Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Rhoda Baer

The European Commission (EC) has expanded the marketing authorization for dasatinib (Sprycel).

The drug is now approved to treat patients ages 1 to 18 with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The EC has also approved a new formulation of dasatinib—a powder for oral suspension (PFOS) intended for patients who cannot swallow tablets whole or who weigh 10 kg or less.

Dasatinib is also EC-approved to treat adults with:

• Newly diagnosed Ph+ CML-CP
• Chronic, accelerated, or blast phase CML with resistance or intolerance to prior therapy, including imatinib
• Ph+ acute lymphoblastic leukemia and lymphoid blast CML with resistance or intolerance to prior therapy.

The EC’s latest approval of dasatinib is supported by results from a phase 2 trial (NCT00777036), which were published in the Journal of Clinical Oncology in March.

The trial included 29 patients with imatinib-resistant/intolerant CML-CP and 84 patients with newly diagnosed CML-CP.

The previously treated patients received dasatinib tablets. Newly diagnosed patients were treated with dasatinib tablets (n=51) or PFOS (n=33).

Patients who started on PFOS could switch to tablets after receiving PFOS for at least 1 year. Sixty-seven percent of patients on PFOS switched to tablets due to patient preference.

The average daily dose of dasatinib was 58.18 mg/m² in the previously treated patients and 59.84 mg/m² in the newly diagnosed patients (for both tablets and PFOS). The median duration of treatment was 49.91 months (range, 1.9 to 90.2) and 42.30 months (range, 0.1 to 75.2), respectively.

Rates of confirmed complete hematologic response (CHR) at any time were 93% in the previously treated patients and 96% in the newly diagnosed patients.

At 12 months, previously treated patients had a major molecular response (MMR) rate of 41% and a complete molecular response (CMR) rate of 7%. In newly diagnosed patients, MMR was 52%, and CMR was 8%.

At 24 months, previously treated patients had an MMR rate of 55% and a CMR rate of 17%. In the newly diagnosed patients, MMR was 70%, and CMR was 21%.

The rate of major cytogenetic response (MCyR) at any time was 89.7% in all previously treated patients and 90% when the researchers excluded patients with MCyR or unknown cytogenetic status at baseline.

The rate of complete cytogenetic response (CCyR) at any time was 94% in all newly diagnosed patients and 93.9% when the researchers excluded patients with CCyR or unknown cytogenetic status at baseline.

The median progression-free survival and overall survival had not been reached at last follow-up.

The estimated 48-month progression-free survival was 78% in the previously treated patients and 93% in the newly diagnosed patients. The estimated 48-month overall survival was 96% and 100%, respectively.

Dasatinib-related adverse events (AEs) occurring in at least 10% of the previously treated patients included nausea/vomiting (31%), myalgia/arthralgia (17%), fatigue (14%), rash (14%), diarrhea (14%), hemorrhage (10%), bone growth and development events (10%), and shortness of breath (10%).

Dasatinib-related AEs occurring in at least 10% of the newly diagnosed patients included nausea/vomiting (20%), myalgia/arthralgia (10%), fatigue (11%), rash (19%), diarrhea (18%), and hemorrhage (10%).

Photo by Chad McNeeley

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

Long-term survival

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

Photo by Chad McNeeley

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

Long-term survival

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

Photo by Chad McNeeley

Transplant with radioimmunotherapy (RIT)-based conditioning is a viable treatment option for patients with indolent—but not aggressive—B-cell non-Hodgkin lymphomas (NHLs), according to researchers.

Long-term follow-up data showed “excellent” outcomes in patients with indolent B-NHL who received conditioning with ⁹⁰Y-ibritumomab tiuxetan plus fludarabine and low-dose total body irradiation (TBI) prior to HLA-matched hematopoietic stem cell transplant (HSCT).

However, long-term outcomes were inferior in patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

Camille E. Puronen, MD, of the University of Washington in Seattle, and her colleagues reported these results in Biology of Blood and Marrow Transplantation.

The study enrolled 40 patients with high-risk B-NHL. This included DLBCL (n=14), chronic lymphocytic leukemia (CLL; n=10), MCL (n=8), follicular lymphoma (FL; n=6); hairy cell leukemia (HCL; n=1), and marginal zone lymphoma (MZL; n=1).

Patients were treated with 0.4 mCi/kg ⁹⁰Y-ibritumomab tiuxetan, given 2 weeks prior to HSCT, to a maximum dose of 32 mCi.

Patients also received fludarabine at 30 mg/m² on day 5, 6, and 7 prior to HSCT and 2 Gy TBI given on the day of transplant.

In an earlier report, the objective response rate (ORR) was 60%, and 35% of patients had a complete response (CR) or unconfirmed CR.

The researchers said early responses were not associated with disease bulk or chemoresistance, as the ORR was 59% in patients with bulky or chemoresistant disease.

However, responses were associated with histology, as the ORR was 38% in patients with DLBCL, 50% in those with MCL, 83% in those with FL, and 90% in those with CLL.

Long-term survival

In the current report, 11 of 40 patients were still alive at a median follow up of 9 years (range, 5.3 to 10.2). Fourteen patients died of disease progression, and 14 died from complications of HSCT.

The 5-year overall survival (OS) was 40%, and the 5-year progression-free survival (PFS) was 28%.

The best survival rates were in patients with indolent histology. The 5-year PFS was 44% in these patients, and the 5-year OS was 67%.

The researchers said early CR was not associated with long-term survival. However, patients who had at least stable disease (SD) at earlier time points did have the opportunity to achieve long-term survival. All patients who progressed before day 84 were dead by the 1-year mark.

Of the 11 patients who were still alive at a median follow up of 9 years, 4 had a CR or unconfirmed CR at day 84 (FL: 1; CLL: 2; MCL: 1); 6 were in partial response (CLL: 3; FL: 1; MCL: 1; MZL: 1); and 1 patient with FL had SD.

Among the 18 patients with indolent NHL, long-term PFS was observed in 5 of the 7 patients who achieved early CR and 8 of the 11 patients who did not achieve early CR.

Two of the 4 MCL patients who achieved an early CR had long-term PFS, but none of the MCL patients without an early CR had long-term PFS.

Among DLBCL patients, 1 of the 4 who achieved early CR had long-term PFS, but none of the patients without an early CR had long-term PFS. Only 1 DLBCL patient survived beyond 5 years. None survived beyond 8 years.

The researchers said the favorable outcomes in patients with indolent B-NHL are consistent with the known efficacy of RIT and the graft-versus-leukemia effect in these patients.

The team also noted that, since this trial began, several novel agents have been approved for the treatment of indolent B-NHL, which means allogeneic HSCT is often moved to later in the disease course.

The researchers concluded that ⁹⁰Y-ibritumomab tiuxetan-based conditioning could “continue to play an important role in these settings,” but “improved strategies are needed” for patients with MCL and DLBCL.

Photo from EHA

STOCKHOLM—The alkylating peptide melflufen has demonstrated activity in patients with treatment-resistant multiple myeloma (MM).

In a phase 2 trial, melflufen plus dexamethasone produced an overall response rate (ORR) of 32.1% in MM patients who were refractory to pomalidomide and/or daratumumab and had failed treatment with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

Nearly all patients experienced an adverse event (AE) related to study treatment, and most of these were hematologic events.

These results, from the ongoing HORIZON trial, were presented at the 23rd Congress of the European Hematology Association (EHA) as abstract PF581.

The research was sponsored by Oncopeptides AB, the company developing melflufen.

“With an increasing number of patients with highly resistant myeloma, there is a real need for additional treatment options based on new mechanisms of action,” said study investigator Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“[Melflufen], a peptidase-enhanced compound, with its potent activity, manageable tolerability, and lack of shared resistance mechanisms with other modalities, is a promising molecule that is making encouraging progress in clinical development.”

Patients and treatment

The data presented at EHA include 62 patients. The data cut-off was May 10, 2018.

The patients had a median age of 62.5 (range, 41-82), 54% had high-risk cytogenetics, and 46% were ISS stage III. The patients had a median of 5.5 prior lines of therapy, and their median time since initial diagnosis was 6.1 years.

All patients were refractory to pomalidomide or daratumumab, 56% were refractory to both drugs, and 89% were double-refractory to IMiDs and PIs. Ninety-eight percent of patients had disease progression on or within 60 days of completing their last therapy.

Patients received melflufen at 40 mg (intravenously over 30 minutes) on day 1 of each 28-day cycle. They also received dexamethasone at 40 mg weekly. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent.

At the data cutoff, 49 patients (79%) had completed at least 2 cycles of melflufen. The median number of cycles was 2 (range, 1-11).

Twenty-one patients (34%) were still receiving study treatment at the data cutoff. Reasons for discontinuation included disease progression (47%), AEs (15%), and physician decision (3%). One discontinuation was due to patient request.

Results

Fifty-six patients received at least 1 dose of melflufen and were evaluable for response.

The ORR was 32.1%, and the clinical benefit rate was 39.3%. ORR was defined as partial response (PR) or better, and clinical benefit rate was defined as minor response or better.

Two percent of patients had a complete response, 9% had a very good PR, 21% had a PR, and 7% had a minor response. Forty-five percent of patients had stable disease, and 16% progressed.

Subgroup analyses showed that response didn’t vary across refractory subsets, but it did vary according to the underlying disease and health status of the patient.

Treatment-related AEs occurred in 97% of all patients (60/62), and grade 3/4 treatment-related AEs occurred in 77% (n=48).

Grade 3/4 treatment-related AEs included neutropenia (60%), thrombocytopenia (60%), anemia (31%), leukopenia (6%), lymphopenia (6%), febrile neutropenia (6%), and infections (6%).

Twenty-one percent of patients had at least 1 treatment-related serious AE. The most frequent were febrile neutropenia (6%) and pneumonia (3%).

There were no treatment-related deaths.

Photo from EHA

STOCKHOLM—The alkylating peptide melflufen has demonstrated activity in patients with treatment-resistant multiple myeloma (MM).

In a phase 2 trial, melflufen plus dexamethasone produced an overall response rate (ORR) of 32.1% in MM patients who were refractory to pomalidomide and/or daratumumab and had failed treatment with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

Nearly all patients experienced an adverse event (AE) related to study treatment, and most of these were hematologic events.

These results, from the ongoing HORIZON trial, were presented at the 23rd Congress of the European Hematology Association (EHA) as abstract PF581.

The research was sponsored by Oncopeptides AB, the company developing melflufen.

“With an increasing number of patients with highly resistant myeloma, there is a real need for additional treatment options based on new mechanisms of action,” said study investigator Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“[Melflufen], a peptidase-enhanced compound, with its potent activity, manageable tolerability, and lack of shared resistance mechanisms with other modalities, is a promising molecule that is making encouraging progress in clinical development.”

Patients and treatment

The data presented at EHA include 62 patients. The data cut-off was May 10, 2018.

The patients had a median age of 62.5 (range, 41-82), 54% had high-risk cytogenetics, and 46% were ISS stage III. The patients had a median of 5.5 prior lines of therapy, and their median time since initial diagnosis was 6.1 years.

All patients were refractory to pomalidomide or daratumumab, 56% were refractory to both drugs, and 89% were double-refractory to IMiDs and PIs. Ninety-eight percent of patients had disease progression on or within 60 days of completing their last therapy.

Patients received melflufen at 40 mg (intravenously over 30 minutes) on day 1 of each 28-day cycle. They also received dexamethasone at 40 mg weekly. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent.

At the data cutoff, 49 patients (79%) had completed at least 2 cycles of melflufen. The median number of cycles was 2 (range, 1-11).

Twenty-one patients (34%) were still receiving study treatment at the data cutoff. Reasons for discontinuation included disease progression (47%), AEs (15%), and physician decision (3%). One discontinuation was due to patient request.

Results

Fifty-six patients received at least 1 dose of melflufen and were evaluable for response.

The ORR was 32.1%, and the clinical benefit rate was 39.3%. ORR was defined as partial response (PR) or better, and clinical benefit rate was defined as minor response or better.

Two percent of patients had a complete response, 9% had a very good PR, 21% had a PR, and 7% had a minor response. Forty-five percent of patients had stable disease, and 16% progressed.

Subgroup analyses showed that response didn’t vary across refractory subsets, but it did vary according to the underlying disease and health status of the patient.

Treatment-related AEs occurred in 97% of all patients (60/62), and grade 3/4 treatment-related AEs occurred in 77% (n=48).

Grade 3/4 treatment-related AEs included neutropenia (60%), thrombocytopenia (60%), anemia (31%), leukopenia (6%), lymphopenia (6%), febrile neutropenia (6%), and infections (6%).

Twenty-one percent of patients had at least 1 treatment-related serious AE. The most frequent were febrile neutropenia (6%) and pneumonia (3%).

There were no treatment-related deaths.

Photo from EHA

STOCKHOLM—The alkylating peptide melflufen has demonstrated activity in patients with treatment-resistant multiple myeloma (MM).

In a phase 2 trial, melflufen plus dexamethasone produced an overall response rate (ORR) of 32.1% in MM patients who were refractory to pomalidomide and/or daratumumab and had failed treatment with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs).

Nearly all patients experienced an adverse event (AE) related to study treatment, and most of these were hematologic events.

These results, from the ongoing HORIZON trial, were presented at the 23rd Congress of the European Hematology Association (EHA) as abstract PF581.

The research was sponsored by Oncopeptides AB, the company developing melflufen.

“With an increasing number of patients with highly resistant myeloma, there is a real need for additional treatment options based on new mechanisms of action,” said study investigator Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.

“[Melflufen], a peptidase-enhanced compound, with its potent activity, manageable tolerability, and lack of shared resistance mechanisms with other modalities, is a promising molecule that is making encouraging progress in clinical development.”

Patients and treatment

The data presented at EHA include 62 patients. The data cut-off was May 10, 2018.

The patients had a median age of 62.5 (range, 41-82), 54% had high-risk cytogenetics, and 46% were ISS stage III. The patients had a median of 5.5 prior lines of therapy, and their median time since initial diagnosis was 6.1 years.

All patients were refractory to pomalidomide or daratumumab, 56% were refractory to both drugs, and 89% were double-refractory to IMiDs and PIs. Ninety-eight percent of patients had disease progression on or within 60 days of completing their last therapy.

Patients received melflufen at 40 mg (intravenously over 30 minutes) on day 1 of each 28-day cycle. They also received dexamethasone at 40 mg weekly. Patients were treated until disease progression, unacceptable toxicity, or withdrawal of consent.

At the data cutoff, 49 patients (79%) had completed at least 2 cycles of melflufen. The median number of cycles was 2 (range, 1-11).

Twenty-one patients (34%) were still receiving study treatment at the data cutoff. Reasons for discontinuation included disease progression (47%), AEs (15%), and physician decision (3%). One discontinuation was due to patient request.

Results

Fifty-six patients received at least 1 dose of melflufen and were evaluable for response.

The ORR was 32.1%, and the clinical benefit rate was 39.3%. ORR was defined as partial response (PR) or better, and clinical benefit rate was defined as minor response or better.

Two percent of patients had a complete response, 9% had a very good PR, 21% had a PR, and 7% had a minor response. Forty-five percent of patients had stable disease, and 16% progressed.

Subgroup analyses showed that response didn’t vary across refractory subsets, but it did vary according to the underlying disease and health status of the patient.

Treatment-related AEs occurred in 97% of all patients (60/62), and grade 3/4 treatment-related AEs occurred in 77% (n=48).

Grade 3/4 treatment-related AEs included neutropenia (60%), thrombocytopenia (60%), anemia (31%), leukopenia (6%), lymphopenia (6%), febrile neutropenia (6%), and infections (6%).

Twenty-one percent of patients had at least 1 treatment-related serious AE. The most frequent were febrile neutropenia (6%) and pneumonia (3%).

There were no treatment-related deaths.

Alaska is a vast state—larger than Texas, Montana, and California combined. It is also home to the highest percentage of American Indian (AI) and Alaska Native (AN) persons in the United States. These two populations—collectively referred to as Native Americans—have been served by the Indian Health Services (IHS) since it was established through the Snyder Act of 1921, in response to the dismal health conditions of the indigenous tribes in this country.¹ Across the US (not only in Alaska), the IHS has partnered with AI/AN peoples to decrease health disparities in a culturally acceptable manner that honors and protects their traditions and values.

The IHS—which in 2016 comprised 2,500 nurses, 750 physicians, 700 pharmacists, 200 PAs and NPs, and 280 dentists, as well as nutritionists, diabetes educators, administrators, and other professionals—has made huge advances in decreasing health disparities in their populations. Among them: decreased rates of tuberculosis and of maternal and infant deaths.

However, life expectancy among Native Americans remains four years shorter than that of the rest of the US population. This disparity can be traced to three recalcitrant factors: unintentional injuries, liver disease, and diabetes.

The IHS practitioners decided to tackle diabetes with a multipronged approach. And what they achieved is astonishing.

WHAT THEY DID

Worldwide, diabetes is the most common cause of kidney failure; identifying patients with diabetes and early-stage chronic kidney disease allows for aggressive treatment that can slow progression to kidney failure and dialysis.

The IHS providers knew when they decided to tackle the problem of diabetes in the AI/AN population that the incidence was 16%—and the rate of diabetes leading to kidney failure in this population was the highest for any ethnic group in the US.^2,3 And yet …

From 1996 to 2013, the rate of diabetes-related kidney failure among Native Americans dropped by 54%.³ Yes—the group of patients with the highest percentage of diabetes diagnoses has had the greatest improvement in prevention of kidney failure.⁴

Continue to: Some of the clinical achievements that contributed to...

Some of the clinical achievements that contributed to this significant change include

• Increased use of ACE inhibitors or angiotensin receptor blockers (ARBs) (from 42% to 74% over a five-year period)
• Reduced average blood pressure among hypertensive patients (to 133/76 mm Hg)
• Improved blood glucose control (by 10%)
• Increased testing for kidney disease among older patients (50% higher than the rest of the Medicare diabetes population).³

HOW THEY DID IT

This is not rocket science. The IHS staff integrated both population- and team-based approaches to achieve a more impressive decrease than ever could have been expected. In retrospect, perhaps this success should not come as such a surprise—many religious beliefs held by Native Americans focus around society, communal harmony, kinship, and cooperation.

The population health approach focused on promoting the wellness of the entire community and connecting people to local resources, including healthy food, transportation, housing, and mental health care. In the team approach, IHS medical experts implemented strategies to improve patient education, community outreach, care coordination, health outcome tracking, and access to a wide variety of health care providers.^3,5

In a place like Alaska—where the northernmost city, Barrow, is more than 700 miles (two hours by plane) from Anchorage, and the southeastern Annette Island is more than 1,000 miles (six hours by plane) from the capital—this can be an especially challenging prospect. To reduce travel burden for rural patients, the IHS sponsors a diabetes team that travels from village to village. Nephrology services are not included in these field visits, however, so the kidney team relies heavily on telehealth. This requires extensive clinic staff coordination, as well as equipment and knowledgeable information systems support teams.

Other challenges require educational and logistical solutions. As noted, the use of ACE inhibitors and ARBs increased through the IHS’s efforts—and contributed to the delayed progression of diabetic kidney disease—but those additional prescriptions necessitate patient education. Understanding of these medications can be limited; many rural patients trust that when the bottle is empty, their practitioner has treated and cured their disease—mistakenly believing that no refills are needed. And even when the need to continue the prescription is understood, rural clinics may have difficulty tracking appointments and prescriptions written by providers at specialty clinics in Anchorage, making ongoing refills an issue.

Continue to: The necessary dietary changes can also be...

The necessary dietary changes can also be difficult for AI/AN populations. For example, in rural Alaska, tap water may not be safe to drink, and soda costs less than bottled water. Fresh produce is expensive and has often begun to spoil by the time it reaches local stores. The Native villagers often prefer their usual diets of gathered berries, fish, and red meat from subsistence hunting, making implementation of dietary changes difficult.

However, as the success of the IHS initiative shows, challenges can be met and overcome by practitioners who see a need, formulate a solution individualized to the circumstance, and think outside the box. One of the keys is developing a trusting relationship with patients. Another is to recognize informational needs and utilize available resources to educate patients. For example, visual representations of kidney function tend to be helpful in explaining the nature and course of disease; the National Kidney Disease Education Program uses an illustration similar to a gas gauge to demonstrate glomerular filtration rate (which would otherwise seem abstract and hard to understand for some patients; see below).⁶ When you understand your patient population and their needs, it makes addressing the challenging aspects of health care and prevention easier.

CONCLUSION

The results that the IHS achieved should serve as an example for all Americans with diabetes and their health care providers. We must be open to delivery of care via different approaches and practitioners in order to successfully help patients of different backgrounds and circumstances. This is the individualization of care that we hear so much about.

In 2016, the costs of caring for the kidney failure population were greater than the entire budget of the NIH. By aggressively identifying and treating patients at risk for kidney failure, we can slow disease progression—saving society money, but more importantly allowing our patients many more years of life free from the constraints of dialysis. —MET, RB

Mandy E. Thompson, PA-C
Kidney Center of Denver Health

Robin Bassett, DNP
Nephrology and Hypertension Associates, Anchorage
Adjunct Professor, NP program, University of Alaska, Anchorage

Alaska is a vast state—larger than Texas, Montana, and California combined. It is also home to the highest percentage of American Indian (AI) and Alaska Native (AN) persons in the United States. These two populations—collectively referred to as Native Americans—have been served by the Indian Health Services (IHS) since it was established through the Snyder Act of 1921, in response to the dismal health conditions of the indigenous tribes in this country.¹ Across the US (not only in Alaska), the IHS has partnered with AI/AN peoples to decrease health disparities in a culturally acceptable manner that honors and protects their traditions and values.

The IHS—which in 2016 comprised 2,500 nurses, 750 physicians, 700 pharmacists, 200 PAs and NPs, and 280 dentists, as well as nutritionists, diabetes educators, administrators, and other professionals—has made huge advances in decreasing health disparities in their populations. Among them: decreased rates of tuberculosis and of maternal and infant deaths.

However, life expectancy among Native Americans remains four years shorter than that of the rest of the US population. This disparity can be traced to three recalcitrant factors: unintentional injuries, liver disease, and diabetes.

The IHS practitioners decided to tackle diabetes with a multipronged approach. And what they achieved is astonishing.

WHAT THEY DID

Worldwide, diabetes is the most common cause of kidney failure; identifying patients with diabetes and early-stage chronic kidney disease allows for aggressive treatment that can slow progression to kidney failure and dialysis.

The IHS providers knew when they decided to tackle the problem of diabetes in the AI/AN population that the incidence was 16%—and the rate of diabetes leading to kidney failure in this population was the highest for any ethnic group in the US.^2,3 And yet …

From 1996 to 2013, the rate of diabetes-related kidney failure among Native Americans dropped by 54%.³ Yes—the group of patients with the highest percentage of diabetes diagnoses has had the greatest improvement in prevention of kidney failure.⁴

Continue to: Some of the clinical achievements that contributed to...

Some of the clinical achievements that contributed to this significant change include

• Increased use of ACE inhibitors or angiotensin receptor blockers (ARBs) (from 42% to 74% over a five-year period)
• Reduced average blood pressure among hypertensive patients (to 133/76 mm Hg)
• Improved blood glucose control (by 10%)
• Increased testing for kidney disease among older patients (50% higher than the rest of the Medicare diabetes population).³

HOW THEY DID IT

This is not rocket science. The IHS staff integrated both population- and team-based approaches to achieve a more impressive decrease than ever could have been expected. In retrospect, perhaps this success should not come as such a surprise—many religious beliefs held by Native Americans focus around society, communal harmony, kinship, and cooperation.

The population health approach focused on promoting the wellness of the entire community and connecting people to local resources, including healthy food, transportation, housing, and mental health care. In the team approach, IHS medical experts implemented strategies to improve patient education, community outreach, care coordination, health outcome tracking, and access to a wide variety of health care providers.^3,5

In a place like Alaska—where the northernmost city, Barrow, is more than 700 miles (two hours by plane) from Anchorage, and the southeastern Annette Island is more than 1,000 miles (six hours by plane) from the capital—this can be an especially challenging prospect. To reduce travel burden for rural patients, the IHS sponsors a diabetes team that travels from village to village. Nephrology services are not included in these field visits, however, so the kidney team relies heavily on telehealth. This requires extensive clinic staff coordination, as well as equipment and knowledgeable information systems support teams.

Other challenges require educational and logistical solutions. As noted, the use of ACE inhibitors and ARBs increased through the IHS’s efforts—and contributed to the delayed progression of diabetic kidney disease—but those additional prescriptions necessitate patient education. Understanding of these medications can be limited; many rural patients trust that when the bottle is empty, their practitioner has treated and cured their disease—mistakenly believing that no refills are needed. And even when the need to continue the prescription is understood, rural clinics may have difficulty tracking appointments and prescriptions written by providers at specialty clinics in Anchorage, making ongoing refills an issue.

Continue to: The necessary dietary changes can also be...

The necessary dietary changes can also be difficult for AI/AN populations. For example, in rural Alaska, tap water may not be safe to drink, and soda costs less than bottled water. Fresh produce is expensive and has often begun to spoil by the time it reaches local stores. The Native villagers often prefer their usual diets of gathered berries, fish, and red meat from subsistence hunting, making implementation of dietary changes difficult.

However, as the success of the IHS initiative shows, challenges can be met and overcome by practitioners who see a need, formulate a solution individualized to the circumstance, and think outside the box. One of the keys is developing a trusting relationship with patients. Another is to recognize informational needs and utilize available resources to educate patients. For example, visual representations of kidney function tend to be helpful in explaining the nature and course of disease; the National Kidney Disease Education Program uses an illustration similar to a gas gauge to demonstrate glomerular filtration rate (which would otherwise seem abstract and hard to understand for some patients; see below).⁶ When you understand your patient population and their needs, it makes addressing the challenging aspects of health care and prevention easier.

CONCLUSION

The results that the IHS achieved should serve as an example for all Americans with diabetes and their health care providers. We must be open to delivery of care via different approaches and practitioners in order to successfully help patients of different backgrounds and circumstances. This is the individualization of care that we hear so much about.

In 2016, the costs of caring for the kidney failure population were greater than the entire budget of the NIH. By aggressively identifying and treating patients at risk for kidney failure, we can slow disease progression—saving society money, but more importantly allowing our patients many more years of life free from the constraints of dialysis. —MET, RB

Mandy E. Thompson, PA-C
Kidney Center of Denver Health

Robin Bassett, DNP
Nephrology and Hypertension Associates, Anchorage
Adjunct Professor, NP program, University of Alaska, Anchorage

Alaska is a vast state—larger than Texas, Montana, and California combined. It is also home to the highest percentage of American Indian (AI) and Alaska Native (AN) persons in the United States. These two populations—collectively referred to as Native Americans—have been served by the Indian Health Services (IHS) since it was established through the Snyder Act of 1921, in response to the dismal health conditions of the indigenous tribes in this country.¹ Across the US (not only in Alaska), the IHS has partnered with AI/AN peoples to decrease health disparities in a culturally acceptable manner that honors and protects their traditions and values.

The IHS—which in 2016 comprised 2,500 nurses, 750 physicians, 700 pharmacists, 200 PAs and NPs, and 280 dentists, as well as nutritionists, diabetes educators, administrators, and other professionals—has made huge advances in decreasing health disparities in their populations. Among them: decreased rates of tuberculosis and of maternal and infant deaths.

However, life expectancy among Native Americans remains four years shorter than that of the rest of the US population. This disparity can be traced to three recalcitrant factors: unintentional injuries, liver disease, and diabetes.

The IHS practitioners decided to tackle diabetes with a multipronged approach. And what they achieved is astonishing.

WHAT THEY DID

Worldwide, diabetes is the most common cause of kidney failure; identifying patients with diabetes and early-stage chronic kidney disease allows for aggressive treatment that can slow progression to kidney failure and dialysis.

The IHS providers knew when they decided to tackle the problem of diabetes in the AI/AN population that the incidence was 16%—and the rate of diabetes leading to kidney failure in this population was the highest for any ethnic group in the US.^2,3 And yet …

From 1996 to 2013, the rate of diabetes-related kidney failure among Native Americans dropped by 54%.³ Yes—the group of patients with the highest percentage of diabetes diagnoses has had the greatest improvement in prevention of kidney failure.⁴

Continue to: Some of the clinical achievements that contributed to...

Some of the clinical achievements that contributed to this significant change include

• Increased use of ACE inhibitors or angiotensin receptor blockers (ARBs) (from 42% to 74% over a five-year period)
• Reduced average blood pressure among hypertensive patients (to 133/76 mm Hg)
• Improved blood glucose control (by 10%)
• Increased testing for kidney disease among older patients (50% higher than the rest of the Medicare diabetes population).³

HOW THEY DID IT

This is not rocket science. The IHS staff integrated both population- and team-based approaches to achieve a more impressive decrease than ever could have been expected. In retrospect, perhaps this success should not come as such a surprise—many religious beliefs held by Native Americans focus around society, communal harmony, kinship, and cooperation.

The population health approach focused on promoting the wellness of the entire community and connecting people to local resources, including healthy food, transportation, housing, and mental health care. In the team approach, IHS medical experts implemented strategies to improve patient education, community outreach, care coordination, health outcome tracking, and access to a wide variety of health care providers.^3,5

In a place like Alaska—where the northernmost city, Barrow, is more than 700 miles (two hours by plane) from Anchorage, and the southeastern Annette Island is more than 1,000 miles (six hours by plane) from the capital—this can be an especially challenging prospect. To reduce travel burden for rural patients, the IHS sponsors a diabetes team that travels from village to village. Nephrology services are not included in these field visits, however, so the kidney team relies heavily on telehealth. This requires extensive clinic staff coordination, as well as equipment and knowledgeable information systems support teams.

Other challenges require educational and logistical solutions. As noted, the use of ACE inhibitors and ARBs increased through the IHS’s efforts—and contributed to the delayed progression of diabetic kidney disease—but those additional prescriptions necessitate patient education. Understanding of these medications can be limited; many rural patients trust that when the bottle is empty, their practitioner has treated and cured their disease—mistakenly believing that no refills are needed. And even when the need to continue the prescription is understood, rural clinics may have difficulty tracking appointments and prescriptions written by providers at specialty clinics in Anchorage, making ongoing refills an issue.

Continue to: The necessary dietary changes can also be...

The necessary dietary changes can also be difficult for AI/AN populations. For example, in rural Alaska, tap water may not be safe to drink, and soda costs less than bottled water. Fresh produce is expensive and has often begun to spoil by the time it reaches local stores. The Native villagers often prefer their usual diets of gathered berries, fish, and red meat from subsistence hunting, making implementation of dietary changes difficult.

However, as the success of the IHS initiative shows, challenges can be met and overcome by practitioners who see a need, formulate a solution individualized to the circumstance, and think outside the box. One of the keys is developing a trusting relationship with patients. Another is to recognize informational needs and utilize available resources to educate patients. For example, visual representations of kidney function tend to be helpful in explaining the nature and course of disease; the National Kidney Disease Education Program uses an illustration similar to a gas gauge to demonstrate glomerular filtration rate (which would otherwise seem abstract and hard to understand for some patients; see below).⁶ When you understand your patient population and their needs, it makes addressing the challenging aspects of health care and prevention easier.

CONCLUSION

The results that the IHS achieved should serve as an example for all Americans with diabetes and their health care providers. We must be open to delivery of care via different approaches and practitioners in order to successfully help patients of different backgrounds and circumstances. This is the individualization of care that we hear so much about.

In 2016, the costs of caring for the kidney failure population were greater than the entire budget of the NIH. By aggressively identifying and treating patients at risk for kidney failure, we can slow disease progression—saving society money, but more importantly allowing our patients many more years of life free from the constraints of dialysis. —MET, RB

Mandy E. Thompson, PA-C
Kidney Center of Denver Health

Robin Bassett, DNP
Nephrology and Hypertension Associates, Anchorage
Adjunct Professor, NP program, University of Alaska, Anchorage

SAN FRANCISCO – Half of migraineurs suspect chocolate can trigger their migraine attacks, but new evidence from a large prospective study suggests almost 99% of them are mistaken.

Additional analyses of this same dataset of 774 individuals with migraine threw cold water on two other widely accepted putative migraine triggers: neck pain/tension and dietary nitrate intake, Stephen Donoghue, PhD, reported at the annual meeting of the American Headache Society.

Bruce Jancin/MDedge News

He presented a series of statistical analyses of often-cited migraine attack triggers conducted in 774 migraineurs who registered to use N1–Headache, a sophisticated proprietary digital headache diary. At the outset, participants rated on a 0-10 scale how strongly they suspected chocolate, neck pain or tension, and other factors acted as triggers for migraine attacks in their own personal experience. They then spent 2-3 minutes daily tracking more than 70 migraine-related elements for at least 90 days, recording the data using an iPhone or iPad rather than using a traditional, more hit-or-miss conventional paper diary.

The N1–Headache software, developed by Curelator of Cambridge, Mass., then tackled the key issue of what proportion of individuals who suspected a given trigger actually showed a statistically significant association prospectively between an individual’s day-to-day variations in experiencing that trigger and their headache risk, explained Dr. Donoghue, vice president for clinical development for Curelator.
 

Chocolate

The Curelator concept involves bringing personalized medicine to headache patients by identifying their true migraine attack triggers, which can enable individuals to deal with those triggers without the disruption involved in unnecessarily avoiding numerous nontriggers or missing real triggers.

The study results punctured some widely held beliefs. For example, at baseline 51% of migraineurs indicated they suspected chocolate served to some degree as a trigger for their own migraine attacks; the majority of them rated their suspicion as moderate or strong. However, in individually determined correlations, chocolate was indeed associated with migraine attacks in only 1.3% of those who suspected it to be a trigger. Moreover, in an another 3.9% of chocolate suspecters, chocolate consumption was actually associated with decreased risk; in other words, for them, chocolate appeared to serve as a protector against migraine, despite their preconceptions.

Also, among the 49% of participants who didn’t consider chocolate to be a personal migraine attack trigger, the Curelator analysis demonstrated that chocolate consumption was associated with a significantly increased risk of migraine attack in 2.2%, and a significantly lower risk of migraine in another 1.5%.
 

Neck pain/tension

Eighty percent of migraineurs who registered to use N1–Headache via the company’s website or the App Store indicated they believed neck pain/tension to be a migraine trigger for them; 46% rated it as a strong trigger. The detailed analysis of 90 days’ worth of data showed that 32% of participants with adequate data showed a statistically significant association between neck pain/tension and migraine headache.

The strength of an individual’s suspicion of neck paint/tension as a trigger was associated with the frequency of a statistically confirmed association. However, unlike for chocolate, there were zero instances where neck pain/tension was associated with protection against migraine.

In a twist, when the investigators reanalyzed their data after eliminating those instances where neck pain/tension occurred 1 day before the start of the headache, the association disappeared.

“The temporal association that we find using the lag-day analysis strongly suggests that neck pain/tension is part of the symptomatology of migraine attacks rather than acting as a trigger,” Dr. Donoghue observed.

This concept is strongly supported by a recent German study that used neck muscle electromyography to establish the same point (J Headache Pain. 2018 Mar 20;19[1]:26), he added.

Dr. Donoghue offered one caveat regarding the Curelator analyses: “We can’t say whether or not neck pain/tension and these other factors are actually triggers. What we’re looking at is associations. We’re not showing causality.”


 

Nitrates in food

Of the participants in this Curelator study, 45% suspected nitrate intake was a trigger for their migraine attacks, including 24% who rated the strength of their suspicion as moderate or severe. Of those who suspected nitrates, Cox proportional hazards modeling identified 2.2% in whom a significant association between nitrate consumption and increased migraine attack risk was present and another 1.1% in whom nitrates were associated with decreased risk, which suggests that they act as a possible protector in some cases. An individual’s strength of suspicion regarding nitrates proved unrelated to the actual risk of an association.

In subjects who did not suspect nitrates as a migraine trigger, Dr. Donoghue and colleagues identified 3.5% in whom nitrate intake was actually statistically associated with increased risk and 1.7% in whom it was linked to decreased risk.

The study was funded by Curelator, where Dr. Donoghue is employed.

[email protected]

SOURCE: Donoghue S et al. Headache. 2018 Jun;58(52):104,109,110.

SAN FRANCISCO – Half of migraineurs suspect chocolate can trigger their migraine attacks, but new evidence from a large prospective study suggests almost 99% of them are mistaken.

Additional analyses of this same dataset of 774 individuals with migraine threw cold water on two other widely accepted putative migraine triggers: neck pain/tension and dietary nitrate intake, Stephen Donoghue, PhD, reported at the annual meeting of the American Headache Society.

Bruce Jancin/MDedge News

He presented a series of statistical analyses of often-cited migraine attack triggers conducted in 774 migraineurs who registered to use N1–Headache, a sophisticated proprietary digital headache diary. At the outset, participants rated on a 0-10 scale how strongly they suspected chocolate, neck pain or tension, and other factors acted as triggers for migraine attacks in their own personal experience. They then spent 2-3 minutes daily tracking more than 70 migraine-related elements for at least 90 days, recording the data using an iPhone or iPad rather than using a traditional, more hit-or-miss conventional paper diary.

The N1–Headache software, developed by Curelator of Cambridge, Mass., then tackled the key issue of what proportion of individuals who suspected a given trigger actually showed a statistically significant association prospectively between an individual’s day-to-day variations in experiencing that trigger and their headache risk, explained Dr. Donoghue, vice president for clinical development for Curelator.
 

Chocolate

The Curelator concept involves bringing personalized medicine to headache patients by identifying their true migraine attack triggers, which can enable individuals to deal with those triggers without the disruption involved in unnecessarily avoiding numerous nontriggers or missing real triggers.

The study results punctured some widely held beliefs. For example, at baseline 51% of migraineurs indicated they suspected chocolate served to some degree as a trigger for their own migraine attacks; the majority of them rated their suspicion as moderate or strong. However, in individually determined correlations, chocolate was indeed associated with migraine attacks in only 1.3% of those who suspected it to be a trigger. Moreover, in an another 3.9% of chocolate suspecters, chocolate consumption was actually associated with decreased risk; in other words, for them, chocolate appeared to serve as a protector against migraine, despite their preconceptions.

Also, among the 49% of participants who didn’t consider chocolate to be a personal migraine attack trigger, the Curelator analysis demonstrated that chocolate consumption was associated with a significantly increased risk of migraine attack in 2.2%, and a significantly lower risk of migraine in another 1.5%.
 

Neck pain/tension

Eighty percent of migraineurs who registered to use N1–Headache via the company’s website or the App Store indicated they believed neck pain/tension to be a migraine trigger for them; 46% rated it as a strong trigger. The detailed analysis of 90 days’ worth of data showed that 32% of participants with adequate data showed a statistically significant association between neck pain/tension and migraine headache.

The strength of an individual’s suspicion of neck paint/tension as a trigger was associated with the frequency of a statistically confirmed association. However, unlike for chocolate, there were zero instances where neck pain/tension was associated with protection against migraine.

In a twist, when the investigators reanalyzed their data after eliminating those instances where neck pain/tension occurred 1 day before the start of the headache, the association disappeared.

“The temporal association that we find using the lag-day analysis strongly suggests that neck pain/tension is part of the symptomatology of migraine attacks rather than acting as a trigger,” Dr. Donoghue observed.

This concept is strongly supported by a recent German study that used neck muscle electromyography to establish the same point (J Headache Pain. 2018 Mar 20;19[1]:26), he added.

Dr. Donoghue offered one caveat regarding the Curelator analyses: “We can’t say whether or not neck pain/tension and these other factors are actually triggers. What we’re looking at is associations. We’re not showing causality.”


 

Nitrates in food

Of the participants in this Curelator study, 45% suspected nitrate intake was a trigger for their migraine attacks, including 24% who rated the strength of their suspicion as moderate or severe. Of those who suspected nitrates, Cox proportional hazards modeling identified 2.2% in whom a significant association between nitrate consumption and increased migraine attack risk was present and another 1.1% in whom nitrates were associated with decreased risk, which suggests that they act as a possible protector in some cases. An individual’s strength of suspicion regarding nitrates proved unrelated to the actual risk of an association.

In subjects who did not suspect nitrates as a migraine trigger, Dr. Donoghue and colleagues identified 3.5% in whom nitrate intake was actually statistically associated with increased risk and 1.7% in whom it was linked to decreased risk.

The study was funded by Curelator, where Dr. Donoghue is employed.

[email protected]

SOURCE: Donoghue S et al. Headache. 2018 Jun;58(52):104,109,110.

SAN FRANCISCO – Half of migraineurs suspect chocolate can trigger their migraine attacks, but new evidence from a large prospective study suggests almost 99% of them are mistaken.

Additional analyses of this same dataset of 774 individuals with migraine threw cold water on two other widely accepted putative migraine triggers: neck pain/tension and dietary nitrate intake, Stephen Donoghue, PhD, reported at the annual meeting of the American Headache Society.

Bruce Jancin/MDedge News

He presented a series of statistical analyses of often-cited migraine attack triggers conducted in 774 migraineurs who registered to use N1–Headache, a sophisticated proprietary digital headache diary. At the outset, participants rated on a 0-10 scale how strongly they suspected chocolate, neck pain or tension, and other factors acted as triggers for migraine attacks in their own personal experience. They then spent 2-3 minutes daily tracking more than 70 migraine-related elements for at least 90 days, recording the data using an iPhone or iPad rather than using a traditional, more hit-or-miss conventional paper diary.

The N1–Headache software, developed by Curelator of Cambridge, Mass., then tackled the key issue of what proportion of individuals who suspected a given trigger actually showed a statistically significant association prospectively between an individual’s day-to-day variations in experiencing that trigger and their headache risk, explained Dr. Donoghue, vice president for clinical development for Curelator.
 

Chocolate

The Curelator concept involves bringing personalized medicine to headache patients by identifying their true migraine attack triggers, which can enable individuals to deal with those triggers without the disruption involved in unnecessarily avoiding numerous nontriggers or missing real triggers.

The study results punctured some widely held beliefs. For example, at baseline 51% of migraineurs indicated they suspected chocolate served to some degree as a trigger for their own migraine attacks; the majority of them rated their suspicion as moderate or strong. However, in individually determined correlations, chocolate was indeed associated with migraine attacks in only 1.3% of those who suspected it to be a trigger. Moreover, in an another 3.9% of chocolate suspecters, chocolate consumption was actually associated with decreased risk; in other words, for them, chocolate appeared to serve as a protector against migraine, despite their preconceptions.

Also, among the 49% of participants who didn’t consider chocolate to be a personal migraine attack trigger, the Curelator analysis demonstrated that chocolate consumption was associated with a significantly increased risk of migraine attack in 2.2%, and a significantly lower risk of migraine in another 1.5%.
 

Neck pain/tension

Eighty percent of migraineurs who registered to use N1–Headache via the company’s website or the App Store indicated they believed neck pain/tension to be a migraine trigger for them; 46% rated it as a strong trigger. The detailed analysis of 90 days’ worth of data showed that 32% of participants with adequate data showed a statistically significant association between neck pain/tension and migraine headache.

The strength of an individual’s suspicion of neck paint/tension as a trigger was associated with the frequency of a statistically confirmed association. However, unlike for chocolate, there were zero instances where neck pain/tension was associated with protection against migraine.

In a twist, when the investigators reanalyzed their data after eliminating those instances where neck pain/tension occurred 1 day before the start of the headache, the association disappeared.

“The temporal association that we find using the lag-day analysis strongly suggests that neck pain/tension is part of the symptomatology of migraine attacks rather than acting as a trigger,” Dr. Donoghue observed.

This concept is strongly supported by a recent German study that used neck muscle electromyography to establish the same point (J Headache Pain. 2018 Mar 20;19[1]:26), he added.

Dr. Donoghue offered one caveat regarding the Curelator analyses: “We can’t say whether or not neck pain/tension and these other factors are actually triggers. What we’re looking at is associations. We’re not showing causality.”


 

Nitrates in food

Of the participants in this Curelator study, 45% suspected nitrate intake was a trigger for their migraine attacks, including 24% who rated the strength of their suspicion as moderate or severe. Of those who suspected nitrates, Cox proportional hazards modeling identified 2.2% in whom a significant association between nitrate consumption and increased migraine attack risk was present and another 1.1% in whom nitrates were associated with decreased risk, which suggests that they act as a possible protector in some cases. An individual’s strength of suspicion regarding nitrates proved unrelated to the actual risk of an association.

In subjects who did not suspect nitrates as a migraine trigger, Dr. Donoghue and colleagues identified 3.5% in whom nitrate intake was actually statistically associated with increased risk and 1.7% in whom it was linked to decreased risk.

The study was funded by Curelator, where Dr. Donoghue is employed.

[email protected]

SOURCE: Donoghue S et al. Headache. 2018 Jun;58(52):104,109,110.

BALTIMORE – Disruption of slow-wave activity may potentially explain the positive influence that sleep deprivation may have on major depressive disorder, according to results of a study presented at the annual meeting of the Associated Professional Sleep Societies.

Jennifer Goldschmied, PhD, of the University of Pennsylvania, Philadelphia, reported preliminary results of a study of slow-wave activity (SWA) disruption in 26 subjects – 12 healthy controls and 14 people diagnosed with major depressive disorder – that found a significant decrease of about 20% in waking theta activity, as measured with EEG, in the MDD group. In the 3-night sleep study, conducted at the University of Michigan, Ann Arbor, an adaptation night was followed by baseline and SWA disruption nights with EEGs performed each night. After the baseline night, patients also had a morning and afternoon EEG.

Across the baseline day, patients with depression showed “no modulation of theta activity whatsoever,” Dr. Goldschmied said. “And then we see, following slow-wave disruption, a significant decrease in theta activity,” whereas, healthy controls showed no change in waking theta following slow-wave disruption. “So what this means is that the presence of SWA may actually be facilitating the reduction of theta or sleep propensity during typical sleep in healthy individuals,” she added. In MDD patients, the decline in theta power following slow-wave disruption was from around 5.4 to 4.3.

Dr. Goldschmied noted that this finding somewhat supports what is known as the synaptic homeostasis hypothesis that University of Wisconsin researchers Giulio Tononi, MD, PhD, and Chiara Cirelli, MD, PhD, reported (Brain Res Bull. 2003;62:143-50). This hypothesis holds that SWA is a marker of synaptic strength and promotes the downscaling of synaptic strength during sleep. No method for measuring synaptic strength in humans exists, Dr. Goldschmied added, but waking theta can be considered a proxy for net synaptic strength across the cortex.

Dr. Goldschmied noted other research that has found SWA disruption improves mood (Psychiatry Res. 2015;228:715-8; J Psychiatr Res. 2011;45:1019-26), but the study she reported on found no role of decreased theta activity in that change. “To go even further,” she said, “we looked at the entire data set and found no relationship between the decrease in theta and any of the measures of sleep architecture – so there’s really no way to predict this decrease in our sample of people with depression.”

SWA plays a significant role in depression and merits more study, Dr. Goldschmied said. She noted that future research should examine the effects of SWA disruption in a larger sample, investigate theta findings with other proxy measures of synaptic strength such as brain-derived neurotrophic factor and transcranial magnetic stimulation, explore differences in SWA between sexes, and explore how SWA enhancement influences mood and theta activity.

Dr. Goldschmied reported having no financial relationships.

SOURCE: Goldschmied J et al. Sleep 2018, Abstract 0245.

BALTIMORE – Disruption of slow-wave activity may potentially explain the positive influence that sleep deprivation may have on major depressive disorder, according to results of a study presented at the annual meeting of the Associated Professional Sleep Societies.

Jennifer Goldschmied, PhD, of the University of Pennsylvania, Philadelphia, reported preliminary results of a study of slow-wave activity (SWA) disruption in 26 subjects – 12 healthy controls and 14 people diagnosed with major depressive disorder – that found a significant decrease of about 20% in waking theta activity, as measured with EEG, in the MDD group. In the 3-night sleep study, conducted at the University of Michigan, Ann Arbor, an adaptation night was followed by baseline and SWA disruption nights with EEGs performed each night. After the baseline night, patients also had a morning and afternoon EEG.

Across the baseline day, patients with depression showed “no modulation of theta activity whatsoever,” Dr. Goldschmied said. “And then we see, following slow-wave disruption, a significant decrease in theta activity,” whereas, healthy controls showed no change in waking theta following slow-wave disruption. “So what this means is that the presence of SWA may actually be facilitating the reduction of theta or sleep propensity during typical sleep in healthy individuals,” she added. In MDD patients, the decline in theta power following slow-wave disruption was from around 5.4 to 4.3.

Dr. Goldschmied noted that this finding somewhat supports what is known as the synaptic homeostasis hypothesis that University of Wisconsin researchers Giulio Tononi, MD, PhD, and Chiara Cirelli, MD, PhD, reported (Brain Res Bull. 2003;62:143-50). This hypothesis holds that SWA is a marker of synaptic strength and promotes the downscaling of synaptic strength during sleep. No method for measuring synaptic strength in humans exists, Dr. Goldschmied added, but waking theta can be considered a proxy for net synaptic strength across the cortex.

Dr. Goldschmied noted other research that has found SWA disruption improves mood (Psychiatry Res. 2015;228:715-8; J Psychiatr Res. 2011;45:1019-26), but the study she reported on found no role of decreased theta activity in that change. “To go even further,” she said, “we looked at the entire data set and found no relationship between the decrease in theta and any of the measures of sleep architecture – so there’s really no way to predict this decrease in our sample of people with depression.”

SWA plays a significant role in depression and merits more study, Dr. Goldschmied said. She noted that future research should examine the effects of SWA disruption in a larger sample, investigate theta findings with other proxy measures of synaptic strength such as brain-derived neurotrophic factor and transcranial magnetic stimulation, explore differences in SWA between sexes, and explore how SWA enhancement influences mood and theta activity.

Dr. Goldschmied reported having no financial relationships.

SOURCE: Goldschmied J et al. Sleep 2018, Abstract 0245.

BALTIMORE – Disruption of slow-wave activity may potentially explain the positive influence that sleep deprivation may have on major depressive disorder, according to results of a study presented at the annual meeting of the Associated Professional Sleep Societies.

Jennifer Goldschmied, PhD, of the University of Pennsylvania, Philadelphia, reported preliminary results of a study of slow-wave activity (SWA) disruption in 26 subjects – 12 healthy controls and 14 people diagnosed with major depressive disorder – that found a significant decrease of about 20% in waking theta activity, as measured with EEG, in the MDD group. In the 3-night sleep study, conducted at the University of Michigan, Ann Arbor, an adaptation night was followed by baseline and SWA disruption nights with EEGs performed each night. After the baseline night, patients also had a morning and afternoon EEG.

Across the baseline day, patients with depression showed “no modulation of theta activity whatsoever,” Dr. Goldschmied said. “And then we see, following slow-wave disruption, a significant decrease in theta activity,” whereas, healthy controls showed no change in waking theta following slow-wave disruption. “So what this means is that the presence of SWA may actually be facilitating the reduction of theta or sleep propensity during typical sleep in healthy individuals,” she added. In MDD patients, the decline in theta power following slow-wave disruption was from around 5.4 to 4.3.

Dr. Goldschmied noted that this finding somewhat supports what is known as the synaptic homeostasis hypothesis that University of Wisconsin researchers Giulio Tononi, MD, PhD, and Chiara Cirelli, MD, PhD, reported (Brain Res Bull. 2003;62:143-50). This hypothesis holds that SWA is a marker of synaptic strength and promotes the downscaling of synaptic strength during sleep. No method for measuring synaptic strength in humans exists, Dr. Goldschmied added, but waking theta can be considered a proxy for net synaptic strength across the cortex.

Dr. Goldschmied noted other research that has found SWA disruption improves mood (Psychiatry Res. 2015;228:715-8; J Psychiatr Res. 2011;45:1019-26), but the study she reported on found no role of decreased theta activity in that change. “To go even further,” she said, “we looked at the entire data set and found no relationship between the decrease in theta and any of the measures of sleep architecture – so there’s really no way to predict this decrease in our sample of people with depression.”

SWA plays a significant role in depression and merits more study, Dr. Goldschmied said. She noted that future research should examine the effects of SWA disruption in a larger sample, investigate theta findings with other proxy measures of synaptic strength such as brain-derived neurotrophic factor and transcranial magnetic stimulation, explore differences in SWA between sexes, and explore how SWA enhancement influences mood and theta activity.

Dr. Goldschmied reported having no financial relationships.

SOURCE: Goldschmied J et al. Sleep 2018, Abstract 0245.

The Patient Protection and Affordable Care Act has increased the number of insured Americans by more than 20 million individuals.¹ Approximately half of the newly insured have an income at or below 138% of the poverty level and are on average younger, sicker, and more likely to report poor to fair health compared to those individuals who already had health care coverage.² Specialties such as dermatology are faced with the challenge of expanding access to these newly insured individuals while also improving quality of care.

Because of the complexity of defining quality in medicine, patient satisfaction is being used as a proxy for quality, with physicians evaluated and reimbursed based on patient satisfaction scores. Little research has been conducted to validate the relationship between patient satisfaction and quality; however, one study showed online reviews from patients on Yelp correlated with traditional markers of quality, such as mortality and readmission rates, lending credibility to the notion that patient satisfaction equates quality of care.³ Moreover, prospective studies have found positive correlations between patient satisfaction and compliance to therapy^4,5; however, these studies may not give a complete picture of the relationship between patient satisfaction and quality of care, as other studies also have illustrated that, more often than not, factors extrinsic to actual medical care (eg, time spent in the waiting room) play a considerable role in patient satisfaction scores.^6-9

When judging the quality of care that is provided, one study found that patients rate physicians based on interpersonal skills and not care delivered.⁸ Another important factor related to patient satisfaction is the anonymity of the surveys. Patients who have negative experiences are more likely to respond to online surveys than those who have positive experiences, skewing overall ratings.⁶ Additionally, because of Health Insurance Portability and Accountability Act regulations, physicians often are unable to respond directly to public patient reviews, resulting in an incomplete picture of the quality of care provided.

Ultimately, even if physicians do not agree that patient satisfaction correlates with quality of care, it is increasingly being used as a marker of such. Leading health care systems are embracing this new weight on patient satisfaction by increasing transparency and publishing patient satisfaction results online, allowing patients more access to physician reviews.

In dermatology, patient satisfaction serves an even more important role, as traditional markers of quality such as mortality and hospital readmission rates are not reasonable measures of patient care in this specialty, leaving patient satisfaction as one of the most accessible markers insurance companies and prospective patients can use to evaluate dermatologists. Furthermore, treatment modalities in dermatology often aim to improve quality of life, of which patient satisfaction arguably serves as an indicator. Ideally, patient satisfaction would allow physicians to identify areas where they may be better able to meet patients’ needs. However, patient satisfaction scores rarely are used as outcome measures in studies and are notoriously difficult to ascertain, as they tend to be inaccurate and may be unreliable in correlation with physician skill and training or may be skewed by patients’ desires to please their physicians.¹⁰ There also is a lack of standardized tools and scales to quantitatively judge outcomes in procedural surgeries.

Although patient satisfaction is being used as a measure of quality of care and is particularly necessary in a field such as dermatology that has outcome measures that are subjective in nature, there is a gap in the current literature regarding patient satisfaction and dermatology. To fill this gap, we conducted a prospective study of targeted interventions administered at outpatient dermatology clinics to determine if they resulted in statistically significant increases in patient satisfaction measures, particularly among Spanish-speaking patients.

Methods

We conducted a prospective study evaluating patient satisfaction in the outpatient dermatology clinics of LAC+USC Medical Center in Los Angeles, California, spanning over 1 year. During this time period, patients were randomly selected to participate and were asked to complete the Short-Form Patient Satisfaction Questionnaire (PSQ-18), which asked patients to rate their care experience on a 5-point Likert scale (1=strongly agree; 5=strongly disagree). The survey was separated into the following 7 subscales or categories looking at different aspects of care: general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with physician, and accessibility and convenience. Patients were given this survey both before and after targeted interventions to improve patient satisfaction were implemented. The targeted interventions were created based on literature review in the factors affecting patient satisfaction. The change in relative satisfaction was then determined using statistical analysis. The study was approved by the University of Southern California Health Science institutional review board.

Results

Of 470 patients surveyed, the average age was 49 years. Fifty percent of respondents were male, 70% self-identified as Hispanic, 45% spoke Spanish as their native language, and 69% reported a mean annual household income of less than $15,000. When scores were stratified, English-speaking patients were significantly more satisfied than Spanish-speaking patients in the categories of technical quality (P.0340), financial aspects (P.0301), interpersonal manner (P.0037), and time spent with physician (P.0059). Specifically, in the time spent with physician category, the lowest scores were found in females, patients aged 18 to 29 years, and patients with a mean annual household income less than $15,000. These demographics correlate well with many of the newly insured and intimate the need for improved patient satisfaction, particularly in this subset of patients.

After analyzing baseline patient satisfaction scores, we implemented targeted interventions such as creating a call tree, developing multilingual disease-specific patient handouts, instituting quarterly nursing in-services, which judged interpersonal and occupational nursing skills, and recruiting bilingual staff. These interventions were implemented simultaneously and were selected with the goal of reducing the impact of the language barrier between physicians and patients and increasing accessibility to clinics. Following approximately 3 months of these interventions, performance on many categories increased in our demographics that were lowest performing when we collected baseline data. In Spanish-speaking respondents, improvement in several categories approached statistical significance, including general satisfaction (P.110), interpersonal skills (P.080), and time spent with physician (P.096). When stratifying by income and age, patients with a mean annual household income less than $15,000 demonstrated an improved technical quality (P.066) subscale score, and participants aged 18 to 29 years showed improvement in both accessibility and convenience (P.053) and financial aspects (P.056) subscales.

Comment

The categories where improvements were found are noteworthy and suggest that certain aspects of care are more important than others. Although it seems intuitive that clinical acumen and training should be important contributors to patient satisfaction, one study that analyzed 1000 online comments regarding patient satisfaction with dermatologists on the website DrScore.com found that most comments concerned physician personality and interpersonal skills rather than medical judgment and acumen,⁴ suggesting that a patient’s perception of the character of the physician directly affects patient satisfaction scores. This notion was reiterated by other studies, including one that found that a patient’s perception of the physician’s kindness and empathy skills, is the most important measure of quality of care scores.⁸ Although this perception can be intimidating to some physicians, as certain interpersonal skills are difficult to change, it is reassuring to note that external environment and cues, such as the clinic building and staff, also seem to affect interpersonal ratings. As seen in our study, patient ratings of a physician’s interpersonal skills increased after educational materials for staff and patients were created and more bilingual staff was recruited. Other environmental changes, such as spending a few more minutes with patients and sitting down when talking to patients, are relatively easy to administer and can improve patient satisfaction scores.⁸

Although some of the scores in our study approached but did not reach statistical significance, likely because of a small sample size, they suggest that targeted interventions can improve patient satisfaction. They also suggested that targeted interventions are particularly useful in Spanish-speaking patients, younger patients, and patients from lower socioeconomic backgrounds, which are all characteristics of the newly insured under the Patient Protection and Affordable Health Care Act.

Our study also is unique in that dermatology as a specialty is lagging in quality improvement studies. In the few studies evaluating patient satisfaction in the literature, the care provided by dermatologists was painted in a positive light.^6,11 One study evaluated 45 dermatology practices and reported average patient satisfaction scores of 3.46 and 4.72 of 5 on Yelp and ZocDoc, respectively.¹¹ Another study looking at dermatologist ratings on DrScore.com found that the majority of patients were satisfied with the care they received.⁶

Although these studies seem encouraging, they have several limitations. First, their results were not stratified by patient demographics and therefore may not be generalizable to low-income populations that constitute much of the newly insured. Secondly, the observational nature and limited number of studies prohibit meaningful conclusions from being drawn and leave many questions unanswered. Additionally, although the raw patient satisfaction scores seem good, dermatology is lacking compared to the patient satisfaction scores within other specialties. A study of more than 28,000 Yelp reviews of 23 specialties found that dermatology ranked second to last, ahead of only psychiatry.⁷ Of course, given the observational nature of this study, it is impossible to generalize, as many confounders (eg, medical comorbidities, patient age) may have skewed the dermatology ranking. Regardless, there is always room for improvement, and luckily improving patient satisfaction is not an elusive goal.

Conclusion

As dermatologists, our interventions often improve quality of life; therefore, we are positioned to be leaders in the quality improvement field. Despite the numerous limitations of using patient satisfaction as a measure for quality of care, it is used by payers to determine reimbursement and patients to select providers. Encouraging initial data from our prospective study demonstrate that small interventions can increase patient satisfaction. Continued work to maximize patient satisfaction is needed to improve outcomes for our patients, help validate the quality of care being provided, and further solidify the importance of having insurers maintain sufficient dermatologists in their networks.

The Patient Protection and Affordable Care Act has increased the number of insured Americans by more than 20 million individuals.¹ Approximately half of the newly insured have an income at or below 138% of the poverty level and are on average younger, sicker, and more likely to report poor to fair health compared to those individuals who already had health care coverage.² Specialties such as dermatology are faced with the challenge of expanding access to these newly insured individuals while also improving quality of care.

Because of the complexity of defining quality in medicine, patient satisfaction is being used as a proxy for quality, with physicians evaluated and reimbursed based on patient satisfaction scores. Little research has been conducted to validate the relationship between patient satisfaction and quality; however, one study showed online reviews from patients on Yelp correlated with traditional markers of quality, such as mortality and readmission rates, lending credibility to the notion that patient satisfaction equates quality of care.³ Moreover, prospective studies have found positive correlations between patient satisfaction and compliance to therapy^4,5; however, these studies may not give a complete picture of the relationship between patient satisfaction and quality of care, as other studies also have illustrated that, more often than not, factors extrinsic to actual medical care (eg, time spent in the waiting room) play a considerable role in patient satisfaction scores.^6-9

When judging the quality of care that is provided, one study found that patients rate physicians based on interpersonal skills and not care delivered.⁸ Another important factor related to patient satisfaction is the anonymity of the surveys. Patients who have negative experiences are more likely to respond to online surveys than those who have positive experiences, skewing overall ratings.⁶ Additionally, because of Health Insurance Portability and Accountability Act regulations, physicians often are unable to respond directly to public patient reviews, resulting in an incomplete picture of the quality of care provided.

Ultimately, even if physicians do not agree that patient satisfaction correlates with quality of care, it is increasingly being used as a marker of such. Leading health care systems are embracing this new weight on patient satisfaction by increasing transparency and publishing patient satisfaction results online, allowing patients more access to physician reviews.

In dermatology, patient satisfaction serves an even more important role, as traditional markers of quality such as mortality and hospital readmission rates are not reasonable measures of patient care in this specialty, leaving patient satisfaction as one of the most accessible markers insurance companies and prospective patients can use to evaluate dermatologists. Furthermore, treatment modalities in dermatology often aim to improve quality of life, of which patient satisfaction arguably serves as an indicator. Ideally, patient satisfaction would allow physicians to identify areas where they may be better able to meet patients’ needs. However, patient satisfaction scores rarely are used as outcome measures in studies and are notoriously difficult to ascertain, as they tend to be inaccurate and may be unreliable in correlation with physician skill and training or may be skewed by patients’ desires to please their physicians.¹⁰ There also is a lack of standardized tools and scales to quantitatively judge outcomes in procedural surgeries.

Although patient satisfaction is being used as a measure of quality of care and is particularly necessary in a field such as dermatology that has outcome measures that are subjective in nature, there is a gap in the current literature regarding patient satisfaction and dermatology. To fill this gap, we conducted a prospective study of targeted interventions administered at outpatient dermatology clinics to determine if they resulted in statistically significant increases in patient satisfaction measures, particularly among Spanish-speaking patients.

Methods

We conducted a prospective study evaluating patient satisfaction in the outpatient dermatology clinics of LAC+USC Medical Center in Los Angeles, California, spanning over 1 year. During this time period, patients were randomly selected to participate and were asked to complete the Short-Form Patient Satisfaction Questionnaire (PSQ-18), which asked patients to rate their care experience on a 5-point Likert scale (1=strongly agree; 5=strongly disagree). The survey was separated into the following 7 subscales or categories looking at different aspects of care: general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with physician, and accessibility and convenience. Patients were given this survey both before and after targeted interventions to improve patient satisfaction were implemented. The targeted interventions were created based on literature review in the factors affecting patient satisfaction. The change in relative satisfaction was then determined using statistical analysis. The study was approved by the University of Southern California Health Science institutional review board.

Results

Of 470 patients surveyed, the average age was 49 years. Fifty percent of respondents were male, 70% self-identified as Hispanic, 45% spoke Spanish as their native language, and 69% reported a mean annual household income of less than $15,000. When scores were stratified, English-speaking patients were significantly more satisfied than Spanish-speaking patients in the categories of technical quality (P.0340), financial aspects (P.0301), interpersonal manner (P.0037), and time spent with physician (P.0059). Specifically, in the time spent with physician category, the lowest scores were found in females, patients aged 18 to 29 years, and patients with a mean annual household income less than $15,000. These demographics correlate well with many of the newly insured and intimate the need for improved patient satisfaction, particularly in this subset of patients.

After analyzing baseline patient satisfaction scores, we implemented targeted interventions such as creating a call tree, developing multilingual disease-specific patient handouts, instituting quarterly nursing in-services, which judged interpersonal and occupational nursing skills, and recruiting bilingual staff. These interventions were implemented simultaneously and were selected with the goal of reducing the impact of the language barrier between physicians and patients and increasing accessibility to clinics. Following approximately 3 months of these interventions, performance on many categories increased in our demographics that were lowest performing when we collected baseline data. In Spanish-speaking respondents, improvement in several categories approached statistical significance, including general satisfaction (P.110), interpersonal skills (P.080), and time spent with physician (P.096). When stratifying by income and age, patients with a mean annual household income less than $15,000 demonstrated an improved technical quality (P.066) subscale score, and participants aged 18 to 29 years showed improvement in both accessibility and convenience (P.053) and financial aspects (P.056) subscales.

Comment

The categories where improvements were found are noteworthy and suggest that certain aspects of care are more important than others. Although it seems intuitive that clinical acumen and training should be important contributors to patient satisfaction, one study that analyzed 1000 online comments regarding patient satisfaction with dermatologists on the website DrScore.com found that most comments concerned physician personality and interpersonal skills rather than medical judgment and acumen,⁴ suggesting that a patient’s perception of the character of the physician directly affects patient satisfaction scores. This notion was reiterated by other studies, including one that found that a patient’s perception of the physician’s kindness and empathy skills, is the most important measure of quality of care scores.⁸ Although this perception can be intimidating to some physicians, as certain interpersonal skills are difficult to change, it is reassuring to note that external environment and cues, such as the clinic building and staff, also seem to affect interpersonal ratings. As seen in our study, patient ratings of a physician’s interpersonal skills increased after educational materials for staff and patients were created and more bilingual staff was recruited. Other environmental changes, such as spending a few more minutes with patients and sitting down when talking to patients, are relatively easy to administer and can improve patient satisfaction scores.⁸

Although some of the scores in our study approached but did not reach statistical significance, likely because of a small sample size, they suggest that targeted interventions can improve patient satisfaction. They also suggested that targeted interventions are particularly useful in Spanish-speaking patients, younger patients, and patients from lower socioeconomic backgrounds, which are all characteristics of the newly insured under the Patient Protection and Affordable Health Care Act.

Our study also is unique in that dermatology as a specialty is lagging in quality improvement studies. In the few studies evaluating patient satisfaction in the literature, the care provided by dermatologists was painted in a positive light.^6,11 One study evaluated 45 dermatology practices and reported average patient satisfaction scores of 3.46 and 4.72 of 5 on Yelp and ZocDoc, respectively.¹¹ Another study looking at dermatologist ratings on DrScore.com found that the majority of patients were satisfied with the care they received.⁶

Although these studies seem encouraging, they have several limitations. First, their results were not stratified by patient demographics and therefore may not be generalizable to low-income populations that constitute much of the newly insured. Secondly, the observational nature and limited number of studies prohibit meaningful conclusions from being drawn and leave many questions unanswered. Additionally, although the raw patient satisfaction scores seem good, dermatology is lacking compared to the patient satisfaction scores within other specialties. A study of more than 28,000 Yelp reviews of 23 specialties found that dermatology ranked second to last, ahead of only psychiatry.⁷ Of course, given the observational nature of this study, it is impossible to generalize, as many confounders (eg, medical comorbidities, patient age) may have skewed the dermatology ranking. Regardless, there is always room for improvement, and luckily improving patient satisfaction is not an elusive goal.

Conclusion

As dermatologists, our interventions often improve quality of life; therefore, we are positioned to be leaders in the quality improvement field. Despite the numerous limitations of using patient satisfaction as a measure for quality of care, it is used by payers to determine reimbursement and patients to select providers. Encouraging initial data from our prospective study demonstrate that small interventions can increase patient satisfaction. Continued work to maximize patient satisfaction is needed to improve outcomes for our patients, help validate the quality of care being provided, and further solidify the importance of having insurers maintain sufficient dermatologists in their networks.

The Patient Protection and Affordable Care Act has increased the number of insured Americans by more than 20 million individuals.¹ Approximately half of the newly insured have an income at or below 138% of the poverty level and are on average younger, sicker, and more likely to report poor to fair health compared to those individuals who already had health care coverage.² Specialties such as dermatology are faced with the challenge of expanding access to these newly insured individuals while also improving quality of care.

Because of the complexity of defining quality in medicine, patient satisfaction is being used as a proxy for quality, with physicians evaluated and reimbursed based on patient satisfaction scores. Little research has been conducted to validate the relationship between patient satisfaction and quality; however, one study showed online reviews from patients on Yelp correlated with traditional markers of quality, such as mortality and readmission rates, lending credibility to the notion that patient satisfaction equates quality of care.³ Moreover, prospective studies have found positive correlations between patient satisfaction and compliance to therapy^4,5; however, these studies may not give a complete picture of the relationship between patient satisfaction and quality of care, as other studies also have illustrated that, more often than not, factors extrinsic to actual medical care (eg, time spent in the waiting room) play a considerable role in patient satisfaction scores.^6-9

When judging the quality of care that is provided, one study found that patients rate physicians based on interpersonal skills and not care delivered.⁸ Another important factor related to patient satisfaction is the anonymity of the surveys. Patients who have negative experiences are more likely to respond to online surveys than those who have positive experiences, skewing overall ratings.⁶ Additionally, because of Health Insurance Portability and Accountability Act regulations, physicians often are unable to respond directly to public patient reviews, resulting in an incomplete picture of the quality of care provided.

Ultimately, even if physicians do not agree that patient satisfaction correlates with quality of care, it is increasingly being used as a marker of such. Leading health care systems are embracing this new weight on patient satisfaction by increasing transparency and publishing patient satisfaction results online, allowing patients more access to physician reviews.

In dermatology, patient satisfaction serves an even more important role, as traditional markers of quality such as mortality and hospital readmission rates are not reasonable measures of patient care in this specialty, leaving patient satisfaction as one of the most accessible markers insurance companies and prospective patients can use to evaluate dermatologists. Furthermore, treatment modalities in dermatology often aim to improve quality of life, of which patient satisfaction arguably serves as an indicator. Ideally, patient satisfaction would allow physicians to identify areas where they may be better able to meet patients’ needs. However, patient satisfaction scores rarely are used as outcome measures in studies and are notoriously difficult to ascertain, as they tend to be inaccurate and may be unreliable in correlation with physician skill and training or may be skewed by patients’ desires to please their physicians.¹⁰ There also is a lack of standardized tools and scales to quantitatively judge outcomes in procedural surgeries.

Although patient satisfaction is being used as a measure of quality of care and is particularly necessary in a field such as dermatology that has outcome measures that are subjective in nature, there is a gap in the current literature regarding patient satisfaction and dermatology. To fill this gap, we conducted a prospective study of targeted interventions administered at outpatient dermatology clinics to determine if they resulted in statistically significant increases in patient satisfaction measures, particularly among Spanish-speaking patients.

Methods

We conducted a prospective study evaluating patient satisfaction in the outpatient dermatology clinics of LAC+USC Medical Center in Los Angeles, California, spanning over 1 year. During this time period, patients were randomly selected to participate and were asked to complete the Short-Form Patient Satisfaction Questionnaire (PSQ-18), which asked patients to rate their care experience on a 5-point Likert scale (1=strongly agree; 5=strongly disagree). The survey was separated into the following 7 subscales or categories looking at different aspects of care: general satisfaction, technical quality, interpersonal manner, communication, financial aspects, time spent with physician, and accessibility and convenience. Patients were given this survey both before and after targeted interventions to improve patient satisfaction were implemented. The targeted interventions were created based on literature review in the factors affecting patient satisfaction. The change in relative satisfaction was then determined using statistical analysis. The study was approved by the University of Southern California Health Science institutional review board.

Results

Of 470 patients surveyed, the average age was 49 years. Fifty percent of respondents were male, 70% self-identified as Hispanic, 45% spoke Spanish as their native language, and 69% reported a mean annual household income of less than $15,000. When scores were stratified, English-speaking patients were significantly more satisfied than Spanish-speaking patients in the categories of technical quality (P.0340), financial aspects (P.0301), interpersonal manner (P.0037), and time spent with physician (P.0059). Specifically, in the time spent with physician category, the lowest scores were found in females, patients aged 18 to 29 years, and patients with a mean annual household income less than $15,000. These demographics correlate well with many of the newly insured and intimate the need for improved patient satisfaction, particularly in this subset of patients.

After analyzing baseline patient satisfaction scores, we implemented targeted interventions such as creating a call tree, developing multilingual disease-specific patient handouts, instituting quarterly nursing in-services, which judged interpersonal and occupational nursing skills, and recruiting bilingual staff. These interventions were implemented simultaneously and were selected with the goal of reducing the impact of the language barrier between physicians and patients and increasing accessibility to clinics. Following approximately 3 months of these interventions, performance on many categories increased in our demographics that were lowest performing when we collected baseline data. In Spanish-speaking respondents, improvement in several categories approached statistical significance, including general satisfaction (P.110), interpersonal skills (P.080), and time spent with physician (P.096). When stratifying by income and age, patients with a mean annual household income less than $15,000 demonstrated an improved technical quality (P.066) subscale score, and participants aged 18 to 29 years showed improvement in both accessibility and convenience (P.053) and financial aspects (P.056) subscales.

Comment

The categories where improvements were found are noteworthy and suggest that certain aspects of care are more important than others. Although it seems intuitive that clinical acumen and training should be important contributors to patient satisfaction, one study that analyzed 1000 online comments regarding patient satisfaction with dermatologists on the website DrScore.com found that most comments concerned physician personality and interpersonal skills rather than medical judgment and acumen,⁴ suggesting that a patient’s perception of the character of the physician directly affects patient satisfaction scores. This notion was reiterated by other studies, including one that found that a patient’s perception of the physician’s kindness and empathy skills, is the most important measure of quality of care scores.⁸ Although this perception can be intimidating to some physicians, as certain interpersonal skills are difficult to change, it is reassuring to note that external environment and cues, such as the clinic building and staff, also seem to affect interpersonal ratings. As seen in our study, patient ratings of a physician’s interpersonal skills increased after educational materials for staff and patients were created and more bilingual staff was recruited. Other environmental changes, such as spending a few more minutes with patients and sitting down when talking to patients, are relatively easy to administer and can improve patient satisfaction scores.⁸

Although some of the scores in our study approached but did not reach statistical significance, likely because of a small sample size, they suggest that targeted interventions can improve patient satisfaction. They also suggested that targeted interventions are particularly useful in Spanish-speaking patients, younger patients, and patients from lower socioeconomic backgrounds, which are all characteristics of the newly insured under the Patient Protection and Affordable Health Care Act.

Our study also is unique in that dermatology as a specialty is lagging in quality improvement studies. In the few studies evaluating patient satisfaction in the literature, the care provided by dermatologists was painted in a positive light.^6,11 One study evaluated 45 dermatology practices and reported average patient satisfaction scores of 3.46 and 4.72 of 5 on Yelp and ZocDoc, respectively.¹¹ Another study looking at dermatologist ratings on DrScore.com found that the majority of patients were satisfied with the care they received.⁶

Although these studies seem encouraging, they have several limitations. First, their results were not stratified by patient demographics and therefore may not be generalizable to low-income populations that constitute much of the newly insured. Secondly, the observational nature and limited number of studies prohibit meaningful conclusions from being drawn and leave many questions unanswered. Additionally, although the raw patient satisfaction scores seem good, dermatology is lacking compared to the patient satisfaction scores within other specialties. A study of more than 28,000 Yelp reviews of 23 specialties found that dermatology ranked second to last, ahead of only psychiatry.⁷ Of course, given the observational nature of this study, it is impossible to generalize, as many confounders (eg, medical comorbidities, patient age) may have skewed the dermatology ranking. Regardless, there is always room for improvement, and luckily improving patient satisfaction is not an elusive goal.

Conclusion

As dermatologists, our interventions often improve quality of life; therefore, we are positioned to be leaders in the quality improvement field. Despite the numerous limitations of using patient satisfaction as a measure for quality of care, it is used by payers to determine reimbursement and patients to select providers. Encouraging initial data from our prospective study demonstrate that small interventions can increase patient satisfaction. Continued work to maximize patient satisfaction is needed to improve outcomes for our patients, help validate the quality of care being provided, and further solidify the importance of having insurers maintain sufficient dermatologists in their networks.

LOS ANGELES—Adjunctive treatment with an investigational antiepileptic drug (AED) reduces the median frequency of partial-onset seizures, according to trial results presented at the 70th Annual Meeting of the American Academy of Neurology.

“The results with cenobamate demonstrated a decrease in overall median seizure frequencies compared to placebo at all doses studied,” said study principal investigator Gregory Krauss, MD, Professor of Neurology at Johns Hopkins University in Baltimore.

Seizure Types

In all, 437 patients received 100 mg per day of cenobamate (n = 108), 200 mg per day of cenobamate (n = 110), 400 mg per day of cenobamate (n = 111), or placebo (n = 108). Patients’ average age was about 40, and patients had a median seizure frequency of between 8.4 and 11 seizures per month. Most patients had a history of complex partial seizures (78.9%) or secondary generalized tonic-clonic seizures (60.0%) and were receiving two or three concomitant AEDs.

Median seizure frequencies decreased for all doses of cenobamate (100 mg/day: 35.5%, 200 mg/day: 55.0%, and 400 mg/day: 55.0%), compared with placebo (24.0%). Median frequencies for simple partial seizures decreased with all doses of cenobamate (100 mg/day: 48.0%; 200 mg/day: 63.0%; and 400 mg/day: 58.5%), compared with placebo (7.0%). Median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with 200 mg per day of cenobamate (55.0% and 91.0%, respectively) and 400 mg per day of cenobamate (60.0% and 78.0%, respectively), compared with placebo (28.5% and 33.0%, respectively).

Compared with patients who received placebo, patients who received cenobamate were more likely to have greater than 50% reductions and 100% reductions in seizure frequency, Dr. Krauss said.

Investigators Adjusted Titration

The most common adverse events were somnolence, dizziness, headache, and balance disorder. The percentage of patients with common adverse events increased with dose, and slightly more patients who received 400 mg per day of cenobamate dropped out of the trial, compared with patients who received lower doses, Dr. Krauss said. Some patients with adverse events in the 400 mg group required modest dose reductions, and some adverse events were related to titration, he said.

Two allergic reactions occurred during initial rapid titration of the drug. After rapid dose titration for the first 10% of patients in the trial, doses for the remaining patients were titrated more slowly. One patient in the fast titration group developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Two patients in the trial had the common morbilliform rash without systemic signs—one during fast titration and one during slower titration.

Most adverse events were mild to moderate, and there were no deaths. In all, 37 adverse events occurred in 28 patients, and the number of adverse events was comparable between placebo and cenobamate, Dr. Krauss said. The most common serious adverse events were seizures in four patients, ataxias in two patients, dizziness in two patients, nystagmus in two patients, and suicidal ideation in two patients.

SK Life Science, based in Fair Lawn, New Jersey, is developing cenobamate.

—Jake Remaly

LOS ANGELES—Adjunctive treatment with an investigational antiepileptic drug (AED) reduces the median frequency of partial-onset seizures, according to trial results presented at the 70th Annual Meeting of the American Academy of Neurology.

“The results with cenobamate demonstrated a decrease in overall median seizure frequencies compared to placebo at all doses studied,” said study principal investigator Gregory Krauss, MD, Professor of Neurology at Johns Hopkins University in Baltimore.

Seizure Types

In all, 437 patients received 100 mg per day of cenobamate (n = 108), 200 mg per day of cenobamate (n = 110), 400 mg per day of cenobamate (n = 111), or placebo (n = 108). Patients’ average age was about 40, and patients had a median seizure frequency of between 8.4 and 11 seizures per month. Most patients had a history of complex partial seizures (78.9%) or secondary generalized tonic-clonic seizures (60.0%) and were receiving two or three concomitant AEDs.

Median seizure frequencies decreased for all doses of cenobamate (100 mg/day: 35.5%, 200 mg/day: 55.0%, and 400 mg/day: 55.0%), compared with placebo (24.0%). Median frequencies for simple partial seizures decreased with all doses of cenobamate (100 mg/day: 48.0%; 200 mg/day: 63.0%; and 400 mg/day: 58.5%), compared with placebo (7.0%). Median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with 200 mg per day of cenobamate (55.0% and 91.0%, respectively) and 400 mg per day of cenobamate (60.0% and 78.0%, respectively), compared with placebo (28.5% and 33.0%, respectively).

Compared with patients who received placebo, patients who received cenobamate were more likely to have greater than 50% reductions and 100% reductions in seizure frequency, Dr. Krauss said.

Investigators Adjusted Titration

The most common adverse events were somnolence, dizziness, headache, and balance disorder. The percentage of patients with common adverse events increased with dose, and slightly more patients who received 400 mg per day of cenobamate dropped out of the trial, compared with patients who received lower doses, Dr. Krauss said. Some patients with adverse events in the 400 mg group required modest dose reductions, and some adverse events were related to titration, he said.

Two allergic reactions occurred during initial rapid titration of the drug. After rapid dose titration for the first 10% of patients in the trial, doses for the remaining patients were titrated more slowly. One patient in the fast titration group developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Two patients in the trial had the common morbilliform rash without systemic signs—one during fast titration and one during slower titration.

Most adverse events were mild to moderate, and there were no deaths. In all, 37 adverse events occurred in 28 patients, and the number of adverse events was comparable between placebo and cenobamate, Dr. Krauss said. The most common serious adverse events were seizures in four patients, ataxias in two patients, dizziness in two patients, nystagmus in two patients, and suicidal ideation in two patients.

SK Life Science, based in Fair Lawn, New Jersey, is developing cenobamate.

—Jake Remaly

LOS ANGELES—Adjunctive treatment with an investigational antiepileptic drug (AED) reduces the median frequency of partial-onset seizures, according to trial results presented at the 70th Annual Meeting of the American Academy of Neurology.

“The results with cenobamate demonstrated a decrease in overall median seizure frequencies compared to placebo at all doses studied,” said study principal investigator Gregory Krauss, MD, Professor of Neurology at Johns Hopkins University in Baltimore.

Seizure Types

In all, 437 patients received 100 mg per day of cenobamate (n = 108), 200 mg per day of cenobamate (n = 110), 400 mg per day of cenobamate (n = 111), or placebo (n = 108). Patients’ average age was about 40, and patients had a median seizure frequency of between 8.4 and 11 seizures per month. Most patients had a history of complex partial seizures (78.9%) or secondary generalized tonic-clonic seizures (60.0%) and were receiving two or three concomitant AEDs.

Median seizure frequencies decreased for all doses of cenobamate (100 mg/day: 35.5%, 200 mg/day: 55.0%, and 400 mg/day: 55.0%), compared with placebo (24.0%). Median frequencies for simple partial seizures decreased with all doses of cenobamate (100 mg/day: 48.0%; 200 mg/day: 63.0%; and 400 mg/day: 58.5%), compared with placebo (7.0%). Median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with 200 mg per day of cenobamate (55.0% and 91.0%, respectively) and 400 mg per day of cenobamate (60.0% and 78.0%, respectively), compared with placebo (28.5% and 33.0%, respectively).

Compared with patients who received placebo, patients who received cenobamate were more likely to have greater than 50% reductions and 100% reductions in seizure frequency, Dr. Krauss said.

Investigators Adjusted Titration

The most common adverse events were somnolence, dizziness, headache, and balance disorder. The percentage of patients with common adverse events increased with dose, and slightly more patients who received 400 mg per day of cenobamate dropped out of the trial, compared with patients who received lower doses, Dr. Krauss said. Some patients with adverse events in the 400 mg group required modest dose reductions, and some adverse events were related to titration, he said.

Two allergic reactions occurred during initial rapid titration of the drug. After rapid dose titration for the first 10% of patients in the trial, doses for the remaining patients were titrated more slowly. One patient in the fast titration group developed drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Two patients in the trial had the common morbilliform rash without systemic signs—one during fast titration and one during slower titration.

Most adverse events were mild to moderate, and there were no deaths. In all, 37 adverse events occurred in 28 patients, and the number of adverse events was comparable between placebo and cenobamate, Dr. Krauss said. The most common serious adverse events were seizures in four patients, ataxias in two patients, dizziness in two patients, nystagmus in two patients, and suicidal ideation in two patients.

SK Life Science, based in Fair Lawn, New Jersey, is developing cenobamate.

—Jake Remaly

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

A transmembrane glycoprotein labeled neuropilin-1 may be a diagnostic biomarker for hepatocellular carcinoma.

In a series of experiments using HCC tissues and cell lines, as well as serum samples from patients with other malignancies or hepatitis, Jiafei Lin, MD, from Shanghai Jiaotong University, Shanghai, China, and colleagues found that neuropilin-1 (NRP1) was up-regulated in hepatocellular carcinoma (HCC) and promotes tumor growth.

“Notably, the concentrations of serum NRP1 in the HCC patients were much higher than those of hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, and lung cancer patients,” they wrote in the journal Clinica Chimica Acta.

They also found that NRP1 has a high degree of sensitivity and specificity for HCC, and suggested that NRP1 could replace alpha fetoprotein (AFP) for early clinical diagnosis of HCC.

They first showed that NRP1 was directly regulated by TEAD, a family of transcription factors essential for developmental processes. The experiments in HCC cell lines showed that messenger RNA levels of NRP1 were increased when TEAD was overexpressed, and decreased when TEAD was knocked down. The experiments also suggested that TEAD binds directly to the promoter of NRP1 to stimulate its transcription in HCC cells.

The investigators then sought to demonstrate that NRP1 promotes tumor development and growth in HCC by testing expression of the protein in both normal liver and HCC tissue samples.

“NRP1 was found highly up-regulated in HCC tissues compared to normal tissues. Moreover, NRP1 was recruited to the membrane in HCC tissues, whereas this protein was not detected in normal tissues,” they wrote.

Furthermore, when they zeroed in on NRP1 using two different short hairpin RNAs to silence its expression, they found that knocking down NRP1 suppressed the viability of tumor cells and inhibited colony formation while also ramping up programmed cell death. Taken together, the data indicate that NRP1 is highly expressed in HCC and promotes tumorigenesis.

They then showed that NRP1 serum concentrations were significantly higher in samples from patients with HCC than in those from healthy individuals or patients with hepatitis B, hepatitis C, cirrhosis, breast cancer, colon cancer, gastric cancer, or lung cancer. In addition, higher NRP1 concentrations were significantly associated with higher HCC tumor stages.

The investigators then looked at the relationship between serum NRP1 and standard liver function markers in HCC, and found that NRP1 serum levels significantly correlated with gamma-glutamyltransferase, albumin, bile acid, ALT, AST, AFP, and prealbumin levels, but not total bilirubin or total protein levels.

Finally, they demonstrated that serum NRP1 is a better diagnostic marker than AFP, with an area under the receiver operating characteristic curve of 0.971, compared with 0.862 for AFP. At an NRP1 cutoff of 68 pg/mL, NRP1 had a sensitivity of 93.7%, and a specificity of 98.7%. Combining NRP1 with AFP only slightly improved the diagnostic accuracy.

“These results indicate that the single use of NRP1 is a promising choice for the diagnosis of HCC,” the investigators wrote.

They noted that the most of the study subjects were of Han Chinese origin, and that the results need to be validated in people of other ethnicities.

The study was supported by the National Natural Science Foundation of China. Potential conflicts of interest were not reported.

SOURCE: Lin J et al. Clin Chim Acta. 2018;485:158-65.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has a social and psychosocial impact on patients with skin of color.¹ It is characterized by recurrent abscesses, draining sinus tracts, and scarring in the intertriginous skin folds. The lesions are difficult to treat and present with considerable frustration for both patients and physicians. Although current treatment ladders can delay procedures and surgical intervention,¹ some believe that surgery should be introduced earlier in HS management.² In this article, we review current procedures for the management of HS, including cryoinsufflation, incision and drainage, deroofing, skin tissue–saving excision with electrosurgical peeling, and wide surgical excision, along with various closure techniques.

Cryoinsufflation

First described in 2014, cryoinsufflation is a novel method for treating sinus tracts.³ Lesions initially are identified on physical examination. Prior to the procedure, local anesthesia is administered to the lesion.³ A 21-gauge needle is mounted onto a cryosurgical unit and inserted into the opening of the sinus tract. Liquid nitrogen is sprayed into the tract for 5 seconds, followed by a 3-second pause; the process is repeated 3 times. Patients return for treatment sessions monthly until the tract is obliterated. This procedure was first performed on 2 patients with satisfactory results.³

Since the initial report, the investigators made 2 changes to refine the procedure.⁴ First, systemic antibiotics should be prescribed 2 months prior to the procedure to clear the sinus tracts of infection. Furthermore, a 21-gauge, olive-tipped cannula is recommended in lieu of a 21-gauge needle to mitigate the risk of adverse events such as air embolism.⁴

Incision and Drainage

Incision and drainage provides rapid pain relief for tense fluctuant abscesses, but recurrence is common and the procedure costs are high.⁵ For drainage, wide circumferential local anesthesia is administered followed by incision.⁶ Pus is eliminated using digital pressure or saline rinses.² Following the elimination of pus, the wound may need gauze packing or placement of a wick for a few days.⁶ The general belief is that incision and drainage should be used, if necessary, to rapidly relieve the patient’s pain; however, other surgical options should be considered if the patient has had multiple incision and drainage procedures.⁷ Currently there are no randomized controlled trials (RCTs) on incision and drainage procedures in HS abscesses.

Deroofing

In 1959, Mullins et al⁸ first described the deroofing procedure, which was refined to preserve the floor of the sinus tract in the 1980s.^9,10 Culp¹⁰ and Brown et al⁹ theorized that preservation of the exposed floor of the sinus tract allowed for the epithelial cells from sweat glands and hair follicle remnants to rapidly reepithelialize the wound. In 2010, van der Zee et al¹¹ performed a prospective study of 88 deroofed lesions in which the investigators removed keratinous debris and epithelial remnants of the floor due to concern for recurrence in this area if the tissues remained. Only 17% (15/88) of the lesions recurred at a median follow-up of 34 months.¹¹

In Hurley stage I or II HS, deroofing remains the primary procedure for persistent nodules and sinus tracts.² The lesion is identified on physical examination and local anesthesia is administered, first to the area surrounding the lesion, then to the lesion itself.¹¹ A blunt probe is used to identify openings and search for connecting fistulas. After defining the sinus tract, the roof and wings created by the incision are removed.^11,12 The material on the floor of the tract is scraped away, and the wound is left to heal by secondary intention.¹¹ In general, deroofed lesions heal with cosmetically acceptable scars. We have used this procedure in skin of color patients with good results and no difficulties with healing. Controlled trials with long-term follow-up are lacking in this population.

Skin Tissue–Saving Excision With Electrosurgical Peeling

Skin tissue–saving excision with electrosurgical peeling was first introduced in 2015.¹³ Blok et al¹⁴ described the procedure as a promising alternative to wide surgical excision for Hurley stage II or III HS. The procedure saves healthy tissue while completely removing lesional tissue, leading to rapid wound healing, excellent cosmesis, and a low risk of contractures^2,14; however, recurrence rates are higher than those seen in wide surgical excision.¹⁵ There are no known RCTs with long-term follow-up for HS patients treated with skin tissue–saving excision with electrosurgical peeling.

The procedure typically is performed under general anesthesia.¹⁴ First, the sinus tract is palpated on physical examination and probed to delineate the extent of the tract. Next, the roof of the tract is incised electrosurgically with a wire loop tip coupled to an electrosurgical generator.¹⁴ Consecutive tangential excisions are made until the floor of the sinus tract is reached. The process of incising sinus tracts followed by tangential peeling off of tissue continues until the entire area is clear of lesional and fibrotic tissue. The wound margins are probed for the presence and subsequent removal of residual sinus tracts. Lastly, the electrosurgical generator is used to achieve hemostasis, steroids are injected to prevent the formation of hypergranulation tissue, and the wound is left to heal by secondary intention.¹⁴ Following intervention, recurrence rates appear to be similar to wide surgical excision.^13,14

Wide Surgical Excision

Wide excision is a widely established technique consisting of surgical excision of a lesion plus an area of surrounding disease-free tissue such as subcutaneous fat or a lateral margin of intertriginous skin.¹⁵ Similar to other surgical techniques, wide excision is considered in cases of severe disease when pharmacologic management cannot remedy extensive fibrosis or architectural loss. It typically is performed in Hurley stage II and III HS, with pathology extending to involve deeper structures inaccessible to more superficial surgical methods.² Prominent areas of use include gluteal, axillary, perineal, and perianal HS lesions on which conservative treatments have little effect and depend on wide excision to provide successful postoperative results.¹⁶ Although retrospective and prospective studies exist on wide excision in HS, there continues to be a dearth of RCTs. Based on the available literature, the primary motive for wide excision is lower recurrence rates (13% overall compared to 22% and 27% for local excision and deroofing, respectively) and longer asymptomatic periods compared to more local techniques.^7,17 Wide excision combined with continued aggressive medical management and dietary modifications currently is an efficacious treatment in providing functional long-term results.⁶ These benefits, however, are not without their drawbacks, as the more extensive nature of wide surgical excision predisposes patients to larger wounds, surgery-induced infection, and prolonged recovery periods.^6,15 If preoperative measurements are not wisely assessed, the excision also can extend to involve neurovascular bundles and other vital structures, contributing to greater postoperative morbidity.¹⁵ Ultrasonography provides useful anatomic information in HS, such as location and extent of fistulous tracts and fluid collections; these findings can assist in guiding the width and depth of the excision itself to ensure the entire area of HS involvement is removed.¹⁸ Published data revealed that 204 of 255 (80%) patients were markedly satisfied with postoperative outcomes of wide excision,¹⁹ which gives credence to the idea that although the complications of wide excision may not be as favorable, the long-lasting improvements in quality of life make wide surgical excision a suggested first-line treatment in all stages of HS.^16,20

Closure Techniques

The best skin closure method following surgical excision is controversial and not well established in literature. Options include healing by secondary intention, primary (suture-based) closure, skin grafts, and skin flaps. Each of these methods has had moderate success in multiple observational studies, and the choice should be made based on individualized assessment of the patient’s HS lesion characteristics, ability to adhere to recovery protocols, and relevant demographics. A systematic review by Mehdizadeh et al¹⁷ provided the following recurrence rates for techniques utilized after wide excision: primary closure, 15%; flaps, 8%; and grafting, 6%. Despite conflicting evidence, allowing wounds to heal by secondary intention is best, based on the author’s experience (I.H.H.).

Secondary Intention
Healing by secondary intention refers to a wound that is intentionally left open to be filled in with granulation tissue and eventual epithelization over time rather than being approximated and closed via sutures or staples as in primary intention. It is a well-established option in wound management and results in a longer but more comfortable period of convalescence in postsurgical HS management.²⁰ Patients can add regular moist wound dressings (eg, silastic foam dressing) to manage the wound at home and continue normal activities for most of the healing period; however, the recovery period can become excessively long and painful, and there is a high risk of formation of retractile scar bands at and around the healing site.¹² Strict adherence to wound-healing protocols is paramount to minimizing unwanted complications.²¹ Secondary intention often is used after wide local excision and has been demonstrated to yield positive functional and aesthetic results in multiple studies, especially in the more severe Hurley stage II or III cases.^21,22 It can be successfully employed after laser treatment and in surgical defects of all sizes with little to no contractures or reduced range of motion.⁶ Ultimately, the choice to heal via secondary intention should be made after thorough assessment of patient needs and with ample education to ensure compliance.

Primary Closure
Primary closure is the suture-mediated closing technique that is most often used in wound closure for lower-grade HS cases, especially smaller excisions. However, it is associated with potential complications. If HS lesions are not effectively excised, disease can then recur at the periphery of the excision and wound dehiscence can manifest more readily, especially as wound size increases.²³ Consequently, primary closure is associated with the highest recurrence rates among closure techniques.¹⁷ Avoiding primary closure in active disease also is recommended due to the potential of burying residual foci of inflammation.⁶ Finally, primary closures lack skin coverage and thus often are not viable options in most perianal and genital lesions that require more extensive reconstruction. Retrospective case series and case reports exist on primary excision, but further study is needed.

Skin Grafts
Skin grafting is a technique of surgically transplanting a piece of healthy skin from one body site to another. Skin grafts typically are used when primary closure or skin flaps are not feasible (eg, in large wounds) and also when shorter time to wound closure is a greater concern in patient recovery.^2,24 Additionally, skin grafts can be employed on large flat surfaces of the body, such as the buttocks or thighs, for timely wound closure when wound contraction is less effective or wound healing is slow via epithelization. Types of skin graft techniques include split-thickness skin graft (STSG), full-thickness skin graft, and recycled skin graft. All 3 types have demonstrated acceptable functional and aesthetic results in observational studies and case reports, and thus deciding which technique to use should include individualized assessment.^2,25 The STSG has several advantages over the full-thickness skin graft, including hairlessness (ie, without hair follicles), ease of harvest, and a less complicated transfer to contaminated lesional areas such as those in HS.²⁶ Additionally, STSGs allow for closure of even the largest wounds with minimal risk of serious infection. Split-thickness skin grafts are considered one of the most efficacious tools for axilla reconstruction; however, they require prolonged immobilization of the arm, result in sequelae in donor sites, and do not always prevent retractile scars.²⁶ The recycled skin graft technique can be used to treat chronic gluteal HS, but reliability and outcomes have not been reported. Skin grafting after excision is associated with increased pain, immobilization, prolonged hospitalization, and longer healing times compared to skin flaps.¹⁹ In a systematic review of wound healing techniques following wide excision, grafting was shown to have the lowest recurrence rate (6%) compared to skin flaps (8%) and primary closure (15%).¹⁷ The absence of hair follicles and sweat glands in STSGs may be advantageous in HS because both hair follicles and sweat glands are thought to play more roles in the pathogenesis of HS.^18,24 Most studies on skin grafts are limited to case reports.

Skin Flaps
Skin flaps are similar to skin grafts in that healthy skin is transplanted from one site to another; the difference is that flaps maintain an intact blood supply, whereas skin grafts depend on growth of new blood vessels.^12,13 The primary advantage of skin flaps is that they provide the best quality of skin due to the thick tissue coverage, which is an important concern, especially in aesthetic scenarios. Additionally, they have been shown to provide shorter healing times than grafts, primary closure, and secondary healing, which can be especially important when functional disability is a concern in the postoperative period.²⁶ However, their use should be limited due to several complications owing to their blood supply, as there is a high risk of ischemia to distant portions of flaps, which often can progress to necrosis and hemorrhage during the harvesting process.² Thus, skin flaps are incredibly difficult to use in larger wounds and often require debulking due to their thickness. Additionally, skin flaps are definitive by nature, which can pose an issue if HS recurs locally. Skin flaps are recommended only when their use is mandatory, such as in the coverage of important anatomic structures (eg, exposed neurovascular bundles and large vessels).² Advances have been made in flap construction, and now several types of flaps are employed in several body areas with differing indications and recommendations.^2,21 As with skin grafts, most studies in the literature are case reports; therefore, further investigation is needed.

Combination Reconstructions
Combination reconstructions refer to the simultaneous use of multiple closure or healing techniques. By combining 2 or more methods, surgeons can utilize the advantages of each technique to provide an individualized approach that can substantially diminish wound surface area and accelerate wound healing.² For example, with the starlike technique, 5 equilateral triangles bordering a foci of axillary disease are excised in addition to the central foci, and the edges of each triangle are then sutured together to create a final scar of considerably smaller size. The starlike technique allows the wound to be partially sutured while leaving the remaining area to heal by secondary intention.² There are a small number of case series and prospective studies on combined reconstructions in HS but no RCTs.

Conclusion

Many procedures exist as options for treatment of patients with HS. Deroofing and cryoinsufflation are options for localized Hurley stage I or II disease. For more severe Hurley stage II or III disease, skin tissue–saving excision with electrosurgical peeling or wide surgical excisions are preferred. Following excision, there are many options for wound closure, but our preference is to allow the wound to heal by secondary intention. It is imperative that dermatologists are informed on the different techniques for treating this disease to determine the best route of care for their patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has a social and psychosocial impact on patients with skin of color.¹ It is characterized by recurrent abscesses, draining sinus tracts, and scarring in the intertriginous skin folds. The lesions are difficult to treat and present with considerable frustration for both patients and physicians. Although current treatment ladders can delay procedures and surgical intervention,¹ some believe that surgery should be introduced earlier in HS management.² In this article, we review current procedures for the management of HS, including cryoinsufflation, incision and drainage, deroofing, skin tissue–saving excision with electrosurgical peeling, and wide surgical excision, along with various closure techniques.

Cryoinsufflation

First described in 2014, cryoinsufflation is a novel method for treating sinus tracts.³ Lesions initially are identified on physical examination. Prior to the procedure, local anesthesia is administered to the lesion.³ A 21-gauge needle is mounted onto a cryosurgical unit and inserted into the opening of the sinus tract. Liquid nitrogen is sprayed into the tract for 5 seconds, followed by a 3-second pause; the process is repeated 3 times. Patients return for treatment sessions monthly until the tract is obliterated. This procedure was first performed on 2 patients with satisfactory results.³

Since the initial report, the investigators made 2 changes to refine the procedure.⁴ First, systemic antibiotics should be prescribed 2 months prior to the procedure to clear the sinus tracts of infection. Furthermore, a 21-gauge, olive-tipped cannula is recommended in lieu of a 21-gauge needle to mitigate the risk of adverse events such as air embolism.⁴

Incision and Drainage

Incision and drainage provides rapid pain relief for tense fluctuant abscesses, but recurrence is common and the procedure costs are high.⁵ For drainage, wide circumferential local anesthesia is administered followed by incision.⁶ Pus is eliminated using digital pressure or saline rinses.² Following the elimination of pus, the wound may need gauze packing or placement of a wick for a few days.⁶ The general belief is that incision and drainage should be used, if necessary, to rapidly relieve the patient’s pain; however, other surgical options should be considered if the patient has had multiple incision and drainage procedures.⁷ Currently there are no randomized controlled trials (RCTs) on incision and drainage procedures in HS abscesses.

Deroofing

In 1959, Mullins et al⁸ first described the deroofing procedure, which was refined to preserve the floor of the sinus tract in the 1980s.^9,10 Culp¹⁰ and Brown et al⁹ theorized that preservation of the exposed floor of the sinus tract allowed for the epithelial cells from sweat glands and hair follicle remnants to rapidly reepithelialize the wound. In 2010, van der Zee et al¹¹ performed a prospective study of 88 deroofed lesions in which the investigators removed keratinous debris and epithelial remnants of the floor due to concern for recurrence in this area if the tissues remained. Only 17% (15/88) of the lesions recurred at a median follow-up of 34 months.¹¹

In Hurley stage I or II HS, deroofing remains the primary procedure for persistent nodules and sinus tracts.² The lesion is identified on physical examination and local anesthesia is administered, first to the area surrounding the lesion, then to the lesion itself.¹¹ A blunt probe is used to identify openings and search for connecting fistulas. After defining the sinus tract, the roof and wings created by the incision are removed.^11,12 The material on the floor of the tract is scraped away, and the wound is left to heal by secondary intention.¹¹ In general, deroofed lesions heal with cosmetically acceptable scars. We have used this procedure in skin of color patients with good results and no difficulties with healing. Controlled trials with long-term follow-up are lacking in this population.

Skin Tissue–Saving Excision With Electrosurgical Peeling

Skin tissue–saving excision with electrosurgical peeling was first introduced in 2015.¹³ Blok et al¹⁴ described the procedure as a promising alternative to wide surgical excision for Hurley stage II or III HS. The procedure saves healthy tissue while completely removing lesional tissue, leading to rapid wound healing, excellent cosmesis, and a low risk of contractures^2,14; however, recurrence rates are higher than those seen in wide surgical excision.¹⁵ There are no known RCTs with long-term follow-up for HS patients treated with skin tissue–saving excision with electrosurgical peeling.

The procedure typically is performed under general anesthesia.¹⁴ First, the sinus tract is palpated on physical examination and probed to delineate the extent of the tract. Next, the roof of the tract is incised electrosurgically with a wire loop tip coupled to an electrosurgical generator.¹⁴ Consecutive tangential excisions are made until the floor of the sinus tract is reached. The process of incising sinus tracts followed by tangential peeling off of tissue continues until the entire area is clear of lesional and fibrotic tissue. The wound margins are probed for the presence and subsequent removal of residual sinus tracts. Lastly, the electrosurgical generator is used to achieve hemostasis, steroids are injected to prevent the formation of hypergranulation tissue, and the wound is left to heal by secondary intention.¹⁴ Following intervention, recurrence rates appear to be similar to wide surgical excision.^13,14

Wide Surgical Excision

Wide excision is a widely established technique consisting of surgical excision of a lesion plus an area of surrounding disease-free tissue such as subcutaneous fat or a lateral margin of intertriginous skin.¹⁵ Similar to other surgical techniques, wide excision is considered in cases of severe disease when pharmacologic management cannot remedy extensive fibrosis or architectural loss. It typically is performed in Hurley stage II and III HS, with pathology extending to involve deeper structures inaccessible to more superficial surgical methods.² Prominent areas of use include gluteal, axillary, perineal, and perianal HS lesions on which conservative treatments have little effect and depend on wide excision to provide successful postoperative results.¹⁶ Although retrospective and prospective studies exist on wide excision in HS, there continues to be a dearth of RCTs. Based on the available literature, the primary motive for wide excision is lower recurrence rates (13% overall compared to 22% and 27% for local excision and deroofing, respectively) and longer asymptomatic periods compared to more local techniques.^7,17 Wide excision combined with continued aggressive medical management and dietary modifications currently is an efficacious treatment in providing functional long-term results.⁶ These benefits, however, are not without their drawbacks, as the more extensive nature of wide surgical excision predisposes patients to larger wounds, surgery-induced infection, and prolonged recovery periods.^6,15 If preoperative measurements are not wisely assessed, the excision also can extend to involve neurovascular bundles and other vital structures, contributing to greater postoperative morbidity.¹⁵ Ultrasonography provides useful anatomic information in HS, such as location and extent of fistulous tracts and fluid collections; these findings can assist in guiding the width and depth of the excision itself to ensure the entire area of HS involvement is removed.¹⁸ Published data revealed that 204 of 255 (80%) patients were markedly satisfied with postoperative outcomes of wide excision,¹⁹ which gives credence to the idea that although the complications of wide excision may not be as favorable, the long-lasting improvements in quality of life make wide surgical excision a suggested first-line treatment in all stages of HS.^16,20

Closure Techniques

The best skin closure method following surgical excision is controversial and not well established in literature. Options include healing by secondary intention, primary (suture-based) closure, skin grafts, and skin flaps. Each of these methods has had moderate success in multiple observational studies, and the choice should be made based on individualized assessment of the patient’s HS lesion characteristics, ability to adhere to recovery protocols, and relevant demographics. A systematic review by Mehdizadeh et al¹⁷ provided the following recurrence rates for techniques utilized after wide excision: primary closure, 15%; flaps, 8%; and grafting, 6%. Despite conflicting evidence, allowing wounds to heal by secondary intention is best, based on the author’s experience (I.H.H.).

Secondary Intention
Healing by secondary intention refers to a wound that is intentionally left open to be filled in with granulation tissue and eventual epithelization over time rather than being approximated and closed via sutures or staples as in primary intention. It is a well-established option in wound management and results in a longer but more comfortable period of convalescence in postsurgical HS management.²⁰ Patients can add regular moist wound dressings (eg, silastic foam dressing) to manage the wound at home and continue normal activities for most of the healing period; however, the recovery period can become excessively long and painful, and there is a high risk of formation of retractile scar bands at and around the healing site.¹² Strict adherence to wound-healing protocols is paramount to minimizing unwanted complications.²¹ Secondary intention often is used after wide local excision and has been demonstrated to yield positive functional and aesthetic results in multiple studies, especially in the more severe Hurley stage II or III cases.^21,22 It can be successfully employed after laser treatment and in surgical defects of all sizes with little to no contractures or reduced range of motion.⁶ Ultimately, the choice to heal via secondary intention should be made after thorough assessment of patient needs and with ample education to ensure compliance.

Primary Closure
Primary closure is the suture-mediated closing technique that is most often used in wound closure for lower-grade HS cases, especially smaller excisions. However, it is associated with potential complications. If HS lesions are not effectively excised, disease can then recur at the periphery of the excision and wound dehiscence can manifest more readily, especially as wound size increases.²³ Consequently, primary closure is associated with the highest recurrence rates among closure techniques.¹⁷ Avoiding primary closure in active disease also is recommended due to the potential of burying residual foci of inflammation.⁶ Finally, primary closures lack skin coverage and thus often are not viable options in most perianal and genital lesions that require more extensive reconstruction. Retrospective case series and case reports exist on primary excision, but further study is needed.

Skin Grafts
Skin grafting is a technique of surgically transplanting a piece of healthy skin from one body site to another. Skin grafts typically are used when primary closure or skin flaps are not feasible (eg, in large wounds) and also when shorter time to wound closure is a greater concern in patient recovery.^2,24 Additionally, skin grafts can be employed on large flat surfaces of the body, such as the buttocks or thighs, for timely wound closure when wound contraction is less effective or wound healing is slow via epithelization. Types of skin graft techniques include split-thickness skin graft (STSG), full-thickness skin graft, and recycled skin graft. All 3 types have demonstrated acceptable functional and aesthetic results in observational studies and case reports, and thus deciding which technique to use should include individualized assessment.^2,25 The STSG has several advantages over the full-thickness skin graft, including hairlessness (ie, without hair follicles), ease of harvest, and a less complicated transfer to contaminated lesional areas such as those in HS.²⁶ Additionally, STSGs allow for closure of even the largest wounds with minimal risk of serious infection. Split-thickness skin grafts are considered one of the most efficacious tools for axilla reconstruction; however, they require prolonged immobilization of the arm, result in sequelae in donor sites, and do not always prevent retractile scars.²⁶ The recycled skin graft technique can be used to treat chronic gluteal HS, but reliability and outcomes have not been reported. Skin grafting after excision is associated with increased pain, immobilization, prolonged hospitalization, and longer healing times compared to skin flaps.¹⁹ In a systematic review of wound healing techniques following wide excision, grafting was shown to have the lowest recurrence rate (6%) compared to skin flaps (8%) and primary closure (15%).¹⁷ The absence of hair follicles and sweat glands in STSGs may be advantageous in HS because both hair follicles and sweat glands are thought to play more roles in the pathogenesis of HS.^18,24 Most studies on skin grafts are limited to case reports.

Skin Flaps
Skin flaps are similar to skin grafts in that healthy skin is transplanted from one site to another; the difference is that flaps maintain an intact blood supply, whereas skin grafts depend on growth of new blood vessels.^12,13 The primary advantage of skin flaps is that they provide the best quality of skin due to the thick tissue coverage, which is an important concern, especially in aesthetic scenarios. Additionally, they have been shown to provide shorter healing times than grafts, primary closure, and secondary healing, which can be especially important when functional disability is a concern in the postoperative period.²⁶ However, their use should be limited due to several complications owing to their blood supply, as there is a high risk of ischemia to distant portions of flaps, which often can progress to necrosis and hemorrhage during the harvesting process.² Thus, skin flaps are incredibly difficult to use in larger wounds and often require debulking due to their thickness. Additionally, skin flaps are definitive by nature, which can pose an issue if HS recurs locally. Skin flaps are recommended only when their use is mandatory, such as in the coverage of important anatomic structures (eg, exposed neurovascular bundles and large vessels).² Advances have been made in flap construction, and now several types of flaps are employed in several body areas with differing indications and recommendations.^2,21 As with skin grafts, most studies in the literature are case reports; therefore, further investigation is needed.

Combination Reconstructions
Combination reconstructions refer to the simultaneous use of multiple closure or healing techniques. By combining 2 or more methods, surgeons can utilize the advantages of each technique to provide an individualized approach that can substantially diminish wound surface area and accelerate wound healing.² For example, with the starlike technique, 5 equilateral triangles bordering a foci of axillary disease are excised in addition to the central foci, and the edges of each triangle are then sutured together to create a final scar of considerably smaller size. The starlike technique allows the wound to be partially sutured while leaving the remaining area to heal by secondary intention.² There are a small number of case series and prospective studies on combined reconstructions in HS but no RCTs.

Conclusion

Many procedures exist as options for treatment of patients with HS. Deroofing and cryoinsufflation are options for localized Hurley stage I or II disease. For more severe Hurley stage II or III disease, skin tissue–saving excision with electrosurgical peeling or wide surgical excisions are preferred. Following excision, there are many options for wound closure, but our preference is to allow the wound to heal by secondary intention. It is imperative that dermatologists are informed on the different techniques for treating this disease to determine the best route of care for their patients.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that has a social and psychosocial impact on patients with skin of color.¹ It is characterized by recurrent abscesses, draining sinus tracts, and scarring in the intertriginous skin folds. The lesions are difficult to treat and present with considerable frustration for both patients and physicians. Although current treatment ladders can delay procedures and surgical intervention,¹ some believe that surgery should be introduced earlier in HS management.² In this article, we review current procedures for the management of HS, including cryoinsufflation, incision and drainage, deroofing, skin tissue–saving excision with electrosurgical peeling, and wide surgical excision, along with various closure techniques.

Cryoinsufflation

First described in 2014, cryoinsufflation is a novel method for treating sinus tracts.³ Lesions initially are identified on physical examination. Prior to the procedure, local anesthesia is administered to the lesion.³ A 21-gauge needle is mounted onto a cryosurgical unit and inserted into the opening of the sinus tract. Liquid nitrogen is sprayed into the tract for 5 seconds, followed by a 3-second pause; the process is repeated 3 times. Patients return for treatment sessions monthly until the tract is obliterated. This procedure was first performed on 2 patients with satisfactory results.³

Since the initial report, the investigators made 2 changes to refine the procedure.⁴ First, systemic antibiotics should be prescribed 2 months prior to the procedure to clear the sinus tracts of infection. Furthermore, a 21-gauge, olive-tipped cannula is recommended in lieu of a 21-gauge needle to mitigate the risk of adverse events such as air embolism.⁴

Incision and Drainage

Incision and drainage provides rapid pain relief for tense fluctuant abscesses, but recurrence is common and the procedure costs are high.⁵ For drainage, wide circumferential local anesthesia is administered followed by incision.⁶ Pus is eliminated using digital pressure or saline rinses.² Following the elimination of pus, the wound may need gauze packing or placement of a wick for a few days.⁶ The general belief is that incision and drainage should be used, if necessary, to rapidly relieve the patient’s pain; however, other surgical options should be considered if the patient has had multiple incision and drainage procedures.⁷ Currently there are no randomized controlled trials (RCTs) on incision and drainage procedures in HS abscesses.

Deroofing

In 1959, Mullins et al⁸ first described the deroofing procedure, which was refined to preserve the floor of the sinus tract in the 1980s.^9,10 Culp¹⁰ and Brown et al⁹ theorized that preservation of the exposed floor of the sinus tract allowed for the epithelial cells from sweat glands and hair follicle remnants to rapidly reepithelialize the wound. In 2010, van der Zee et al¹¹ performed a prospective study of 88 deroofed lesions in which the investigators removed keratinous debris and epithelial remnants of the floor due to concern for recurrence in this area if the tissues remained. Only 17% (15/88) of the lesions recurred at a median follow-up of 34 months.¹¹

In Hurley stage I or II HS, deroofing remains the primary procedure for persistent nodules and sinus tracts.² The lesion is identified on physical examination and local anesthesia is administered, first to the area surrounding the lesion, then to the lesion itself.¹¹ A blunt probe is used to identify openings and search for connecting fistulas. After defining the sinus tract, the roof and wings created by the incision are removed.^11,12 The material on the floor of the tract is scraped away, and the wound is left to heal by secondary intention.¹¹ In general, deroofed lesions heal with cosmetically acceptable scars. We have used this procedure in skin of color patients with good results and no difficulties with healing. Controlled trials with long-term follow-up are lacking in this population.

Skin Tissue–Saving Excision With Electrosurgical Peeling

Skin tissue–saving excision with electrosurgical peeling was first introduced in 2015.¹³ Blok et al¹⁴ described the procedure as a promising alternative to wide surgical excision for Hurley stage II or III HS. The procedure saves healthy tissue while completely removing lesional tissue, leading to rapid wound healing, excellent cosmesis, and a low risk of contractures^2,14; however, recurrence rates are higher than those seen in wide surgical excision.¹⁵ There are no known RCTs with long-term follow-up for HS patients treated with skin tissue–saving excision with electrosurgical peeling.

The procedure typically is performed under general anesthesia.¹⁴ First, the sinus tract is palpated on physical examination and probed to delineate the extent of the tract. Next, the roof of the tract is incised electrosurgically with a wire loop tip coupled to an electrosurgical generator.¹⁴ Consecutive tangential excisions are made until the floor of the sinus tract is reached. The process of incising sinus tracts followed by tangential peeling off of tissue continues until the entire area is clear of lesional and fibrotic tissue. The wound margins are probed for the presence and subsequent removal of residual sinus tracts. Lastly, the electrosurgical generator is used to achieve hemostasis, steroids are injected to prevent the formation of hypergranulation tissue, and the wound is left to heal by secondary intention.¹⁴ Following intervention, recurrence rates appear to be similar to wide surgical excision.^13,14

Wide Surgical Excision

Wide excision is a widely established technique consisting of surgical excision of a lesion plus an area of surrounding disease-free tissue such as subcutaneous fat or a lateral margin of intertriginous skin.¹⁵ Similar to other surgical techniques, wide excision is considered in cases of severe disease when pharmacologic management cannot remedy extensive fibrosis or architectural loss. It typically is performed in Hurley stage II and III HS, with pathology extending to involve deeper structures inaccessible to more superficial surgical methods.² Prominent areas of use include gluteal, axillary, perineal, and perianal HS lesions on which conservative treatments have little effect and depend on wide excision to provide successful postoperative results.¹⁶ Although retrospective and prospective studies exist on wide excision in HS, there continues to be a dearth of RCTs. Based on the available literature, the primary motive for wide excision is lower recurrence rates (13% overall compared to 22% and 27% for local excision and deroofing, respectively) and longer asymptomatic periods compared to more local techniques.^7,17 Wide excision combined with continued aggressive medical management and dietary modifications currently is an efficacious treatment in providing functional long-term results.⁶ These benefits, however, are not without their drawbacks, as the more extensive nature of wide surgical excision predisposes patients to larger wounds, surgery-induced infection, and prolonged recovery periods.^6,15 If preoperative measurements are not wisely assessed, the excision also can extend to involve neurovascular bundles and other vital structures, contributing to greater postoperative morbidity.¹⁵ Ultrasonography provides useful anatomic information in HS, such as location and extent of fistulous tracts and fluid collections; these findings can assist in guiding the width and depth of the excision itself to ensure the entire area of HS involvement is removed.¹⁸ Published data revealed that 204 of 255 (80%) patients were markedly satisfied with postoperative outcomes of wide excision,¹⁹ which gives credence to the idea that although the complications of wide excision may not be as favorable, the long-lasting improvements in quality of life make wide surgical excision a suggested first-line treatment in all stages of HS.^16,20

Closure Techniques

The best skin closure method following surgical excision is controversial and not well established in literature. Options include healing by secondary intention, primary (suture-based) closure, skin grafts, and skin flaps. Each of these methods has had moderate success in multiple observational studies, and the choice should be made based on individualized assessment of the patient’s HS lesion characteristics, ability to adhere to recovery protocols, and relevant demographics. A systematic review by Mehdizadeh et al¹⁷ provided the following recurrence rates for techniques utilized after wide excision: primary closure, 15%; flaps, 8%; and grafting, 6%. Despite conflicting evidence, allowing wounds to heal by secondary intention is best, based on the author’s experience (I.H.H.).

Secondary Intention
Healing by secondary intention refers to a wound that is intentionally left open to be filled in with granulation tissue and eventual epithelization over time rather than being approximated and closed via sutures or staples as in primary intention. It is a well-established option in wound management and results in a longer but more comfortable period of convalescence in postsurgical HS management.²⁰ Patients can add regular moist wound dressings (eg, silastic foam dressing) to manage the wound at home and continue normal activities for most of the healing period; however, the recovery period can become excessively long and painful, and there is a high risk of formation of retractile scar bands at and around the healing site.¹² Strict adherence to wound-healing protocols is paramount to minimizing unwanted complications.²¹ Secondary intention often is used after wide local excision and has been demonstrated to yield positive functional and aesthetic results in multiple studies, especially in the more severe Hurley stage II or III cases.^21,22 It can be successfully employed after laser treatment and in surgical defects of all sizes with little to no contractures or reduced range of motion.⁶ Ultimately, the choice to heal via secondary intention should be made after thorough assessment of patient needs and with ample education to ensure compliance.

Primary Closure
Primary closure is the suture-mediated closing technique that is most often used in wound closure for lower-grade HS cases, especially smaller excisions. However, it is associated with potential complications. If HS lesions are not effectively excised, disease can then recur at the periphery of the excision and wound dehiscence can manifest more readily, especially as wound size increases.²³ Consequently, primary closure is associated with the highest recurrence rates among closure techniques.¹⁷ Avoiding primary closure in active disease also is recommended due to the potential of burying residual foci of inflammation.⁶ Finally, primary closures lack skin coverage and thus often are not viable options in most perianal and genital lesions that require more extensive reconstruction. Retrospective case series and case reports exist on primary excision, but further study is needed.

Skin Grafts
Skin grafting is a technique of surgically transplanting a piece of healthy skin from one body site to another. Skin grafts typically are used when primary closure or skin flaps are not feasible (eg, in large wounds) and also when shorter time to wound closure is a greater concern in patient recovery.^2,24 Additionally, skin grafts can be employed on large flat surfaces of the body, such as the buttocks or thighs, for timely wound closure when wound contraction is less effective or wound healing is slow via epithelization. Types of skin graft techniques include split-thickness skin graft (STSG), full-thickness skin graft, and recycled skin graft. All 3 types have demonstrated acceptable functional and aesthetic results in observational studies and case reports, and thus deciding which technique to use should include individualized assessment.^2,25 The STSG has several advantages over the full-thickness skin graft, including hairlessness (ie, without hair follicles), ease of harvest, and a less complicated transfer to contaminated lesional areas such as those in HS.²⁶ Additionally, STSGs allow for closure of even the largest wounds with minimal risk of serious infection. Split-thickness skin grafts are considered one of the most efficacious tools for axilla reconstruction; however, they require prolonged immobilization of the arm, result in sequelae in donor sites, and do not always prevent retractile scars.²⁶ The recycled skin graft technique can be used to treat chronic gluteal HS, but reliability and outcomes have not been reported. Skin grafting after excision is associated with increased pain, immobilization, prolonged hospitalization, and longer healing times compared to skin flaps.¹⁹ In a systematic review of wound healing techniques following wide excision, grafting was shown to have the lowest recurrence rate (6%) compared to skin flaps (8%) and primary closure (15%).¹⁷ The absence of hair follicles and sweat glands in STSGs may be advantageous in HS because both hair follicles and sweat glands are thought to play more roles in the pathogenesis of HS.^18,24 Most studies on skin grafts are limited to case reports.

Skin Flaps
Skin flaps are similar to skin grafts in that healthy skin is transplanted from one site to another; the difference is that flaps maintain an intact blood supply, whereas skin grafts depend on growth of new blood vessels.^12,13 The primary advantage of skin flaps is that they provide the best quality of skin due to the thick tissue coverage, which is an important concern, especially in aesthetic scenarios. Additionally, they have been shown to provide shorter healing times than grafts, primary closure, and secondary healing, which can be especially important when functional disability is a concern in the postoperative period.²⁶ However, their use should be limited due to several complications owing to their blood supply, as there is a high risk of ischemia to distant portions of flaps, which often can progress to necrosis and hemorrhage during the harvesting process.² Thus, skin flaps are incredibly difficult to use in larger wounds and often require debulking due to their thickness. Additionally, skin flaps are definitive by nature, which can pose an issue if HS recurs locally. Skin flaps are recommended only when their use is mandatory, such as in the coverage of important anatomic structures (eg, exposed neurovascular bundles and large vessels).² Advances have been made in flap construction, and now several types of flaps are employed in several body areas with differing indications and recommendations.^2,21 As with skin grafts, most studies in the literature are case reports; therefore, further investigation is needed.

Combination Reconstructions
Combination reconstructions refer to the simultaneous use of multiple closure or healing techniques. By combining 2 or more methods, surgeons can utilize the advantages of each technique to provide an individualized approach that can substantially diminish wound surface area and accelerate wound healing.² For example, with the starlike technique, 5 equilateral triangles bordering a foci of axillary disease are excised in addition to the central foci, and the edges of each triangle are then sutured together to create a final scar of considerably smaller size. The starlike technique allows the wound to be partially sutured while leaving the remaining area to heal by secondary intention.² There are a small number of case series and prospective studies on combined reconstructions in HS but no RCTs.

Conclusion

Many procedures exist as options for treatment of patients with HS. Deroofing and cryoinsufflation are options for localized Hurley stage I or II disease. For more severe Hurley stage II or III disease, skin tissue–saving excision with electrosurgical peeling or wide surgical excisions are preferred. Following excision, there are many options for wound closure, but our preference is to allow the wound to heal by secondary intention. It is imperative that dermatologists are informed on the different techniques for treating this disease to determine the best route of care for their patients.