The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

The Food and Drug Administration has approved a deep brain stimulation system that has been shown to reduce seizures in a select group of patients with epilepsy.

• Medtronics DBS System for Epilepsy has been cleared as adjunct treatment for patients with partial onset seizures with or without secondary generalization.
• The system is only indicated for patients who have not responded to 3 or more antiepileptic drugs and who have experienced an average of 6 or more seizures each month for the last 3 months.
• The FDA approval also stipulates that the patients’ seizures be no more than 30 days apart.
• The DBS System includes a pulse generator that is implanted in a patient’s chest and 2 lead wires implanted in the brain.

Voelker R. Electrical stimulation for epilepsy. JAMA; 2018;319(21):2164.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Clinicians need to pay more attention to the psychological impact of epilepsy and its treatment according to a report from the International League Against Epilepsy Psychology Task Force.

• The task force identified the best interventions for depression, neurocognitive problems, and medication adherence.
• Several psychological strategies are worth consideration according to the task force, including cognitive behavioral therapy and mindfulness-based treatment.
• These interventions have the potential to improve health-related quality of life among adults and children.
• The recommendations outlined by the League are based primarily on evidence discussed in a recent Cochrane review of randomized clinical trials that evaluated psychological treatment of patients with epilepsy.

Michaelis R, Tang V, Goldstein LH, et al. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. 2018;59(7):1282-1302.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

Switching patients from brand name antiepileptic drugs to generics is generally safe and cost effective according to an analysis published in Epilepsia.

• Researchers looked at data on bioequivalence, health care utilization, and clinical studies on the safety of antiepileptic agents, including a comparison of area under the plasma concentration-time curve (AUC) and peak plasma concentration.
• For most of the drugs that were evaluated, there were negligible differences in AUC and peak plasma concentration between generic drugs and brand name equivalents.
• There were significant increases in health care usage when patients were switched from brand name to generic versions.
• Clinical studies were unable to detect differences in seizure frequency or tolerability.

Holtkamp M, Theodore WH. Generic antiepileptic drugs—safe or harmful in patients with epilepsy? Epilepsia. 2018;59(7):1273-1281.

WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.

“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.

In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.

In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.

From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.

An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.

“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”

Courtesy Linda Moffat

“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.

The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.

The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”

But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.

Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.

The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.

Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.

The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.

The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.

Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.

Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.

The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.

But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.

Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.

[email protected]

WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.

“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.

In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.

In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.

From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.

An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.

“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”

Courtesy Linda Moffat

“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.

The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.

The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”

But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.

Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.

The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.

Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.

The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.

The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.

Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.

Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.

The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.

But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.

Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.

[email protected]

WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.

“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.

In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.

In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.

From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.

An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.

“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”

Courtesy Linda Moffat

“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.

The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.

The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”

But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.

Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.

The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.

Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.

The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.

The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.

Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.

Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.

The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.

But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.

Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.

[email protected]

A new index of frailty predicts survival in older patients with multiple myeloma based on accumulation of aging-associated deficits, rather than chronological age alone, investigators report. A 16% increased risk of death was seen for each 10% increase in the deficit-accumulation frailty index (DAFI), which includes 25 variables related health, function, and activities of daily living.

There was only a weak correlation between chronological age and increase in deficits tracked by the index, in contrast to a cohort without cancer, in which age and frailty were strongly correlated, the investigators reported in JCO Clinical Cancer Informatics.

“Our results demonstrate that, for patients with multiple myeloma, chronological age alone is not a good measure for assessing overall health,” study author Tanya M. Wildes, MD, of Washington University, St. Louis, said in a news release from the American Society of Clinical Oncology.

Existing tools to assess frailty include an index proposed by the International Myeloma Working Group that looks at age plus other indexes related to comorbidities and activities of daily living, and the revised Myeloma Comorbidity Index that incorporates age with other prognostic factors.

“Although both tools provide prognostic information, chronological age automatically increases frailty without taking biologic or functional age into account,” Dr. Wildes and her coauthors wrote in their report.

By contrast, the DAFI is based on the concept of biologic age, in which the health status of an individual is measured based on the proportion of aging-associated deficits they have accumulated, according to the authors.

To create the DAFI, Dr. Wildes and her colleagues analyzed nearly 2.7 million records of noncancer patients aged 66 years or older in the SEER Medicare Health Outcomes Survey (MHOS) database. They identified 25 variables in the database representing chronic health conditions, activities of daily living, functioning, mental health, and general health.

An individual’s DAFI score was calculated as the sum of scores for each of the 25 variables as 0 for absent, 0.5 for limited, and 1 for present. Predicted DAFI means were calculated for each year of age and used to create age-specific cut points to determine whether an individual would be considered frail or not versus others of the same age.

“In other words, the same frailty score may qualify an 80-year-old individual as fit and a 70-year-old as frail, depending on the cutoff for their respective age group,” investigators explained in their report.

They applied the index to 305 patients with newly diagnosed myeloma in the SEER-MHOS database who were 66 years of age or older (median age, 76 years) and had completed the survey within 1 year of diagnosis.

The DAFI classified 52% of the myeloma patients as frail, and for that group, median overall survival was 26.8 months, versus 43.7 months for nonfrail patients (P = .015), according to the reported data. For each 10% increase in score, the risk of death increased by 16% (P less than .001).

Notably, advancing age was very weakly correlated with increased age-related deficits in the myeloma cohort (r2 = 0.15; P = .010), according to investigators, but very strongly correlated with deficits in the cohort of noncancer patients (r2 = 0.98; P less than .001).

“This suggests that, in patients with multiple myeloma, the prevalence of impairments across domains of function, chronic comorbidities, general health, and mental health are more related to the overall burden of myeloma rather than chronological age alone,” the investigators wrote.

The information used to calculate a DAFI score is easily obtainable during a clinic visit, according to the authors, who provided an overview of all 25 variables in the journal article.

Further development of a computerized program would further enhance usability in the clinic, allowing for real-time calculation during a patient visit, they said.

Survivorship expert Merry Jennifer Markham, MD, said in the ASCO news release that this frailty index is notable because it accounts for more than just chronological age. “Knowing this information can help oncologists have more informed discussions with patients about their prognosis, which in turn can empower patients and families as they weigh treatment options,” she said.

The research was supported by National Cancer Institute. Dr. Wildes reported honoraria from Carevive Systems and research funding from Janssen Oncology. Another coauthor reported honoraria from Celgene and Janssen, and a consulting or advisory role with Amgen and Takeda.

 

SOURCE: Mian HS et al. JCO Clin Cancer Inform. 2018 Jul 25. 2018 Jul 25. doi: 10.1200/CCI.18.00043.

A new index of frailty predicts survival in older patients with multiple myeloma based on accumulation of aging-associated deficits, rather than chronological age alone, investigators report. A 16% increased risk of death was seen for each 10% increase in the deficit-accumulation frailty index (DAFI), which includes 25 variables related health, function, and activities of daily living.

There was only a weak correlation between chronological age and increase in deficits tracked by the index, in contrast to a cohort without cancer, in which age and frailty were strongly correlated, the investigators reported in JCO Clinical Cancer Informatics.

“Our results demonstrate that, for patients with multiple myeloma, chronological age alone is not a good measure for assessing overall health,” study author Tanya M. Wildes, MD, of Washington University, St. Louis, said in a news release from the American Society of Clinical Oncology.

Existing tools to assess frailty include an index proposed by the International Myeloma Working Group that looks at age plus other indexes related to comorbidities and activities of daily living, and the revised Myeloma Comorbidity Index that incorporates age with other prognostic factors.

“Although both tools provide prognostic information, chronological age automatically increases frailty without taking biologic or functional age into account,” Dr. Wildes and her coauthors wrote in their report.

By contrast, the DAFI is based on the concept of biologic age, in which the health status of an individual is measured based on the proportion of aging-associated deficits they have accumulated, according to the authors.

To create the DAFI, Dr. Wildes and her colleagues analyzed nearly 2.7 million records of noncancer patients aged 66 years or older in the SEER Medicare Health Outcomes Survey (MHOS) database. They identified 25 variables in the database representing chronic health conditions, activities of daily living, functioning, mental health, and general health.

An individual’s DAFI score was calculated as the sum of scores for each of the 25 variables as 0 for absent, 0.5 for limited, and 1 for present. Predicted DAFI means were calculated for each year of age and used to create age-specific cut points to determine whether an individual would be considered frail or not versus others of the same age.

“In other words, the same frailty score may qualify an 80-year-old individual as fit and a 70-year-old as frail, depending on the cutoff for their respective age group,” investigators explained in their report.

They applied the index to 305 patients with newly diagnosed myeloma in the SEER-MHOS database who were 66 years of age or older (median age, 76 years) and had completed the survey within 1 year of diagnosis.

The DAFI classified 52% of the myeloma patients as frail, and for that group, median overall survival was 26.8 months, versus 43.7 months for nonfrail patients (P = .015), according to the reported data. For each 10% increase in score, the risk of death increased by 16% (P less than .001).

Notably, advancing age was very weakly correlated with increased age-related deficits in the myeloma cohort (r2 = 0.15; P = .010), according to investigators, but very strongly correlated with deficits in the cohort of noncancer patients (r2 = 0.98; P less than .001).

“This suggests that, in patients with multiple myeloma, the prevalence of impairments across domains of function, chronic comorbidities, general health, and mental health are more related to the overall burden of myeloma rather than chronological age alone,” the investigators wrote.

The information used to calculate a DAFI score is easily obtainable during a clinic visit, according to the authors, who provided an overview of all 25 variables in the journal article.

Further development of a computerized program would further enhance usability in the clinic, allowing for real-time calculation during a patient visit, they said.

Survivorship expert Merry Jennifer Markham, MD, said in the ASCO news release that this frailty index is notable because it accounts for more than just chronological age. “Knowing this information can help oncologists have more informed discussions with patients about their prognosis, which in turn can empower patients and families as they weigh treatment options,” she said.

The research was supported by National Cancer Institute. Dr. Wildes reported honoraria from Carevive Systems and research funding from Janssen Oncology. Another coauthor reported honoraria from Celgene and Janssen, and a consulting or advisory role with Amgen and Takeda.

 

SOURCE: Mian HS et al. JCO Clin Cancer Inform. 2018 Jul 25. 2018 Jul 25. doi: 10.1200/CCI.18.00043.

A new index of frailty predicts survival in older patients with multiple myeloma based on accumulation of aging-associated deficits, rather than chronological age alone, investigators report. A 16% increased risk of death was seen for each 10% increase in the deficit-accumulation frailty index (DAFI), which includes 25 variables related health, function, and activities of daily living.

There was only a weak correlation between chronological age and increase in deficits tracked by the index, in contrast to a cohort without cancer, in which age and frailty were strongly correlated, the investigators reported in JCO Clinical Cancer Informatics.

“Our results demonstrate that, for patients with multiple myeloma, chronological age alone is not a good measure for assessing overall health,” study author Tanya M. Wildes, MD, of Washington University, St. Louis, said in a news release from the American Society of Clinical Oncology.

Existing tools to assess frailty include an index proposed by the International Myeloma Working Group that looks at age plus other indexes related to comorbidities and activities of daily living, and the revised Myeloma Comorbidity Index that incorporates age with other prognostic factors.

“Although both tools provide prognostic information, chronological age automatically increases frailty without taking biologic or functional age into account,” Dr. Wildes and her coauthors wrote in their report.

By contrast, the DAFI is based on the concept of biologic age, in which the health status of an individual is measured based on the proportion of aging-associated deficits they have accumulated, according to the authors.

To create the DAFI, Dr. Wildes and her colleagues analyzed nearly 2.7 million records of noncancer patients aged 66 years or older in the SEER Medicare Health Outcomes Survey (MHOS) database. They identified 25 variables in the database representing chronic health conditions, activities of daily living, functioning, mental health, and general health.

An individual’s DAFI score was calculated as the sum of scores for each of the 25 variables as 0 for absent, 0.5 for limited, and 1 for present. Predicted DAFI means were calculated for each year of age and used to create age-specific cut points to determine whether an individual would be considered frail or not versus others of the same age.

“In other words, the same frailty score may qualify an 80-year-old individual as fit and a 70-year-old as frail, depending on the cutoff for their respective age group,” investigators explained in their report.

They applied the index to 305 patients with newly diagnosed myeloma in the SEER-MHOS database who were 66 years of age or older (median age, 76 years) and had completed the survey within 1 year of diagnosis.

The DAFI classified 52% of the myeloma patients as frail, and for that group, median overall survival was 26.8 months, versus 43.7 months for nonfrail patients (P = .015), according to the reported data. For each 10% increase in score, the risk of death increased by 16% (P less than .001).

Notably, advancing age was very weakly correlated with increased age-related deficits in the myeloma cohort (r2 = 0.15; P = .010), according to investigators, but very strongly correlated with deficits in the cohort of noncancer patients (r2 = 0.98; P less than .001).

“This suggests that, in patients with multiple myeloma, the prevalence of impairments across domains of function, chronic comorbidities, general health, and mental health are more related to the overall burden of myeloma rather than chronological age alone,” the investigators wrote.

The information used to calculate a DAFI score is easily obtainable during a clinic visit, according to the authors, who provided an overview of all 25 variables in the journal article.

Further development of a computerized program would further enhance usability in the clinic, allowing for real-time calculation during a patient visit, they said.

Survivorship expert Merry Jennifer Markham, MD, said in the ASCO news release that this frailty index is notable because it accounts for more than just chronological age. “Knowing this information can help oncologists have more informed discussions with patients about their prognosis, which in turn can empower patients and families as they weigh treatment options,” she said.

The research was supported by National Cancer Institute. Dr. Wildes reported honoraria from Carevive Systems and research funding from Janssen Oncology. Another coauthor reported honoraria from Celgene and Janssen, and a consulting or advisory role with Amgen and Takeda.

 

SOURCE: Mian HS et al. JCO Clin Cancer Inform. 2018 Jul 25. 2018 Jul 25. doi: 10.1200/CCI.18.00043.

Benzodiazepines’ potential antidepressant properties and their role in the treatment of depression were fairly extensively examined during the 1980s and early 1990s. There were various reasons for this investigation—from the adverse effects of available antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors) to the delay of action of the existing antidepressants and treatment resistance of a significant portion of depressed patients. Benzodiazepines had already been used in the treatment of depressive disorders for decades, but not as monotherapy or main treatment agents, but rather in combination with existing antidepressants to alleviate initial or persistent anxiety, and to help with insomnia. Some authors¹ felt that specific benzodiazepines, such as alprazolam, were effective in mild and moderate depression, although not as effective as TCAs for patients with endogenous or melancholic depression. Others² proposed that benzodiazepines, particularly alprazolam, may be a useful treatment option for patients for whom antidepressants are contraindicated, poorly tolerated, or ineffective. Petty et al² suggested that the antidepressant efficacy of benzodiazepines was consistent with the then-entertained γ-aminobutyric acid theory of depression.

A shift from benzodiazepines to antidepressants

The evidence for using benzodiazepines in anxious depression was based on results of several studies, but it has not been adequately analyzed, summarized, and promoted. Then, after the arrival of the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine arrived in the United States in 1987, and paroxetine and sertraline arrived in 1992), interest in benzodiazepines gradually waned. Within a few years, the SSRIs were also approved for various anxiety disorders. The SSRIs were heavily promoted not only for the treatment of depressive disorders, but also anxiety disorders, and were touted as well-tolerated medications without abuse potential. Benzodiazepines, on the other hand, were frequently described as less effective and having a substantial abuse potential.

Looking back, these claims were not properly substantiated. Berney et al³ concluded in a systematic review that comparative data of a high level of proof for using newer antidepressants in anxiety disorders rather that benzodiazepines were not available. Then, 5 years later, Offidani et al⁴ demonstrated in a systematic review and meta-analysis that benzodiazepines were more effective and better tolerated in the treatment of various anxiety disorders than TCAs. In addition, in a few studies comparing benzodiazepines with newer antidepressants such as paroxetine and venlafaxine, benzodiazepines were either comparable or showed greater improvement and fewer adverse effects that these antidepressants. Similarly to Berney et al,³ Offidani et al⁴ concluded that the change in the prescribing pattern favoring newer antidepressants over benzodiazepines for the treatment of anxiety disorders occurred without supporting evidence.

As far as abuse potential, the American Psychiatric Association Task Force on Benzodiazepine Dependency concluded that benzodiazepines do not strongly reinforce their own use and are not widely abused.⁵ When abuse occurs, it is almost always in the context of abusing other substances. The Task Force also noted that physiological dependence develops when benzodiazepines are used chronically; dependence being defined mostly in terms of symptoms of discontinuance.⁵ Thus, benzodiazepines need to be used appropriately, not in extremely high doses, and under medical supervision.

Nevertheless, the judgment, right or wrong, was out—benzodiazepines were deemed problematic and to be avoided. This has become, unfortunately, a pattern of many prescribing psychiatrists’ practice.

What about benzodiazepines for anxious depression?

Recently Benasi et al⁶ filled the void by investigating data from studies using benzodiazepines as monotherapy in depressive disorders (I was one of the co-authors of this study). They conducted a systematic review of 38 published randomized controlled trials that used benzodiazepines as a monotherapy vs placebo, antidepressants, or both. Patients in these trials were primarily diagnosed with depressive disorder or anxious depression. The majority of these studies used alprazolam as the benzodiazepine (other benzodiazepines used were adinazolam, bromazepam, chlordiazepoxide, and lorazepam) and imipramine or amitriptyline as the antidepressant comparator (other antidepressants used were desipramine, dothiepin, doxepin, and only one newer antidepressant, fluvoxamine, in one study). There was a lack of significant differences in response rate between benzodiazepines and placebo, and between benzodiazepines and TCAs.

In more than half of the studies comparing benzodiazepines with TCAs and/or placebo, benzodiazepines were significantly more effective than placebo and as effective as TCAs. In 11 studies, TCAs were better than benzodiazepines, while benzodiazepines were better than TCAs in one study. In 12 studies, benzodiazepines were associated with a faster onset of action than TCAs. Adverse effects occurred more frequently with TCAs, with the exception of drowsiness and cognitive impairment, which occurred more frequently with benzodiazepines. The findings of the meta-analysis (22 studies) confirmed the low response of anxious depression to psychotropic medications, whether TCAs or benzodiazepines. There was no demonstrated superiority of antidepressants over benzodiazepines for anxious depression. Thus, clearly, benzodiazepines are a bona fide therapeutic option for anxious depression and so far, there is no indication that antidepressants are preferable for this indication.

Continue to: However, it is important to note...

However, it is important to note that there are almost no studies comparing benzodiazepines to newer antidepressants for anxious depression. One double-blind 6-week study of 112 patients⁷ compared fluvoxamine with lorazepam for mixed anxiety and depression in general practice. There were no significant differences between treatments at any point in the study. Lorazepam produced more sedation, while fluvoxamine produced more nausea and vomiting.

We clearly need randomized controlled trials comparing benzodiazepines with newer antidepressants in anxious depression. However, as in the case with anxiety disorders, these types of trials are strikingly missing.

Any clinical wisdom?

Anxiety could be a serious clinical problem in the treatment of patients with depressive disorder(s). We have not always paid enough attention to anxiety and related issues in depressed patients. Interestingly, anxiety has not been listed among symptoms of major depression disorder (MDD) in several editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Only and finally did DSM-5⁸ add a specifier “with anxious distress” for both MDD and persistent depressive disorder (dysthymia), although this specifier still avoids the word “anxiety” in the description of its symptomatology.

It is difficult to disentangle whether the anxiety is part of depressive disorder symptomatology or whether it is a comorbid anxiety disorder. As I noted in a previous article,⁹ psychiatric comorbidity is a confusing phenomenon. Nevertheless, anxiety and depression are highly comorbid or co-symptomatologic. In a study by Kessler et al,¹⁰ 45.7% of survey responders with lifetime MDD had ≥1 lifetime anxiety disorder. Similarly, in a STAR*D study,¹¹ in Level 1, 53.2% of patients had anxious depression.

Kessler et al¹⁰ raised an interesting question about the importance of temporally primary anxiety disorders as risk markers vs causal risk factors for the onset and persistence of subsequent MDD, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence. As is well-known, mood disorders should be treated as soon as possible after they are diagnosed, and should be treated vigorously, addressing the major symptomatology.

Continue to: These findings emphasize the need to...

These findings emphasize the need to pay more attention to anxiety in depressed patients (especially those newly diagnosed) and for forceful treatment of anxious depression. Importantly, in the STAR*D study,¹¹ remission in anxious Level 1 (treated with citalopram) depressed patients was significantly less likely and took longer to occur than in patients with nonanxious depression. In addition, ratings of adverse effects frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2 (either switched to bupropion, sertraline or venlafaxine, or citalopram augmented with bupropion or buspirone), patients with anxious depression fared significantly worse in both the switching and augmentation options. One wonders if Level 1 patients treated with benzodiazepines, and Level 2 patients switched to benzodiazepines or offered augmentation with them would not have fared better, especially in view of the fact that many old and new antidepressants have significant adverse effects and are difficult to discontinue due to withdrawal symptoms such as dizziness, vertigo, and, in case of newer antidepressants, brain “zaps.” Benzodiazepines certainly have serious withdrawal symptoms, including anxiety, rebound insomnia, and withdrawal seizures, especially when discontinued abruptly and when the dose was high. Thus, as is the case for many other medications (eg, steroids, anticoagulants, and some antidepressants), benzodiazepines must be tapered carefully in order to avoid discontinuance signs and symptoms. Because benzodiazepines have been involved in nearly one-third of overdose-related deaths (either separately or in combination with opioids), and the FDA strongly warns against co-prescribing benzodiazepines and opioids, they need to be prescribed appropriately, carefully weighing their risks and benefits.¹²

Because the analysis by Benasi et al⁶ demonstrated that benzodiazepines seem comparably effective as antidepressants in anxious depression, we should be considering using benzodiazepines as monotherapy for this indication more frequently and vigorously, considering their similar efficacy, faster onset of action, and better tolerability, while also considering their risks. Clinicians use them in combinations anyway. We also need rigorous trials comparing benzodiazepines with newer antidepressants for anxious depression.

Benzodiazepines’ potential antidepressant properties and their role in the treatment of depression were fairly extensively examined during the 1980s and early 1990s. There were various reasons for this investigation—from the adverse effects of available antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors) to the delay of action of the existing antidepressants and treatment resistance of a significant portion of depressed patients. Benzodiazepines had already been used in the treatment of depressive disorders for decades, but not as monotherapy or main treatment agents, but rather in combination with existing antidepressants to alleviate initial or persistent anxiety, and to help with insomnia. Some authors¹ felt that specific benzodiazepines, such as alprazolam, were effective in mild and moderate depression, although not as effective as TCAs for patients with endogenous or melancholic depression. Others² proposed that benzodiazepines, particularly alprazolam, may be a useful treatment option for patients for whom antidepressants are contraindicated, poorly tolerated, or ineffective. Petty et al² suggested that the antidepressant efficacy of benzodiazepines was consistent with the then-entertained γ-aminobutyric acid theory of depression.

A shift from benzodiazepines to antidepressants

The evidence for using benzodiazepines in anxious depression was based on results of several studies, but it has not been adequately analyzed, summarized, and promoted. Then, after the arrival of the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine arrived in the United States in 1987, and paroxetine and sertraline arrived in 1992), interest in benzodiazepines gradually waned. Within a few years, the SSRIs were also approved for various anxiety disorders. The SSRIs were heavily promoted not only for the treatment of depressive disorders, but also anxiety disorders, and were touted as well-tolerated medications without abuse potential. Benzodiazepines, on the other hand, were frequently described as less effective and having a substantial abuse potential.

Looking back, these claims were not properly substantiated. Berney et al³ concluded in a systematic review that comparative data of a high level of proof for using newer antidepressants in anxiety disorders rather that benzodiazepines were not available. Then, 5 years later, Offidani et al⁴ demonstrated in a systematic review and meta-analysis that benzodiazepines were more effective and better tolerated in the treatment of various anxiety disorders than TCAs. In addition, in a few studies comparing benzodiazepines with newer antidepressants such as paroxetine and venlafaxine, benzodiazepines were either comparable or showed greater improvement and fewer adverse effects that these antidepressants. Similarly to Berney et al,³ Offidani et al⁴ concluded that the change in the prescribing pattern favoring newer antidepressants over benzodiazepines for the treatment of anxiety disorders occurred without supporting evidence.

As far as abuse potential, the American Psychiatric Association Task Force on Benzodiazepine Dependency concluded that benzodiazepines do not strongly reinforce their own use and are not widely abused.⁵ When abuse occurs, it is almost always in the context of abusing other substances. The Task Force also noted that physiological dependence develops when benzodiazepines are used chronically; dependence being defined mostly in terms of symptoms of discontinuance.⁵ Thus, benzodiazepines need to be used appropriately, not in extremely high doses, and under medical supervision.

Nevertheless, the judgment, right or wrong, was out—benzodiazepines were deemed problematic and to be avoided. This has become, unfortunately, a pattern of many prescribing psychiatrists’ practice.

What about benzodiazepines for anxious depression?

Recently Benasi et al⁶ filled the void by investigating data from studies using benzodiazepines as monotherapy in depressive disorders (I was one of the co-authors of this study). They conducted a systematic review of 38 published randomized controlled trials that used benzodiazepines as a monotherapy vs placebo, antidepressants, or both. Patients in these trials were primarily diagnosed with depressive disorder or anxious depression. The majority of these studies used alprazolam as the benzodiazepine (other benzodiazepines used were adinazolam, bromazepam, chlordiazepoxide, and lorazepam) and imipramine or amitriptyline as the antidepressant comparator (other antidepressants used were desipramine, dothiepin, doxepin, and only one newer antidepressant, fluvoxamine, in one study). There was a lack of significant differences in response rate between benzodiazepines and placebo, and between benzodiazepines and TCAs.

In more than half of the studies comparing benzodiazepines with TCAs and/or placebo, benzodiazepines were significantly more effective than placebo and as effective as TCAs. In 11 studies, TCAs were better than benzodiazepines, while benzodiazepines were better than TCAs in one study. In 12 studies, benzodiazepines were associated with a faster onset of action than TCAs. Adverse effects occurred more frequently with TCAs, with the exception of drowsiness and cognitive impairment, which occurred more frequently with benzodiazepines. The findings of the meta-analysis (22 studies) confirmed the low response of anxious depression to psychotropic medications, whether TCAs or benzodiazepines. There was no demonstrated superiority of antidepressants over benzodiazepines for anxious depression. Thus, clearly, benzodiazepines are a bona fide therapeutic option for anxious depression and so far, there is no indication that antidepressants are preferable for this indication.

Continue to: However, it is important to note...

However, it is important to note that there are almost no studies comparing benzodiazepines to newer antidepressants for anxious depression. One double-blind 6-week study of 112 patients⁷ compared fluvoxamine with lorazepam for mixed anxiety and depression in general practice. There were no significant differences between treatments at any point in the study. Lorazepam produced more sedation, while fluvoxamine produced more nausea and vomiting.

We clearly need randomized controlled trials comparing benzodiazepines with newer antidepressants in anxious depression. However, as in the case with anxiety disorders, these types of trials are strikingly missing.

Any clinical wisdom?

Anxiety could be a serious clinical problem in the treatment of patients with depressive disorder(s). We have not always paid enough attention to anxiety and related issues in depressed patients. Interestingly, anxiety has not been listed among symptoms of major depression disorder (MDD) in several editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Only and finally did DSM-5⁸ add a specifier “with anxious distress” for both MDD and persistent depressive disorder (dysthymia), although this specifier still avoids the word “anxiety” in the description of its symptomatology.

It is difficult to disentangle whether the anxiety is part of depressive disorder symptomatology or whether it is a comorbid anxiety disorder. As I noted in a previous article,⁹ psychiatric comorbidity is a confusing phenomenon. Nevertheless, anxiety and depression are highly comorbid or co-symptomatologic. In a study by Kessler et al,¹⁰ 45.7% of survey responders with lifetime MDD had ≥1 lifetime anxiety disorder. Similarly, in a STAR*D study,¹¹ in Level 1, 53.2% of patients had anxious depression.

Kessler et al¹⁰ raised an interesting question about the importance of temporally primary anxiety disorders as risk markers vs causal risk factors for the onset and persistence of subsequent MDD, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence. As is well-known, mood disorders should be treated as soon as possible after they are diagnosed, and should be treated vigorously, addressing the major symptomatology.

Continue to: These findings emphasize the need to...

These findings emphasize the need to pay more attention to anxiety in depressed patients (especially those newly diagnosed) and for forceful treatment of anxious depression. Importantly, in the STAR*D study,¹¹ remission in anxious Level 1 (treated with citalopram) depressed patients was significantly less likely and took longer to occur than in patients with nonanxious depression. In addition, ratings of adverse effects frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2 (either switched to bupropion, sertraline or venlafaxine, or citalopram augmented with bupropion or buspirone), patients with anxious depression fared significantly worse in both the switching and augmentation options. One wonders if Level 1 patients treated with benzodiazepines, and Level 2 patients switched to benzodiazepines or offered augmentation with them would not have fared better, especially in view of the fact that many old and new antidepressants have significant adverse effects and are difficult to discontinue due to withdrawal symptoms such as dizziness, vertigo, and, in case of newer antidepressants, brain “zaps.” Benzodiazepines certainly have serious withdrawal symptoms, including anxiety, rebound insomnia, and withdrawal seizures, especially when discontinued abruptly and when the dose was high. Thus, as is the case for many other medications (eg, steroids, anticoagulants, and some antidepressants), benzodiazepines must be tapered carefully in order to avoid discontinuance signs and symptoms. Because benzodiazepines have been involved in nearly one-third of overdose-related deaths (either separately or in combination with opioids), and the FDA strongly warns against co-prescribing benzodiazepines and opioids, they need to be prescribed appropriately, carefully weighing their risks and benefits.¹²

Because the analysis by Benasi et al⁶ demonstrated that benzodiazepines seem comparably effective as antidepressants in anxious depression, we should be considering using benzodiazepines as monotherapy for this indication more frequently and vigorously, considering their similar efficacy, faster onset of action, and better tolerability, while also considering their risks. Clinicians use them in combinations anyway. We also need rigorous trials comparing benzodiazepines with newer antidepressants for anxious depression.

Benzodiazepines’ potential antidepressant properties and their role in the treatment of depression were fairly extensively examined during the 1980s and early 1990s. There were various reasons for this investigation—from the adverse effects of available antidepressants (tricyclic antidepressants [TCAs] and monoamine oxidase inhibitors) to the delay of action of the existing antidepressants and treatment resistance of a significant portion of depressed patients. Benzodiazepines had already been used in the treatment of depressive disorders for decades, but not as monotherapy or main treatment agents, but rather in combination with existing antidepressants to alleviate initial or persistent anxiety, and to help with insomnia. Some authors¹ felt that specific benzodiazepines, such as alprazolam, were effective in mild and moderate depression, although not as effective as TCAs for patients with endogenous or melancholic depression. Others² proposed that benzodiazepines, particularly alprazolam, may be a useful treatment option for patients for whom antidepressants are contraindicated, poorly tolerated, or ineffective. Petty et al² suggested that the antidepressant efficacy of benzodiazepines was consistent with the then-entertained γ-aminobutyric acid theory of depression.

A shift from benzodiazepines to antidepressants

The evidence for using benzodiazepines in anxious depression was based on results of several studies, but it has not been adequately analyzed, summarized, and promoted. Then, after the arrival of the selective serotonin reuptake inhibitors (SSRIs) (fluoxetine arrived in the United States in 1987, and paroxetine and sertraline arrived in 1992), interest in benzodiazepines gradually waned. Within a few years, the SSRIs were also approved for various anxiety disorders. The SSRIs were heavily promoted not only for the treatment of depressive disorders, but also anxiety disorders, and were touted as well-tolerated medications without abuse potential. Benzodiazepines, on the other hand, were frequently described as less effective and having a substantial abuse potential.

Looking back, these claims were not properly substantiated. Berney et al³ concluded in a systematic review that comparative data of a high level of proof for using newer antidepressants in anxiety disorders rather that benzodiazepines were not available. Then, 5 years later, Offidani et al⁴ demonstrated in a systematic review and meta-analysis that benzodiazepines were more effective and better tolerated in the treatment of various anxiety disorders than TCAs. In addition, in a few studies comparing benzodiazepines with newer antidepressants such as paroxetine and venlafaxine, benzodiazepines were either comparable or showed greater improvement and fewer adverse effects that these antidepressants. Similarly to Berney et al,³ Offidani et al⁴ concluded that the change in the prescribing pattern favoring newer antidepressants over benzodiazepines for the treatment of anxiety disorders occurred without supporting evidence.

As far as abuse potential, the American Psychiatric Association Task Force on Benzodiazepine Dependency concluded that benzodiazepines do not strongly reinforce their own use and are not widely abused.⁵ When abuse occurs, it is almost always in the context of abusing other substances. The Task Force also noted that physiological dependence develops when benzodiazepines are used chronically; dependence being defined mostly in terms of symptoms of discontinuance.⁵ Thus, benzodiazepines need to be used appropriately, not in extremely high doses, and under medical supervision.

Nevertheless, the judgment, right or wrong, was out—benzodiazepines were deemed problematic and to be avoided. This has become, unfortunately, a pattern of many prescribing psychiatrists’ practice.

What about benzodiazepines for anxious depression?

Recently Benasi et al⁶ filled the void by investigating data from studies using benzodiazepines as monotherapy in depressive disorders (I was one of the co-authors of this study). They conducted a systematic review of 38 published randomized controlled trials that used benzodiazepines as a monotherapy vs placebo, antidepressants, or both. Patients in these trials were primarily diagnosed with depressive disorder or anxious depression. The majority of these studies used alprazolam as the benzodiazepine (other benzodiazepines used were adinazolam, bromazepam, chlordiazepoxide, and lorazepam) and imipramine or amitriptyline as the antidepressant comparator (other antidepressants used were desipramine, dothiepin, doxepin, and only one newer antidepressant, fluvoxamine, in one study). There was a lack of significant differences in response rate between benzodiazepines and placebo, and between benzodiazepines and TCAs.

In more than half of the studies comparing benzodiazepines with TCAs and/or placebo, benzodiazepines were significantly more effective than placebo and as effective as TCAs. In 11 studies, TCAs were better than benzodiazepines, while benzodiazepines were better than TCAs in one study. In 12 studies, benzodiazepines were associated with a faster onset of action than TCAs. Adverse effects occurred more frequently with TCAs, with the exception of drowsiness and cognitive impairment, which occurred more frequently with benzodiazepines. The findings of the meta-analysis (22 studies) confirmed the low response of anxious depression to psychotropic medications, whether TCAs or benzodiazepines. There was no demonstrated superiority of antidepressants over benzodiazepines for anxious depression. Thus, clearly, benzodiazepines are a bona fide therapeutic option for anxious depression and so far, there is no indication that antidepressants are preferable for this indication.

Continue to: However, it is important to note...

However, it is important to note that there are almost no studies comparing benzodiazepines to newer antidepressants for anxious depression. One double-blind 6-week study of 112 patients⁷ compared fluvoxamine with lorazepam for mixed anxiety and depression in general practice. There were no significant differences between treatments at any point in the study. Lorazepam produced more sedation, while fluvoxamine produced more nausea and vomiting.

We clearly need randomized controlled trials comparing benzodiazepines with newer antidepressants in anxious depression. However, as in the case with anxiety disorders, these types of trials are strikingly missing.

Any clinical wisdom?

Anxiety could be a serious clinical problem in the treatment of patients with depressive disorder(s). We have not always paid enough attention to anxiety and related issues in depressed patients. Interestingly, anxiety has not been listed among symptoms of major depression disorder (MDD) in several editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Only and finally did DSM-5⁸ add a specifier “with anxious distress” for both MDD and persistent depressive disorder (dysthymia), although this specifier still avoids the word “anxiety” in the description of its symptomatology.

It is difficult to disentangle whether the anxiety is part of depressive disorder symptomatology or whether it is a comorbid anxiety disorder. As I noted in a previous article,⁹ psychiatric comorbidity is a confusing phenomenon. Nevertheless, anxiety and depression are highly comorbid or co-symptomatologic. In a study by Kessler et al,¹⁰ 45.7% of survey responders with lifetime MDD had ≥1 lifetime anxiety disorder. Similarly, in a STAR*D study,¹¹ in Level 1, 53.2% of patients had anxious depression.

Kessler et al¹⁰ raised an interesting question about the importance of temporally primary anxiety disorders as risk markers vs causal risk factors for the onset and persistence of subsequent MDD, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence. As is well-known, mood disorders should be treated as soon as possible after they are diagnosed, and should be treated vigorously, addressing the major symptomatology.

Continue to: These findings emphasize the need to...

These findings emphasize the need to pay more attention to anxiety in depressed patients (especially those newly diagnosed) and for forceful treatment of anxious depression. Importantly, in the STAR*D study,¹¹ remission in anxious Level 1 (treated with citalopram) depressed patients was significantly less likely and took longer to occur than in patients with nonanxious depression. In addition, ratings of adverse effects frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2 (either switched to bupropion, sertraline or venlafaxine, or citalopram augmented with bupropion or buspirone), patients with anxious depression fared significantly worse in both the switching and augmentation options. One wonders if Level 1 patients treated with benzodiazepines, and Level 2 patients switched to benzodiazepines or offered augmentation with them would not have fared better, especially in view of the fact that many old and new antidepressants have significant adverse effects and are difficult to discontinue due to withdrawal symptoms such as dizziness, vertigo, and, in case of newer antidepressants, brain “zaps.” Benzodiazepines certainly have serious withdrawal symptoms, including anxiety, rebound insomnia, and withdrawal seizures, especially when discontinued abruptly and when the dose was high. Thus, as is the case for many other medications (eg, steroids, anticoagulants, and some antidepressants), benzodiazepines must be tapered carefully in order to avoid discontinuance signs and symptoms. Because benzodiazepines have been involved in nearly one-third of overdose-related deaths (either separately or in combination with opioids), and the FDA strongly warns against co-prescribing benzodiazepines and opioids, they need to be prescribed appropriately, carefully weighing their risks and benefits.¹²

Because the analysis by Benasi et al⁶ demonstrated that benzodiazepines seem comparably effective as antidepressants in anxious depression, we should be considering using benzodiazepines as monotherapy for this indication more frequently and vigorously, considering their similar efficacy, faster onset of action, and better tolerability, while also considering their risks. Clinicians use them in combinations anyway. We also need rigorous trials comparing benzodiazepines with newer antidepressants for anxious depression.

Cannabis did not improve outcomes or reduce prescription opioid use among 1,514 Australians with noncancer pain, according to a recent report in Lancet Public Health.

Smithore

[email protected]

SOURCE: Campbell G et al. Lancet Public Health. 2018 Jul. doi: 10.1016/S2468-2667(18)30110-5.

Cannabis did not improve outcomes or reduce prescription opioid use among 1,514 Australians with noncancer pain, according to a recent report in Lancet Public Health.

Smithore

[email protected]

SOURCE: Campbell G et al. Lancet Public Health. 2018 Jul. doi: 10.1016/S2468-2667(18)30110-5.

Cannabis did not improve outcomes or reduce prescription opioid use among 1,514 Australians with noncancer pain, according to a recent report in Lancet Public Health.

Smithore

[email protected]

SOURCE: Campbell G et al. Lancet Public Health. 2018 Jul. doi: 10.1016/S2468-2667(18)30110-5.

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.¹ Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.²

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.³

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.⁴ This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.^5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.⁷

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.^8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.^2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.¹³ Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.¹⁴ These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.^15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

• acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
• erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence^4,15
• pyrexia: body temperature greater than 100.4°F
• history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
• tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
• unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall¹⁸
• leukocytosis: white blood cell count greater than 10.0×10⁹/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ² analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ² analysis (Table 3).

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.^13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).^20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.¹ Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.²

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.³

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.⁴ This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.^5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.⁷

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.^8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.^2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.¹³ Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.¹⁴ These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.^15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

• acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
• erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence^4,15
• pyrexia: body temperature greater than 100.4°F
• history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
• tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
• unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall¹⁸
• leukocytosis: white blood cell count greater than 10.0×10⁹/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ² analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ² analysis (Table 3).

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.^13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).^20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.¹ Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.²

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.³

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.⁴ This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.^5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.⁷

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.^8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.^2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.¹³ Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.¹⁴ These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.^15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

• acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
• erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence^4,15
• pyrexia: body temperature greater than 100.4°F
• history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
• tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
• unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall¹⁸
• leukocytosis: white blood cell count greater than 10.0×10⁹/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ² analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ² analysis (Table 3).

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.^13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).^20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

Gene expression profiling and/or immunohistochemistry can identify occult renal cell carcinoma (RCC) in a subset of patients diagnosed with carcinoma of unknown primary (CUP), suggesting that these patients could benefit from RCC-specific targeted therapy or immunotherapy, investigators contend.

Of 539 patients presenting at a single center with CUP, a 92-gene reverse transcription polymerase chain reaction molecular cancer classifier assay (MCCA) performed on biopsy specimens identified 24 as having RCC. All of the patients had clinical characteristics typical of advanced RCC, but none had suspicious renal lesions on CT scans, reported F. Anthony Greco, MD and John D. Hainsworth, MD, of the Sarah Cannon Cancer Center and Research Institute in Nashville, Tenn.

“Although further experience is necessary, these patients responded to RCC-specific therapy in a manner consistent with advanced RCC. These patients are unlikely to benefit from treatment with empiric chemotherapy. The reliable identification of RCC patients within the heterogeneous CUP population is possible using MCCA, and has potentially important therapeutic implications,” they wrote. The report was published in Clinical Genitourinary Cancer.

They noted that previously the only therapeutic option for patients with CUP suspected of being renal in origin was ineffective systemic chemotherapy, making a specific diagnosis of more academic interest than clinical importance.

“This situation has now changed because of the introduction of several targeted agents and immune checkpoint blockers that improve survival in patients with advanced RCC. It is likely that these new RCC treatments are also more effective than empiric chemotherapy for patients with CUP who have an occult renal primary site. Therefore, recognition of the RCC subset of patients within the CUP population has practical therapeutic importance,” they wrote.

Dr. Greco and Dr. Hainsworth conducted a retrospective review of patients at their center with CUP from 2008 through 2013 who had RCC predicted by MCCA.

A total of 539 patients presented with CUP during the study period, and of this group, 24 (4.4%) had RCC identified by MCCA.

The patients, 18 men and 6 women, with a median age of 61 years, all had abdominal CT scans that failed to show renal lesions suggestive of a primary RCC. Nine of the 24 patients had baseline MCCA performed as part of a prospective phase 2 clinical trial; the other 15 were patients treated at the center who had MCCA performed later in the clinical course, usually during or after first-line empiric chemotherapy.

Sixteen patients had metastases in the retroperitoneum, 10 in the mediastinum, 6 in bone, 5 in the liver, and 5 in lungs and/or pleura.

Pathologic studies using light microscopy showed poorly differentiated carcinomas in eight patients, poorly differentiated adenocarcinomas in nine, and well or moderately differentiated adenocarcinomas in seven patients.

A pathologist identified RCC as the possible primary in only 4 of the 24 patients. Immunohistochemistry tests in these patients were consistent with a diagnosis of RCC. Only 5 of the 24 had focal features suggestive of RCC, including one clear-cell and four papillary histologies.

Sixteen of the 24 patients received first-line treatment for advanced RCC, including sunitinib, temsirolimus, bevacizumab, and/or interleukin 1. Four other patients received RCC-specific therapy following empiric chemotherapy (three patients who received RCC-specific therapies in the first line also received it in the second line).

Among the 16 patients who received first-line RCC-specific therapies there were 3 partial responses (PR), 10 cases of stable disease (SD), 2 of progressive disease (PD), and 1 patient was not evaluable. The median duration of both PR and SD was 8 months.

Of the eight patients who received first-line empiric chemotherapy, one had a PR, two had SD, and five had PD.

For the seven patients who received second-line RCC-specific therapy after either first-line chemotherapy or site-specific therapy, responses included one PR, two SD, two PD, and two not evaluable.

Median survival for all 24 patients was 12 months (range 2 to more than 43 months). Median survival of the 16 patients who received first-line RCC-specific treatment was 14 months (range 2-25 months).

Median survival for all 20 patients who received RCC-specific treatment at some time during their course was 16 months (range, 2 to more than 43 months).

The authors called for further prospective studies of this subset of patients with CUP.

SOURCE: Greco FA, Hainsworth JD. Clin Genitourin Cancer. 2018 Aug;16(4):e893-8.

Gene expression profiling and/or immunohistochemistry can identify occult renal cell carcinoma (RCC) in a subset of patients diagnosed with carcinoma of unknown primary (CUP), suggesting that these patients could benefit from RCC-specific targeted therapy or immunotherapy, investigators contend.

Of 539 patients presenting at a single center with CUP, a 92-gene reverse transcription polymerase chain reaction molecular cancer classifier assay (MCCA) performed on biopsy specimens identified 24 as having RCC. All of the patients had clinical characteristics typical of advanced RCC, but none had suspicious renal lesions on CT scans, reported F. Anthony Greco, MD and John D. Hainsworth, MD, of the Sarah Cannon Cancer Center and Research Institute in Nashville, Tenn.

“Although further experience is necessary, these patients responded to RCC-specific therapy in a manner consistent with advanced RCC. These patients are unlikely to benefit from treatment with empiric chemotherapy. The reliable identification of RCC patients within the heterogeneous CUP population is possible using MCCA, and has potentially important therapeutic implications,” they wrote. The report was published in Clinical Genitourinary Cancer.

They noted that previously the only therapeutic option for patients with CUP suspected of being renal in origin was ineffective systemic chemotherapy, making a specific diagnosis of more academic interest than clinical importance.

“This situation has now changed because of the introduction of several targeted agents and immune checkpoint blockers that improve survival in patients with advanced RCC. It is likely that these new RCC treatments are also more effective than empiric chemotherapy for patients with CUP who have an occult renal primary site. Therefore, recognition of the RCC subset of patients within the CUP population has practical therapeutic importance,” they wrote.

Dr. Greco and Dr. Hainsworth conducted a retrospective review of patients at their center with CUP from 2008 through 2013 who had RCC predicted by MCCA.

A total of 539 patients presented with CUP during the study period, and of this group, 24 (4.4%) had RCC identified by MCCA.

The patients, 18 men and 6 women, with a median age of 61 years, all had abdominal CT scans that failed to show renal lesions suggestive of a primary RCC. Nine of the 24 patients had baseline MCCA performed as part of a prospective phase 2 clinical trial; the other 15 were patients treated at the center who had MCCA performed later in the clinical course, usually during or after first-line empiric chemotherapy.

Sixteen patients had metastases in the retroperitoneum, 10 in the mediastinum, 6 in bone, 5 in the liver, and 5 in lungs and/or pleura.

Pathologic studies using light microscopy showed poorly differentiated carcinomas in eight patients, poorly differentiated adenocarcinomas in nine, and well or moderately differentiated adenocarcinomas in seven patients.

A pathologist identified RCC as the possible primary in only 4 of the 24 patients. Immunohistochemistry tests in these patients were consistent with a diagnosis of RCC. Only 5 of the 24 had focal features suggestive of RCC, including one clear-cell and four papillary histologies.

Sixteen of the 24 patients received first-line treatment for advanced RCC, including sunitinib, temsirolimus, bevacizumab, and/or interleukin 1. Four other patients received RCC-specific therapy following empiric chemotherapy (three patients who received RCC-specific therapies in the first line also received it in the second line).

Among the 16 patients who received first-line RCC-specific therapies there were 3 partial responses (PR), 10 cases of stable disease (SD), 2 of progressive disease (PD), and 1 patient was not evaluable. The median duration of both PR and SD was 8 months.

Of the eight patients who received first-line empiric chemotherapy, one had a PR, two had SD, and five had PD.

For the seven patients who received second-line RCC-specific therapy after either first-line chemotherapy or site-specific therapy, responses included one PR, two SD, two PD, and two not evaluable.

Median survival for all 24 patients was 12 months (range 2 to more than 43 months). Median survival of the 16 patients who received first-line RCC-specific treatment was 14 months (range 2-25 months).

Median survival for all 20 patients who received RCC-specific treatment at some time during their course was 16 months (range, 2 to more than 43 months).

The authors called for further prospective studies of this subset of patients with CUP.

SOURCE: Greco FA, Hainsworth JD. Clin Genitourin Cancer. 2018 Aug;16(4):e893-8.

Gene expression profiling and/or immunohistochemistry can identify occult renal cell carcinoma (RCC) in a subset of patients diagnosed with carcinoma of unknown primary (CUP), suggesting that these patients could benefit from RCC-specific targeted therapy or immunotherapy, investigators contend.

Of 539 patients presenting at a single center with CUP, a 92-gene reverse transcription polymerase chain reaction molecular cancer classifier assay (MCCA) performed on biopsy specimens identified 24 as having RCC. All of the patients had clinical characteristics typical of advanced RCC, but none had suspicious renal lesions on CT scans, reported F. Anthony Greco, MD and John D. Hainsworth, MD, of the Sarah Cannon Cancer Center and Research Institute in Nashville, Tenn.

“Although further experience is necessary, these patients responded to RCC-specific therapy in a manner consistent with advanced RCC. These patients are unlikely to benefit from treatment with empiric chemotherapy. The reliable identification of RCC patients within the heterogeneous CUP population is possible using MCCA, and has potentially important therapeutic implications,” they wrote. The report was published in Clinical Genitourinary Cancer.

They noted that previously the only therapeutic option for patients with CUP suspected of being renal in origin was ineffective systemic chemotherapy, making a specific diagnosis of more academic interest than clinical importance.

“This situation has now changed because of the introduction of several targeted agents and immune checkpoint blockers that improve survival in patients with advanced RCC. It is likely that these new RCC treatments are also more effective than empiric chemotherapy for patients with CUP who have an occult renal primary site. Therefore, recognition of the RCC subset of patients within the CUP population has practical therapeutic importance,” they wrote.

Dr. Greco and Dr. Hainsworth conducted a retrospective review of patients at their center with CUP from 2008 through 2013 who had RCC predicted by MCCA.

A total of 539 patients presented with CUP during the study period, and of this group, 24 (4.4%) had RCC identified by MCCA.

The patients, 18 men and 6 women, with a median age of 61 years, all had abdominal CT scans that failed to show renal lesions suggestive of a primary RCC. Nine of the 24 patients had baseline MCCA performed as part of a prospective phase 2 clinical trial; the other 15 were patients treated at the center who had MCCA performed later in the clinical course, usually during or after first-line empiric chemotherapy.

Sixteen patients had metastases in the retroperitoneum, 10 in the mediastinum, 6 in bone, 5 in the liver, and 5 in lungs and/or pleura.

Pathologic studies using light microscopy showed poorly differentiated carcinomas in eight patients, poorly differentiated adenocarcinomas in nine, and well or moderately differentiated adenocarcinomas in seven patients.

A pathologist identified RCC as the possible primary in only 4 of the 24 patients. Immunohistochemistry tests in these patients were consistent with a diagnosis of RCC. Only 5 of the 24 had focal features suggestive of RCC, including one clear-cell and four papillary histologies.

Sixteen of the 24 patients received first-line treatment for advanced RCC, including sunitinib, temsirolimus, bevacizumab, and/or interleukin 1. Four other patients received RCC-specific therapy following empiric chemotherapy (three patients who received RCC-specific therapies in the first line also received it in the second line).

Among the 16 patients who received first-line RCC-specific therapies there were 3 partial responses (PR), 10 cases of stable disease (SD), 2 of progressive disease (PD), and 1 patient was not evaluable. The median duration of both PR and SD was 8 months.

Of the eight patients who received first-line empiric chemotherapy, one had a PR, two had SD, and five had PD.

For the seven patients who received second-line RCC-specific therapy after either first-line chemotherapy or site-specific therapy, responses included one PR, two SD, two PD, and two not evaluable.

Median survival for all 24 patients was 12 months (range 2 to more than 43 months). Median survival of the 16 patients who received first-line RCC-specific treatment was 14 months (range 2-25 months).

Median survival for all 20 patients who received RCC-specific treatment at some time during their course was 16 months (range, 2 to more than 43 months).

The authors called for further prospective studies of this subset of patients with CUP.

SOURCE: Greco FA, Hainsworth JD. Clin Genitourin Cancer. 2018 Aug;16(4):e893-8.