Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

Medicare, the government-run health insurance program for elderly and disabled Americans, paid physicians $90 billion in 2013, up 17% from $77 billion in 2012, U.S. healthcare officials reported earlier this month.

Physician payments accounted for less than one-fifth of Medicare's 2013 net outlays of $492 billion, which rose from $466 billion in 2012. Payments to hospitals for the top 100 inpatient stays cost Medicare $62 billion in 2013, while the rest went for drugs, privately run Medicare Advantage plans, and other program costs.

The single-greatest hospital expense was to replace knees, hips, and other joints in 446,148 operations, with $6.6 billion paid to hospitals.

The second-greatest hospital payment, $5.6 billion, went for 398,004 cases of septicemia, or blood poisoning, often a sign of poor inpatient care. TH

—Reuters Health

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

CHICAGO – Combining ibrutinib with standard chemoimmunotherapy extended progression-free survival in patients with relapsed chronic lymphocytic leukemia (CLL), according to interim results from the HELIOS trial.

In fact, while median progression-free survival was approximately 13 months in the placebo arm, the median progression-free survival had not been reached yet in the study’s ibrutinib arm, explained lead study author Dr. Asher Chanan-Khan.

“I believe that ibrutinib has now become the backbone of treatment of patients with relapsed CLL,” said Dr. Chanan-Khan, professor of medicine at the Mayo Clinic in Jacksonville, Fla.

In a video interview at the annual meeting of the American Society of Clinical Oncology, Dr. Chanan-Khan discussed ibrutinib’s significant impact on the risk of progression and death, even in the presence of factors associated with aggressive disease or poor outcome.

[email protected]

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Messe Wien, site of EHA 2015

VIENNA—Researchers say they have found a way to unsickle red blood cells (RBCs), at least in vitro.

Using pegylated carboxyhemoglobin bovine gas transfer, the team restored sickled RBCs to a more normal, rounder shape in as little as 5 minutes.

Ronald Jubin, PhD, of Prolong Pharmaceuticals, the company developing carboxyhemoglobin, described this process at the 20th Congress of the European Hematology Association (abstract S140).

Pegylated carboxyhemoglobin bovine (Sanguinate [SG]) was designed to reduce vasoconstriction, counteract inflammatory responses, and deliver oxygen to hypoxic cells by releasing carbon monoxide.

The investigators contend that using SG early in a vasooclusive crisis (VOC) can limit the crisis and reduce pain severity.

They evaluated SG treatment using RBCs from healthy volunteers and patients with sickle cell disease (SCD).

The researchers monitored carboxyhemoglobin and oxyhemoglobin levels and analyzed patient samples using light microscopy and image capture flow cytometry. In this manner, they were able to visualize and quantify the effects of SG treatment on reversing the sickling of RBCs.

The investigators found that SG rapidly transferred its carbon monoxide component to oxygenated RBCs along with oxygen loading of SG.

“SG restored more normal RBC shape in as little as 5 minutes,” Dr Jubin said.

SG was also able to continually facilitate gas transfer through multiple exposure events and limited inflammatory marker expression in SCD blood samples.

The researchers concluded that SG can serve as an active gas transport agent, providing either carbon monoxide or oxygen to sickled RBCs. They also noted that image capture flow cytometry allowed for a quantitative measurement of decreased sickling and may provide a way to monitor SG treatment effects on SCD patients in future studies.

Dr Jubin said phase 1 safety trials of SG have been completed, and phase 2 trials are in development for VOC, SCD leg ulcers, delayed cerebral ischemia, prevention of delayed kidney graft function, and pulmonary hypertension in beta-thalassemia.

SG was recently awarded orphan drug status by the US Food and Drug Administration.

Orphan designation provides the company developing a drug with certain benefits and incentives, including a 7-year period of marketing exclusivity upon regulatory approval, potential tax credits for certain activities, eligibility for orphan drug grants, and the waiver of certain administrative fees.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing MM

VIENNA—Combination therapy consisting of the HDAC6 inhibitor ricolinostat, pomalidomide, and dexamethasone can provide a clinical benefit for patients with relapsed and refractory multiple myeloma (MM), according to a researchers.

In a phase 1b/2 trial, the triplet produced an overall response rate (ORR) of 29% and a clinical benefit rate of 50%.

The most common treatment-related adverse events were fatigue, diarrhea, and neutropenia.

“As a physician, it is encouraging to see patients whose multiple myeloma has progressed while receiving standard-of-care therapy achieve clinical benefit with the combination of ricolinostat, [pomalidomide], and dexamethasone,” said study investigator Noopur Raje, MD, of the Massachusetts General Hospital Cancer Center in Boston.

Dr Raje and her colleagues presented results with this combination at the 20th Congress of the European Hematology Association (abstract P279*). The research was sponsored by Acetylon Pharmaceuticals, Inc., the company developing ricolinostat.

The phase 1b portion of this trial was a 3+3 design in which ricolinostat (160 mg) was given once daily (QD) or twice daily (BID) along with pomalidomide (4 mg) for 21 days of a 28-day cycle with dexamethasone (40 mg) on days 1, 8, 15, and 22. Seven patients were treated in the phase 1b portion, with 3 at 160 mg QD and 4 at 160 mg BID.

In the ongoing phase 2 portion of the study, 32 patients were enrolled as of April 27, 2015, and 28 of these patients were evaluable for response. Nineteen of the patients received ricolinostat at 160 mg QD, and 9 received the drug at 160 mg BID.

The median age for all 39 patients was 68 (range, 48-80), and they had received a median of 3 prior therapies (range, 2-5). Seventy-four percent of patients were refractory to lenalidomide, 59% to bortezomib, and 38% to both drugs.

Treatment results

At a median follow-up of 12 weeks, the ORR among the 28 evaluable phase 2 patients was 29%. Clinical benefit, defined as minimal response or greater, was 50%.

Three patients had a very good partial response, 5 had a partial response, 6 had a minimal response, 5 had stable disease, 3 progressed, and 6 had an unconfirmed response at the time of data cutoff.

All 7 patients in the phase 1b portion of the study had discontinued treatment due to progressive disease.

Of the 28 evaluable patients in the phase 2 portion, 57% (n=16) remained on the study after a median of 3 months on therapy. The other 43% discontinued treatment due to progressive disease (n=6), a non-fatal adverse event (n=3), patient decision (n=2), or investigator decision (n=1).

The researchers said the optimal dose and schedule for ricolinostat in combination with pomalidomide and dexamethasone was 160 mg QD on days 1-21 of a 28-day cycle. Patients treated at this dose experienced no dose-limiting toxicities. At 160 mg BID, some clinically relevant grade 2 diarrhea was observed.

In all 39 patients, the common treatment-emergent adverse events were fatigue (41%), diarrhea (38%), neutropenia (36%), anemia (31%), a decrease in platelet count (26%), constipation (21%), hypertension (18%), hyponatremia (18%), upper respiratory tract infection (15%), and a decrease in white cell count (15%).

Grade 3 and 4 adverse events, apart from neutropenia (26%), were uncommon (occurring in 8% of patients or fewer).

Grade 3/4 adverse events considered possibly related to ricolinostat included neutropenia (n=5), diarrhea (n=3), bronchitis (n=1), anemia (n=1), chronic cardiac failure (n=1), leukopenia (n=1), lymphopenia (n=1), pneumonia (n=1), increased alanine aminotransferase (n=1), fatigue (n=1), thrombocytopenia (n=1), and renal failure (n=1).

“This all-oral combination has been very well-tolerated,” Dr Raje said, “making it potentially suitable for treatment of a broad range of patients, including older patients, patients for whom a non-oral drug regimen is limiting, and potentially as a part of an all-oral maintenance regimen.”

*Information in the abstract differs from that presented at the meeting.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Micrograph showing CLL

VIENNA—Results of the COMPLEMENT 2 trial indicate that adding ofatumumab to treatment with fludarabine and cyclophosphamide (OFC) can improve some outcome measures in patients with relapsed chronic lymphocytic leukemia (CLL), when compared to fludarabine and cyclophosphamide alone (FC).

Patients who received OFC had a significantly higher overall response rate and longer median progression-free survival than patients who received FC.

On the other hand, there was no significant difference between the treatment arms with regard to response duration or overall survival. And there were more grade 3 or higher adverse events (AEs) in the 3-drug arm than the 2-drug arm.

“There are limited treatment options for patients who have stopped responding to current CLL treatments, which happens in many patients with this disease over time,” said study investigator Tadeusz Robak, MD, PhD, of the Medical University of Lodz and Copernicus Memorial Hospital in Lodz, Poland.

“These data showed that the addition of ofatumumab to fludarabine and cyclophosphamide extended the amount of time before a patient’s CLL progressed, and further add to the body of evidence supporting the potential use of ofatumumab for these patients.”

The data were presented at the 20th Congress of the European Hematology Association (abstract LB219). The study was sponsored by GlaxoSmithKline and Genmab, which were previously co-developing ofatumumab. The drug is now an asset of Novartis AG.

Efficacy data

COMPLEMENT 2 is a phase 3 trial of 365 patients with relapsed CLL. Patients were randomized 1:1 to receive treatment with up to 6 cycles of OFC or FC. Baseline characteristics were well-balanced between the treatment arms.

The overall response rate was higher in the OFC arm than the FC arm—84% and 68%, respectively (P=0.0003)—as was the complete response rate—27% and 7%, respectively.

However, there was no significant difference in time to response or response duration. The median duration of response was 29.6 months in the OFC arm and 24.9 months in the FC arm (P=0.0878). And the median time to response was 0.99 months in both arms (P=0.449).

Still, patients in the OFC arm experienced a 54% improvement in progression-free survival. The median progression-free survival was 28.9 months in the OFC arm and 18.8 months in the FC arm (P=0.0032). And time to progression was 42.1 months and 26.8 months, respectively (P=0.0036).

But there was no significant difference in overall survival or time to next cancer treatment between the arms. The median overall survival was 56.4 months in the OFC arm and 45.8 months in the FC arm (P=0.1410). The median time to next therapy was 48.13 months and 40.08 months, respectively (P=0.0735).

Safety data

The rate of treatment-related AEs was 93% in the OFC arm and 85% in the FC arm. The rate of grade 3 or higher AEs was 74% and 69%, respectively.

The most common treatment-related AEs occurring in the OFC and FC arms, respectively, were neutropenia (58% vs 41%), thrombocytopenia (26% vs 32%), anemia (15% vs 26%), nausea (19% in both), leukopenia (14% vs 6%), vomiting (7% vs 10%), pyrexia (10% vs 3%), rash (10% vs 2%), fatigue (6% vs 4%), and pneumonia (6% vs 4%).

Treatment-related infections occurred in 20% of patients in the OFC arm and 15% in the FC arm. Infusion reactions occurred in 60% and 28% of patients, respectively.

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”

Thrombus

Image by Andre E.X. Brown

Splanchnic venous thrombosis (SVT) may be an indicator of undiagnosed cancer, according to research published in Blood.

The study showed that patients with SVT had a particularly high incidence of myeloproliferative neoplasms (MPNs), liver cancer, and pancreatic cancer.

The presence of SVT also appeared to predict poorer survival in patients with liver and pancreatic cancers. The researchers were unable to calculate the impact of SVT on survival in MPN patients.

“As we learn more about the association between many types of thromboses and cancer, we also want to better understand these more rare clots and how they can perhaps signal a hidden cancer,” said study author Kirstine K. Søgaard, MD, of Aarhus University Hospital in Aarhus, Denmark.

“In this case, we had access to comprehensive data that we believed could provide insights useful to clinicians caring for patients with this condition.”

Dr Søgaard and her colleagues analyzed the medical discharge diagnoses of more than 1191 Danish patients diagnosed with SVT from 1994 to 2011. The researchers followed the patients for a median of 1.6 years, calculating their risk of having a subsequent cancer diagnosis compared to the expected risk in the general population in Denmark.

In all, 183 SVT patients were diagnosed with cancer, for an overall standardized incidence ratio (SIR) of 4.2. More than half of the cancers (n=95) were identified within 3 months of SVT diagnosis. The 3-month absolute risk of cancer was 8%, and the absolute risk at 5 years was 14.8%.

During the first 3 months of follow-up, the SIR for cancer among SVT patients was 33. The SIR fell to 2.7 between 3 and 12 months, then to 2.1 past the 1-year mark.

SIRs were highest for liver and pancreatic cancers and MPNs. The overall SIRs were 138, 21, and 133, respectively.

For MPNs, the SIR was 764 in the first 3 months of SVT diagnosis, 119 from 3 to 12 months, and 88 after the 12-month mark. For liver cancer, the SIR was 1805 in the first 3 months, 92 from 3 to 12 months, and 7.4 after the 12-month mark. For pancreatic cancer, the SIR was 256 in the first 3 months, 0 from 3 to 12 months, and 4 after the 12-month mark.

The researchers also found an excess risk of lymphoma, leukemia, and myelodysplastic syndromes in the first 3 months after SVT diagnosis. After that, the risk did not differ from that of the general population.

Patients with liver or pancreatic cancer had a poor outcome regardless of SVT, but patients with SVT and these cancers had markedly worse 3-month survival outcomes than cancer patients without SVT—44% vs 55% for patients with liver cancer and 33% vs 53% for patients with pancreatic cancer.

Patients with MPNs had a much better prognosis, regardless of SVT. And because so few MPN patients died, the researchers did not analyze the impact of SVT on relative mortality.

“This study is the first to demonstrate, in a large population, that patients who develop splanchnic venous thrombosis are likely to be diagnosed with cancer within a relatively short time period,” Dr Søgaard said. “As we continue to learn more about patients who suffer from these blood clots, it will be important to examine the pros and cons of screening for these hidden cancers.”

Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.

In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.

This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.

VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.

The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.

With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.

A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”

The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”

But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”

There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.

Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.

In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.

This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.

VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.

The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.

With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.

A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”

The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”

But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”

There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.

Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

Urban legends never seem to die. They haunt those who chase the truth because most legends have a kernel of truth. Reflux nephropathy is one of those legends.

In the 1970s, neurosurgeons began treating children with spina bifida rather than allowing them to die shortly after birth. As these children entered their second and third decade of life, episodes of renal failure were noted. The reflux and recurring urinary tract infections (UTIs) from neurogenic bladders damaged kidneys. Self-catheter programs were invented and were effective. Surgical correction of anatomic urinary obstructions and severe reflux yielded similar benefits. By the 1990s, this paradigm had been extrapolated to all children with vesicoureteral reflux (VUR) and codified in the 1999 practice parameter. The unproven hope was that aggressive antibiotic prophylaxis to protect young, growing kidneys from infections would reduce the incidence of renal failure and hypertension in adults.

This is a common methodology for quality improvement at a Mortality and Morbidity conference. A problem is identified. A solution is developed to prevent the bad outcome. The solution is implemented without fully proving that the obvious, customized intervention truly works. No one ever assesses whether the remedy causes more mischief than benefit.

VUR has a pyramid shaped spectrum. Few children have the severe grade V reflux which responds to surgical intervention. At the base of the pyramid are a much larger group of children with mild reflux that usually resolves spontaneously by age 5 years. This pyramid is a setup for overdiagnosis and overtreatment of mild disease. Pediatricians soon recognized that the small portion of the 1999 practice parameter addressing reflux nephropathy was overly aggressive and based on unsound science. However, that same lack of clear evidence delayed creating a new consensus until 2011.

The recent efforts to prove the benefit of prophylaxis used exemplary evidence-based medicine. The RIVUR study over 4 years assessed 10,000 children in a multicenter study involving 19 locations. It enrolled 600 children in a prospective, double-blind, randomized, controlled trial with a placebo control. It followed the children for 2 years. Even by modern standards, this was a huge, prolonged and well-designed trial. It did demonstrate a benefit. About 20% of children on placebo had a recurrent UTI in that 2-year time frame. There was a 50% reduction in the number of UTIs in the children treated with antibiotic prophylaxis. Phrased that way, it was a success. But the numbers can be spun differently. The article duly noted a number needed to treat of eight. Eight children treated for 2 years at 365 days per year and one dose per day, means that 6,000 doses of antibiotics were necessary to prevent one UTI. There was no demonstrated benefit in renal scarring, renal failure, or other long-term outcomes. There was a downside. The rate of antibiotic-resistant organisms in the breakthrough UTIs tripled from 19% of the placebo group to 63% of the prophylaxis group. As large as this study was, it wasn’t able to measure the rate of other known adverse outcomes, such as Stevens-Johnson syndrome from the use of sulfa medications or the impact on resistant infections elsewhere in the body.

With the 2011 practice parameter, pediatricians became less aggressive at working up first UTIs. Urologists disagreed. The May 2015 issue of AAP News had a full page article by Dr. Saul Greenfield, who is the chairperson-elect for the Executive Committee of the American Academy of Pediatrics Section on Urology, a urologist in Buffalo, N.Y., and one of the RIVUR trial’s investigators (AAP News 2015;36:13). He rehashed the RIVUR study results emphasizing the reduction in UTIs, but offered no quantitative assessment of the risks, costs, and harms of prophylaxis.

A June 2015 article in Pediatrics gives the results of the CUTIE study, which ran in parallel with the RIVUR study (Pediatrics 2015 [doi:10.1542/peds.2015-0409]). The conclusions: “VUR and BBD [bladder and bowel dysfunction] are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD.”

The article concludes with, “Therefore, clinicians must help families decide whether the benefits of prophylaxis outweigh the risks and inconvenience. … Additional research is needed to validate the risk factors and profiles that we identified.”

But six pages of discussing renal scarring (which is only a proxy for a small risk of future renal failure or hypertension), followed by a couple paragraphs, without numbers, about the risks of prophylaxis, does not provide the balanced presentation clinicians need to help families make wise decisions. In the new era of Choosing Wisely, scientific articles making clinical recommendations should not be published without an accompanying risk-benefit analysis, either in the article or in an editorial. The maxim in surgery, channeling Voltaire, is that “perfect is the enemy of good.”

There is mounting evidence that giving any antibiotics to young infants is harmful. Even 2 days of antibiotics before 1 month of age leads to measurable changes in the gut microbiota 6 months later. Antibiotics in infancy are associated with obesity at 24 months and at 48 months of age. All medical treatments introduce a substantial risk of harm. As Shakespeare wrote 400 years ago, “Striving to better, oft we mar what’s well.” I don’t doubt the conclusion that prophylaxis reduces UTIs, but giving 6,000 doses to prevent one UTI?! Even Kaley Cuoco can’t sell that.

Ultimately, this choice is not up to the hospitalist, the emergency department doctor, or the urologist. The decision belongs to the parents guided by a primary care doctor they trust. Our professional duty, ethically and legally, is to communicate the risks and benefits to the parents in a manner which they can understand and to provide them the support and counseling necessary to make a wise choice for their child. By focusing on the child and that duty, medical professionals can defuse any clashes of egos, departmental power struggles, or autocratic hierarchy that might interfere. Doctors educate and recommend, but the parent decides what is best for his or her child.

Dr. Powell is a pediatric hospitalist and clinical ethics consultant living in St. Louis. Dr. Powell said he had no relevant financial disclosures or conflicts of interest. E-mail him at [email protected].

NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.

Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.

VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).

On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.

In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."

As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."

Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH

—Reuters Health

NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.

Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.

VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).

On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.

In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."

As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."

Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH

—Reuters Health

NEW YORK—Although venous thromboembolism (VTE) rates are low in hospitalized patients following colorectal surgery, the increasing use of prophylaxis seems to have little impact, according to Washington state-based researchers.

Dr. Scott R. Steele, of Madigan Army Medical Center, Tacoma, and colleagues in JAMA Surgery note that although VTE is an important complication of such surgery its incidence in the current era of prophylaxis is unclear. To investigate further, the team examined Washington state data on more than 16,000 patients who underwent colorectal surgery between 2006 and 2011. Over the study period, the use of perioperative VTE chemoprophylaxis increased significantly from 31.6% to 86.4%. In-hospital VTE chemoprophylaxis rose from 59.6% to 91.4%. A total of 10.6% were discharged on VTE prophylaxis.

VTE within 90 days was seen in 360 patients (2.2%) overall. Patients undergoing abdominal operations had higher rates than those having pelvic operations (2.5% versus 1.8%, p=0.001). Rates were similar, but nonsignificant, in patients having an operation for cancer or for nonmalignant processes (2.1% versus 2.3%).

On adjusted analysis, being older, non-elective surgery, a history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE. However, despite the steady increase in chemoprophylaxis use in the perioperative and in-hospital settings, the annual VTE incidence remained low and largely unchanged, the researchers say. For example, the rate was 2.6% in 2007 and 3.0% in 2011.

In fact, the investigators say, "If nonselective perioperative and in-hospital prophylaxis is not successful in reducing rates of in-hospital VTE over time, are we placing patients at undue risk without significant benefit? With almost 40% of VTE events occurring after discharge, this may represent an area for quality improvement implementation."

As Dr. Steele told Reuters Health by email, "Despite our best practices, a small percentage of patients may still develop a VTE."

Prophylaxis efforts have improved greatly in the preoperative and perioperative in-hospital settings, but "in the post-discharge setting, we likely need a much larger randomized prospective study involving patients with similar risk profiles evaluating extended prophylaxis versus none to demonstrate whether or not this is a benefit." TH

—Reuters Health

A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”

Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”

The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.

EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas. 

Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.

What is the diagnosis?

DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)

Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.

Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.

A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.

The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.

TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.

• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.

• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.

• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).

• Such patients need to be examined periodically for skin cancer.

• Younger patients with dermatoheliosis are well advised to use better sun protection. 

A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”

Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”

The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.

EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas. 

Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.

What is the diagnosis?

DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)

Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.

Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.

A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.

The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.

TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.

• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.

• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.

• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).

• Such patients need to be examined periodically for skin cancer.

• Younger patients with dermatoheliosis are well advised to use better sun protection. 

A 72-year-old man self-refers to dermatology at the insistence of his wife, who wants confirmation of her assertion that he needs to use a moisturizer on his arms. “They’re just so dry!” she says. “They’d look so much better if he’d use moisturizer every day, like I do.”

Her husband says he tried it and it didn’t help, so he stopped. “Besides, I can’t stand the greasy feeling it leaves behind!”

The patient claims to be in decent health aside from mild arthritis. He is retired from his job with the local power company, which kept him outdoors for many years. His employer required workers to wear long-sleeved khaki shirts, but, like all his fellow employees, the patient rolled up the sleeves in hot weather, exposing his forearms.

EXAMINATION
The patient has type II skin, blue eyes, and light brown hair. The skin on the dorsa of both arms is flecked with innumerable tan to orange macules from the mid forearms to (and including) the hands. Many old scars are seen in these same areas. 

Closer examination reveals that the skin in these areas is quite thin and dry. Fine telangiectasias and focal scaling are also noted. The effect is much less pronounced from about the elbow up and is totally absent on both volar forearms.

What is the diagnosis?

DISCUSSION
The patient’s admittedly dry skin is not his primary problem, and all the moisturizers in the world will not make much difference. The term we use for his problem is dermatoheliosis , literally “sun condition,” which includes predictable indicators of past overexposure to UV sources. Specific lesions include solar lentigines, the tan to orange freckles that are commonly called “age spots” or “liver spots.” (Given enough sun exposure, a 25-year-old can develop solar lentigines, so age is not the cause. Likewise, the liver is not involved at all.)

Chronic overexposure to the sun thins the skin (solar atrophy), making it more susceptible to minor trauma and resultant scarring and also making the tortuous red blood vessels (telangiectasias) visible. Other indications of sun damage include actinic keratoses (flaky white papules), solar elastosis (creamy yellow to white “chicken skin”), and solar purpura. The combination of these superimposed colors (white, red, tan, orange, pink) in the context of dermatoheliosis is sometimes termed poikilodermatous change.

Although dermatoheliosis is a problem in terms of the potential for skin cancer and for cosmetic reasons, it will not be helped much by moisturizers. Sunscreen, too, will have minimal impact so long after the damage has been done. Laser resurfacing could erase most of these skin changes, but it would also knock out all the normal skin pigment, making the area contrast sharply with the rest of the patient’s skin.

A combination of fade cream (4% hydroquinone, applied bid) and sunscreen could reduce the brown discoloration to a degree. Twice-daily application of 5-fluorouracil cream for two weeks would erase much of the redness, but only for a few months. Various other methods have been tried with modest success.

The main outcome of this patient’s visit was to establish the need for periodic examination. His wife’s opinion notwithstanding, the utility of moisturizers is dubious.

TAKE-HOME LEARNING POINTS
• Dermatoheliosis is the collective term for skin changes associated with chronic overexposure to the sun.

• The white, red, pink, and yellow discoloration seen on this kind of sun-damaged skin is known as poikilodermatous change.

• In addition to poikiloderma, patients with advanced dermatoheliosis also have solar atrophy, multiple scars, telangiectasias, actinic keratoses, dry skin, and often solar purpura.

• Moisturizers play a minimal role in treating dermatoheliosis (providing skin-smoothing effects, if anything).

• Such patients need to be examined periodically for skin cancer.

• Younger patients with dermatoheliosis are well advised to use better sun protection.