ALS and SMA

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are neuromuscular diseases often deteriorating to progressive respiratory failure. Two medications received recent FDA approval and are now available in clinical practice – edaravone for ALS and nusinersen for SMA. We present a balanced overview of the favorable data along with realistic challenges.

Edaravone (Radicava) is the second FDA-approved medication for management of ALS (Riluzole was approved over 20 years ago). Edaravone is a free radical scavenger that reduces oxidative stress, resulting in a protective effect on neuronal cells. It originally showed promise in acute ischemic stroke in Japan and was subsequently studied for ALS. A phase 3 randomized, double-blind placebo-controlled study performed in Japan (Lancet Neurol. 2017;16[7]:505) compared ALSFRS-R scores of a specific subset of ALS patients receiving edaravone vs placebo. This study revealed that patients with early ALS (2 years duration or less) with rapid progression (ALSFRS-R score of 7.5 in 6 months) had a 33% decrease in their degree of progression (reducing their ALSFRS-R score to 5) in the edaravone group. Of note, there was also slowing in the decline of FVC, though not clinically significant. Although the drug was rapidly approved by the FDA, there are obvious challenges that must be recognized. First, it is unclear if patients will discern such a mild degree of slowing of disease progression. In addition, the annual cost may be prohibitive, and lifelong IV administration of the medication for 10 days every month may pose logistical barriers.

Nusinersen (Spinraza) is the first FDA-approved therapeutic medication for spinal muscular atrophy (SMA). SMA is a hereditary neuromuscular disorder leading to degeneration of motor neuron cells and ultimately diffuse muscle weakness and often respiratory failure. Nusinersen is an antisense oligonucleotide that modifies splicing of the SMN-2 gene to increase production of normal, full-length SMN protein, which is deficient in SMA. The ENDEAR trial (Finkel RS, et al. N Engl J Med. 2017;377[18]:1723) was a phase 3, multicenter, double-blind study that enrolled SMA infants to receive nusinersen vs sham. Infants who received treatment had improvements in motor milestones (41% vs 0%) and less permanent-assisted ventilation or death in the nusinersen group (39% vs 68%), a 47% reduction in risk of death. The therapy is safe and tolerable, although there is reported risk of bleeding abnormalities, renal toxicity, and constipation. Administered intrathecally, there is a series of four loading doses, followed by maintenance doses every 4 months – presumably lifelong. Although FDA approved all three SMA subtypes, the eventual impact is uncertain, especially in cases of advanced muscle weakness. There are realistic challenges: the high cost ($125,000/dose), limited longitudinal evidence, technical administration, and limited access.

Pulmonologists should be aware of both medications as new therapeutic options for ALS and SMA; however, the long-term impact is yet to be determined.

Ashraf Elsayegh, MD, FCCP
Steering Committee Member

Won Y. Lee, MD
Steering Committee Member

Interstitial and Diffuse Lung Disease

Frailty as a measure of disease activity in ILD

Frailty is a systemic geriatric syndrome characterized by age-related accumulation of physiologic deficits across several systems with an attenuated response to biological stress. Considering that interstitial lung disease (ILD), particularly, idiopathic pulmonary fibrosis (IPF), is a disease of the aging population, frailty is an emerging area of clinical interest. The biological pathways driving the association of frailty with worse prognosis are complex but hinge on cellular senescence, systemic inflammation, and sarcopenia.

There is a high prevalence of frailty in adults with chronic lung diseases and is associated with worse prognosis. The current literature, though, is mostly derived from patients with COPD. Frailty measured using the 42-item patient-reported frailty index is associated with dyspnea severity in patients with fibrotic ILD (Milne et al. Respirology. 2017;22[4]:728) and systemic sclerosis-associated ILD (Guler et al. Respir Med. 2017 Aug;129:1-7. doi: 10.1016/j.rmed.2017.05.012. Epub 2017 May 25.). The SHARE-Frailty and the Edmonton Frail Scale instruments utilized to measure frailty in the University of Alabama at Birmingham IPF cohort detected a high-percentage of frail and pre-frail patients (Luckhardt et al. Am J Respir Crit Care Med. 2017;195:A7012). However, there are differences in targeted domains between the various frailty instruments, and this could affect the identification of the frailty syndrome in patients.

Frailty as a measure of disease activity and progression is not currently employed in clinical trials for ILD, primarily due to lack of standardized tools for this patient population. Future studies designed to utilize the frailty syndrome as outcome measures may further our understanding of the clinical manifestations and underlying mechanisms, as well as identify potential therapeutic interventions for patients with ILD.

Tejaswini Kulkarni MD, MPH
Fellow-in-Training Member

Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Cardiac surgery patients are sicker today than in previous decades due to an aging population and a rising complexity in medical care. There is an increasing reliance on noncardiac surgeons to care for these patients. The optimal postoperative providers and structure of the ICU where patients are cared for remain unclear, but what is irrefutable is patients’ increased postoperative morbidity. Pulmonary complications are a leading cause of morbidity in these patients, occurring in up to one-fifth of cases (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Common pulmonary complications of cardiac surgery are listed in Table 1. Those complications, captured by The Society of Thoracic Surgeons (STS) Cardiac Surgery Database, include receiving ventilation longer than 24 hours, pneumonia, pulmonary embolism, and pleural effusion requiring drainage (The Society of Thoracic Surgeons. STS National Database. https://www.sts.org/registries-research-center/sts-national-database. Accessed January 9, 2018).

It should come as no surprise that cardiac surgery can have pronounced effects on lung function. The anesthetic agents, chest wall alteration, and direct lung manipulation can all affect pulmonary parameters. Functional residual capacity (FRC) can decrease by up to 20% with anesthesia (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531), and the thoracic manipulation and alteration of rib cage mechanics with a classic median sternotomy approach can lead to decreases in forced vital capacity (FVC) and expiratory volume in the first second of forced expiration (FEV₁) that can last for months after surgery. Use of the cardiopulmonary bypass circuit can also lead to bronchoconstriction. These changes in pulmonary function are less pronounced in alternative surgical approaches, such as partial sternotomies (Weissman C. Seminars in Cardiothoracic and Vascular Anesthesia: Pulmonary Complications After Cardiac Surgery. Glen Head, NY: Westminister Publications; 2004).

The most frequent pulmonary consequence of cardiac surgery is atelectasis, seen on postoperative chest radiographs in approximately 50% to 90% of patients (Szelowski LA, et al. Curr Probl Surg. 2015;52[1]:531). Induction, apnea during cardiopulmonary bypass, manual compression of the lungs for surgical exposure, internal mammary harvesting, and pleurotomy can lead to atelectasis in the intraoperative setting while weak cough, poor inspiratory efforts, interstitial edema, and immobility further contribute postoperatively (Weissman 2004). While frequently seen, clinically significant pulmonary consequences from this radiographic finding alone are rare (Weissman 2004).

Pleural effusions are seen on immediate postoperative chest radiographs in the majority of patients. Additionally, 10% to 40% of patients develop pleural effusions 2 to 3 weeks after surgery secondary to postpericardiotomy syndrome. While some effusions require drainage and further intervention (eg, hemothorax), most effusions require no specific treatment and resolve over time (Weissman 2004).

The prevalence of pneumonia following cardiac surgery varies based on differences in study populations and diagnostic criteria, but it remains an important source of morbidity and mortality. In one series, postoperative pneumonia occurred in 3.1% of patients, with higher rates observed in patients who were older, had worse left ventricular ejection fraction, had COPD, experienced longer bypass times, and received more red blood cell transfusions in the operating room (Allou N, et al. Crit Care Med. 2014;42[5]:1150). A meta-analysis found that an average of 6.37% of patients developed ventilator-associated pneumonia (VAP), and this rose to 35.2% in those receiving ventilation for greater than 48 hours. Those who developed VAP had an odds ratio of dying of 15.18 (95% CI 5.81-39.68) compared with those who did not (He S, et al. J Thorac Cardiovasc Surg. 2014;148[6]:3148).

A small proportion of patients go on to develop ARDS. While relatively uncommon, ARDS carries a high mortality rate. Many possible etiologies for ARDS in cardiac surgery patients have been proposed, including an inflammatory response related to the cardiopulmonary bypass circuit, reperfusion injury secondary to reduced pulmonary blood flow during bypass, protamine administration, transfusion, hypothermia, and lack of ventilation during bypass (Weissman 2004); (Stephens RS, et al. Ann Thorac Surg. 2013;95[3]:1122). Type of surgery may also play a role, as patients who undergo aortic surgery are at an even greater risk (Stephens 2013). As with other cases of ARDS, treatment is supportive: low tidal volume ventilation and careful management of fluid balance, as well as paralysis, prone positioning, and consideration for extracorporeal membrane oxygenation (ECMO), as appropriate (Stephens 2013).

Therapies to prevent postoperative pulmonary complications have included early extubation, aggressive pain control, deep breathing, physical therapy, early mobilization, and noninvasive ventilation in the form of CPAP and intermittent positive pressure breathing. A meta-analysis of 18 trials looking at the use of various forms of prophylactic postoperative physiotherapy did not show a difference in any measured clinical outcome (Pasquina P, Walder B. Br Med J. 2003;327[7428]:1379).

However, the heterogeneity, short follow-up, and low quality of included studies made it difficult to draw meaningful conclusions on the benefit or lack thereof for these therapies. More recent studies have shown promise for chest physiotherapy started several weeks prior to elective coronary bypass graft surgery and extended CPAP via nasal CPAP mask immediately following extubation (Hulzebos EH. JAMA. 2006;296[15]:1851), (Stephens 2013).

Ongoing areas for improvement include further clarification and standardization of best practices for postcardiac surgery patients, including blood product transfusion, optimal tidal volumes for surgical and postsurgical ventilation, timing of extubation, and the use of preventive therapies in the pre- and postsurgical periods. As providers who care for these patients, understanding how we can improve their postoperative pulmonary recovery will allow us to enhance our patient’s experience.

Dr. Noel is a Critical Care Fellow, Cooper Medical School of Rowan University, Camden, New Jersey.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

dwatson@frontlinemedcom.com

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

dwatson@frontlinemedcom.com

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.

Office blood pressure measurement is not sufficient monitoring for women who have experienced severe preeclampsia, as it misses forms of hypertension commonly experienced in that population, according to a study published Feb. 5 in Hypertension.

Researchers at Erasmus University, Rotterdam, the Netherlands, conducted a retrospective cohort study of 200 women who underwent 24-hour ambulatory BP monitoring and office BP measurement at a 1-year follow-up for delivery with severe preeclampsia. Measurements were taken between 9 months and 15 months after delivery.

copyright Sohel_Parvez_Haque/Thinkstock

dwatson@frontlinemedcom.com

SOURCE: Benschop L et al. Hypertension. 2018 Feb;71:491-8.