Clinical question: Is there an association between time to completion of discharge summary and hospital readmission?

Background: Thirty-day hospital readmission is one of the quality indicators for inpatient care and a higher rate can result in monetary penalties. Several interventions aimed at reducing this occurrence have been studied in different settings with variable success. Timely completion of discharge summary can possibly affect readmissions by providing crucial information to outpatient providers caring for patients across the care continuum.

Study design: Retrospective cohort study.

Setting: Johns Hopkins University, Baltimore.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Clinical question: Is there an association between time to completion of discharge summary and hospital readmission?

Background: Thirty-day hospital readmission is one of the quality indicators for inpatient care and a higher rate can result in monetary penalties. Several interventions aimed at reducing this occurrence have been studied in different settings with variable success. Timely completion of discharge summary can possibly affect readmissions by providing crucial information to outpatient providers caring for patients across the care continuum.

Study design: Retrospective cohort study.

Setting: Johns Hopkins University, Baltimore.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Clinical question: Is there an association between time to completion of discharge summary and hospital readmission?

Background: Thirty-day hospital readmission is one of the quality indicators for inpatient care and a higher rate can result in monetary penalties. Several interventions aimed at reducing this occurrence have been studied in different settings with variable success. Timely completion of discharge summary can possibly affect readmissions by providing crucial information to outpatient providers caring for patients across the care continuum.

Study design: Retrospective cohort study.

Setting: Johns Hopkins University, Baltimore.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Clinical question: What are the epidemiology, risk factors, and associated morbidity and mortality of acute kidney injury (AKI) in critically ill children and young adults?

Background: Adult studies on acute kidney injury have shown increasing mortality and morbidity when both plasma creatinine and urine output were used to diagnose AKI than when used alone. Studies of AKI in children have also been limited.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Clinical question: What are the epidemiology, risk factors, and associated morbidity and mortality of acute kidney injury (AKI) in critically ill children and young adults?

Background: Adult studies on acute kidney injury have shown increasing mortality and morbidity when both plasma creatinine and urine output were used to diagnose AKI than when used alone. Studies of AKI in children have also been limited.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Clinical question: What are the epidemiology, risk factors, and associated morbidity and mortality of acute kidney injury (AKI) in critically ill children and young adults?

Background: Adult studies on acute kidney injury have shown increasing mortality and morbidity when both plasma creatinine and urine output were used to diagnose AKI than when used alone. Studies of AKI in children have also been limited.

Dr. Rachoin is an assistant professor of clinical medicine and associate division head, Hospital Medicine, at Cooper Medical School at Rowan University. He works as a hospitalist at Cooper University Hospital in Camden, N.J.

Acquired BTK^C481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.

These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTK^C481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”

Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).

To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.

In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTK^C481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTK^C481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.

At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).

Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).

In the prospective study, all eight patients with BTK^C481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.

Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”

Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to ^C481S detection.

Acquired BTK^C481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.

These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTK^C481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”

Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).

To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.

In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTK^C481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTK^C481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.

At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).

Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).

In the prospective study, all eight patients with BTK^C481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.

Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”

Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to ^C481S detection.

Acquired BTK^C481S and PLCG2 mutations led to ibrutinib resistance in chronic lymphocytic leukemia (CLL), investigators reported online in the Journal of Clinical Oncology.

These mutations preceded 85% of clinical relapses, appearing a median of 9.3 months beforehand, Jennifer A. Woyach, MD, and her associates from the Ohio State University, Columbus, concluded from a retrospective study of 308 patients. In a separate prospective study of 112 patients, acquired BTK^C481S mutation and clonal expansion preceded all eight cases of relapse, they said. “Relapse of CLL after ibrutinib is an issue of increasing clinical significance,” they concluded. “We show that mutations in Bruton tyrosine kinase (BTK) and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.”

Ibrutinib has transformed the CLL treatment landscape, but patients face poor outcomes if they relapse with Richter transformation or develop progressive disease. Past work has linked ibrutinib resistance to acquired mutations in BTK at the binding site of ibrutinib and in PLCG2 located just downstream. But the scope of ibrutinib resistance in CLL and key mutational players were unknown (J Clin Oncol. 2017. doi: 10.1200/JCO.2016.70.2282).

To fill that gap, the researchers retrospectively analyzed data from four sequential ibrutinib CLL trials at the Ohio State University. The separate prospective analysis involved analyzing the entire BTK and PLCG2 coding regions every 3 months.

In the retrospective study, patients had received a median of 3 and up to 16 prior therapies. Given the median follow-up period of 3.4 years, about 19% of patients experienced clinical relapse within 4 years of starting ibrutinib, the researchers estimated (95% confidence interval, 14%-24%). Deep sequencing by Ion Torrent (Life Technologies) identified mutations in BTK^C481S and/or PLCG2, in 40 of 47 (85%) relapses. In 31 cases, BTK^C481S was the sole mutation. Mutational burdens varied among patients, but generally correlated with CLL progression in peripheral blood versus primarily nodal relapse.

At baseline, 172 (58%) of retrospective study participants had complex cytogenetics, 52% had del(13q), 40% had del(17p), and 21% had MYC abnormality. Median age was 65 years (range, 26-91 years) and 70% of patients were female. Multivariable analyses linked transformation to complex karyotype (hazard ratio, 5.0; 95% CI, 1.5-16.5) and MYC abnormality (HR, 2.5; 95% CI, 1.0-4.7), and linked progressive CLL to age younger than 65 years, complex karyotype, and del(17)(p13.1).

Richter transformation usually occurred within 2 years of starting ibrutinib and had a cumulative 4-year incidence of 10%, the investigators also reported. Patients survived a median of only 3.9 months after stopping ibrutinib because of transformation. The cumulative rate of progressive CLL was higher (19.1%), but early progression was rare, and patients who stopped ibrutinib because of progression survived longer (median, 22.7 months).

In the prospective study, all eight patients with BTK^C481S who had not yet clinically relapsed nonetheless had increasing frequency of this mutation over time, the investigators reported. Together, the findings confirm BTK and PLCG2 mutations as the key players in CLL resistance to ibrutinib, they stated. Perhaps most importantly, they reveal “a prolonged period of asymptomatic clonal expression” in CLL that precedes clinical relapse and provides a window of opportunity to target these cells with novel therapies in clinical trials, they wrote.

Given that ibrutinib was approved for use in relapsed CLL only 2 years ago, “We are likely just starting to see the first emergence of relapse in the community setting,” the researchers concluded. “Enhanced knowledge of both the molecular and clinical mechanisms of relapse may allow for strategic alterations in monitoring and management that could change the natural history of ibrutinib resistance.”

Funding sources included the D. Warren Brown Foundation, Mr. and Mrs. Michael Thomas, the Four Winds Foundation, the Leukemia and Lymphoma Society, Pelotonia, and the National Cancer Institute. Pharmacyclics also provided partial support. Dr. Woyach disclosed ties to Janssen, Acerta Pharma, Karyopharm Therapeutics, and MorphoSys, and a provisional patent related to ^C481S detection.

The number of outpatient visits for CNS polypharmacy by adults aged 65 and older more than doubled between 2004 and 2013, especially among those who reside in rural areas, results from a large analysis of national data showed.

“With each new revision of the Beers Criteria, the list of psychotropic medications considered potentially inappropriate in the elderly has grown,” researchers led by Donovan T. Maust, MD, wrote in a research letter published online Feb. 13, 2017, in JAMA Internal Medicine. “Opioids have recently been included in a Beers measure of central nervous system polypharmacy. Prescribing related drug combinations also received increased regulatory attention when the U.S. Food and Drug Administration recently ordered a black box warning to alert patients of serious risks, including death, caused by opioids coprescribed with CNS depressants.”

iStock/Thinkstock.com

[email protected]

The number of outpatient visits for CNS polypharmacy by adults aged 65 and older more than doubled between 2004 and 2013, especially among those who reside in rural areas, results from a large analysis of national data showed.

“With each new revision of the Beers Criteria, the list of psychotropic medications considered potentially inappropriate in the elderly has grown,” researchers led by Donovan T. Maust, MD, wrote in a research letter published online Feb. 13, 2017, in JAMA Internal Medicine. “Opioids have recently been included in a Beers measure of central nervous system polypharmacy. Prescribing related drug combinations also received increased regulatory attention when the U.S. Food and Drug Administration recently ordered a black box warning to alert patients of serious risks, including death, caused by opioids coprescribed with CNS depressants.”

iStock/Thinkstock.com

[email protected]

The number of outpatient visits for CNS polypharmacy by adults aged 65 and older more than doubled between 2004 and 2013, especially among those who reside in rural areas, results from a large analysis of national data showed.

“With each new revision of the Beers Criteria, the list of psychotropic medications considered potentially inappropriate in the elderly has grown,” researchers led by Donovan T. Maust, MD, wrote in a research letter published online Feb. 13, 2017, in JAMA Internal Medicine. “Opioids have recently been included in a Beers measure of central nervous system polypharmacy. Prescribing related drug combinations also received increased regulatory attention when the U.S. Food and Drug Administration recently ordered a black box warning to alert patients of serious risks, including death, caused by opioids coprescribed with CNS depressants.”

iStock/Thinkstock.com

[email protected]

Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.

For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).

lolostock/Thinkstock

Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.

For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).

lolostock/Thinkstock

Clinicians and patients should prioritize nonpharmacologic therapies for low back pain of any duration, according to an updated guideline from the American College of Physicians.

For acute and subacute low back pain, first-line choices include heat, massage, acupuncture, and spinal manipulation, Amir Qaseem, MD, PhD, and his associates wrote in the Annals of Internal Medicine. Patients with chronic low back pain have many nondrug options, ranging from exercise and tai chi to mindfulness-based stress reduction and spinal manipulation, the authors add (Ann Intern Med. 2017 Feb 14. doi: 10.7326/M16-2367).

lolostock/Thinkstock

BRCA1/2 reversion mutations that restore protein function and lead to clinically significant rates of acquired resistance can be detected in an unbiased analysis of cell-free DNA, an analysis of plasma and tumor samples from 30 patients with high-grade serous ovarian cancer (HGSC) and BRCA1 or BRCA2 germline mutation shows.

The findings suggest that detection of these mutations could be useful for predicting chemotherapy response in recurrent HGSC, reported Elizabeth L. Christie, PhD, of Peter MacCallum Cancer Centre, Melbourne, and her colleagues.

copyright kgtoh/Thinkstock

[email protected]

BRCA1/2 reversion mutations that restore protein function and lead to clinically significant rates of acquired resistance can be detected in an unbiased analysis of cell-free DNA, an analysis of plasma and tumor samples from 30 patients with high-grade serous ovarian cancer (HGSC) and BRCA1 or BRCA2 germline mutation shows.

The findings suggest that detection of these mutations could be useful for predicting chemotherapy response in recurrent HGSC, reported Elizabeth L. Christie, PhD, of Peter MacCallum Cancer Centre, Melbourne, and her colleagues.

copyright kgtoh/Thinkstock

[email protected]

BRCA1/2 reversion mutations that restore protein function and lead to clinically significant rates of acquired resistance can be detected in an unbiased analysis of cell-free DNA, an analysis of plasma and tumor samples from 30 patients with high-grade serous ovarian cancer (HGSC) and BRCA1 or BRCA2 germline mutation shows.

The findings suggest that detection of these mutations could be useful for predicting chemotherapy response in recurrent HGSC, reported Elizabeth L. Christie, PhD, of Peter MacCallum Cancer Centre, Melbourne, and her colleagues.

copyright kgtoh/Thinkstock

[email protected]

Patients with early-stage, hormone-receptor positive breast cancer who used cholesterol-lowering medication at baseline of a long-term randomized study had more beneficial tumor characteristics and improved outcomes, compared with nonusers.

The findings come from an observation study of a randomized, phase III, double-blind trial conducted by the Breast International Group (BIG) known as BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer from 1998 to 2003. As reported online in the Feb. 13, 2017 issue of the Journal of Clinical Oncology, researchers measured systemic levels of total cholesterol and use of cholesterol-lowering medication at study entry and every 6 months up to 5.5 years. Endpoints of interest were disease-free survival, breast cancer–free interval, and distant recurrence–free interval.

Of the 789 patients who initiated cholesterol-lowering medication during endocrine therapy, most were assigned to letrozole monotherapy (318), followed by sequential tamoxifen-letrozole (189), letrozole-tamoxifen (176), and tamoxifen monotherapy (106).

The results showed that initiation of cholesterol-lowering medication during endocrine therapy was related to improved disease-free survival (hazard ratio 0.79; P = .01), breast cancer–free interval (HR, 0.76; P = .02), and distant recurrence–free interval (HR, 0.74; P = .03).

“The evidence from our observational study warrants consideration of a large, prospective, randomized clinical trial to confirm the value of CLM concomitant with endocrine treatment of breast cancer,” corresponding author Signe Borgquist, MD, PhD, of the division of oncology and pathology at Lund University, Sweden, and her associates concluded. “Further elucidation of the effect upon outcome of the clinical interaction between CLM and endocrine agents – both widely used by patients with breast cancer – will provide exclusive insight to future trial designs.”

The BIG 1-98 trial was supported by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Of the 17 study authors, 7 reported having relevant financial disclosures.

[email protected]
 

Patients with early-stage, hormone-receptor positive breast cancer who used cholesterol-lowering medication at baseline of a long-term randomized study had more beneficial tumor characteristics and improved outcomes, compared with nonusers.

The findings come from an observation study of a randomized, phase III, double-blind trial conducted by the Breast International Group (BIG) known as BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer from 1998 to 2003. As reported online in the Feb. 13, 2017 issue of the Journal of Clinical Oncology, researchers measured systemic levels of total cholesterol and use of cholesterol-lowering medication at study entry and every 6 months up to 5.5 years. Endpoints of interest were disease-free survival, breast cancer–free interval, and distant recurrence–free interval.

Of the 789 patients who initiated cholesterol-lowering medication during endocrine therapy, most were assigned to letrozole monotherapy (318), followed by sequential tamoxifen-letrozole (189), letrozole-tamoxifen (176), and tamoxifen monotherapy (106).

The results showed that initiation of cholesterol-lowering medication during endocrine therapy was related to improved disease-free survival (hazard ratio 0.79; P = .01), breast cancer–free interval (HR, 0.76; P = .02), and distant recurrence–free interval (HR, 0.74; P = .03).

“The evidence from our observational study warrants consideration of a large, prospective, randomized clinical trial to confirm the value of CLM concomitant with endocrine treatment of breast cancer,” corresponding author Signe Borgquist, MD, PhD, of the division of oncology and pathology at Lund University, Sweden, and her associates concluded. “Further elucidation of the effect upon outcome of the clinical interaction between CLM and endocrine agents – both widely used by patients with breast cancer – will provide exclusive insight to future trial designs.”

The BIG 1-98 trial was supported by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Of the 17 study authors, 7 reported having relevant financial disclosures.

[email protected]
 

Patients with early-stage, hormone-receptor positive breast cancer who used cholesterol-lowering medication at baseline of a long-term randomized study had more beneficial tumor characteristics and improved outcomes, compared with nonusers.

The findings come from an observation study of a randomized, phase III, double-blind trial conducted by the Breast International Group (BIG) known as BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer from 1998 to 2003. As reported online in the Feb. 13, 2017 issue of the Journal of Clinical Oncology, researchers measured systemic levels of total cholesterol and use of cholesterol-lowering medication at study entry and every 6 months up to 5.5 years. Endpoints of interest were disease-free survival, breast cancer–free interval, and distant recurrence–free interval.

Of the 789 patients who initiated cholesterol-lowering medication during endocrine therapy, most were assigned to letrozole monotherapy (318), followed by sequential tamoxifen-letrozole (189), letrozole-tamoxifen (176), and tamoxifen monotherapy (106).

The results showed that initiation of cholesterol-lowering medication during endocrine therapy was related to improved disease-free survival (hazard ratio 0.79; P = .01), breast cancer–free interval (HR, 0.76; P = .02), and distant recurrence–free interval (HR, 0.74; P = .03).

“The evidence from our observational study warrants consideration of a large, prospective, randomized clinical trial to confirm the value of CLM concomitant with endocrine treatment of breast cancer,” corresponding author Signe Borgquist, MD, PhD, of the division of oncology and pathology at Lund University, Sweden, and her associates concluded. “Further elucidation of the effect upon outcome of the clinical interaction between CLM and endocrine agents – both widely used by patients with breast cancer – will provide exclusive insight to future trial designs.”

The BIG 1-98 trial was supported by Novartis and coordinated by the International Breast Cancer Study Group (IBCSG). Of the 17 study authors, 7 reported having relevant financial disclosures.

[email protected]
 

WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.

The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.

Bruce Jancin/Frontline Medical News

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

[email protected]
 

WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.

The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.

Bruce Jancin/Frontline Medical News

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

[email protected]
 

WAILEA, HAWAII – The Eighth Edition of the American Joint Committee on Cancer Staging Manual includes significant changes in how melanoma is classified.

The manual has already been published and is available for purchase. However, its implementation will be delayed until Jan. 1, 2018, to give physicians, software vendors, and all other interested parties time to get up to speed. All cancers newly diagnosed through Dec. 31, 2017 should be staged in accord with the seventh edition, released in 2010.

Bruce Jancin/Frontline Medical News

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

[email protected]
 

Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Mycetoma is a subcutaneous disease that can be caused by aerobic bacteria (actinomycetoma) or fungi (eumycetoma). Diagnosis is based on clinical manifestations, including swelling and deformity of affected areas, as well as the presence of granulation tissue, scars, abscesses, sinus tracts, and a purulent exudate that contains the microorganisms.

The worldwide proportion of mycetomas is 60% actinomycetomas and 40% eumycetomas.¹ The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela.¹

Although mycetoma is rare in developed countries, migration of patients from endemic areas makes knowledge of this condition crucial for dermatologists worldwide. We present a review of the current concepts in the epidemiology, clinical presentation, diagnosis, and treatment of actinomycetoma.

Epidemiology

Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico.² The majority of cases of mycetoma in Mexico are actinomycetoma (98%), including Nocardia (86%) and Actinomadura madurae (10%). Eumycetoma is rare in Mexico, constituting only 2% of cases.² Worldwide, men are affected more commonly than women, which is thought to be related to a higher occupational risk during agricultural labor.

Clinical Features

Mycetoma can affect the skin, subcutaneous tissue, bones, and occasionally the internal organs. It is characterized by swelling, deformation of the affected area, and fistulae that drain serosanguineous or purulent exudates.

In Mexico, 60% of cases of mycetoma affect the lower extremities; the feet are the most commonly affected area, followed by the trunk (back and chest), arms, forearms, legs, knees, and thighs.¹ Other sites include the hands, shoulders, and abdominal wall. The head and neck area are seldom affected.³ Mycetoma lesions grow and disseminate locally. Bone lesions are possible depending on the osteophilic affinity of the etiological agent and on the interactions between the fungus and the host’s immune system. In severe advanced cases of mycetoma, the lesions may involve tendons and nerves. Dissemination via blood or lymphatics is extremely rare.⁴

Diagnosis

Diagnosis of actinomycetoma is suspected based on clinical features and confirmed by direct examination of exudates with Lugol iodine or saline solution. On direct microscopy, actinomycetes are recognized by the production of filaments with a width of 0.5 to 1 μm. On hematoxylin and eosin stain, the small grains of Nocardia appear eosinophilic with a blue center and pink filaments. On Gram stain, actinomycetoma grains show positive branching filaments. Culture of grains recovered from aspirated material or biopsy specimens provides specific etiologic diagnosis. Cultures should be held for at least 4 weeks. Additionally, there are some enzymatic, molecular, and serologic tests available for diagnosis.^5-7 Serologic diagnosis is available in a few centers in Mexico and can be helpful in some cases for diagnosis or follow-up during treatment. Antibodies can be determined via enzyme-linked immunosorbent assay, Western blot analysis, immunodiffusion, or counterimmunoelectrophoresis.⁸

The causative agents of actinomycetoma can be isolated in Sabouraud dextrose agar. Deep wedge biopsies (or puncture aspiration) are useful in observing the diagnostic grains, which can be identified adequately with Gram stain. Grains usually are surrounded and/or infiltrated by neutrophils. The size, form, and color of grains can identify the causative agent.¹ The granules of Nocardia are small (80–130 mm) and reniform or wormlike, with club structures in their periphery (Figure 1). Actinomadura madurae is characterized by large, white-yellow granules that can be seen with the naked eye (1–3 mm). On microscopic examination with hematoxylin and eosin stain, these grains are purple and exhibit peripheral pink pseudofilaments (Figure 2).² The grains of Actinomadura pelletieri are large (1–3 mm) and red or violaceous. They fragment or break easily, giving the appearance of a broken dish (Figure 3). Streptomyces somaliensis forms round grains approximately 0.5 to 1 cm in diameter. These grains stain poorly and are extremely hard. Cutting the grains during processing results in striation, giving them the appearance of a potato chip (Figure 4).²

Treatment of Actinomycetoma

Precise identification of the etiologic agent is essential to provide effective treatment of actinomycetoma. Without treatment, or in resistant cases, progressive osseous and visceral involvement is inevitable.⁹ Actinomycetoma without osseous involvement usually responds well to medical treatment.

The treatment of choice for actinomycetoma involving Nocardia brasiliensis is a combination of dapsone 100 to 200 mg once daily and trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 to 160/800 mg once daily for 2 to 3 years.¹⁰ Other treatments have included the following: (1) amikacin 15 mg/kg or 500 mg intramuscularly twice daily for 3 weeks plus dapsone 100 to 200 mg once daily plus TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years (amikacin, however, is expensive and potentially toxic [nephrotoxicity and ototoxicity] and therefore is used only in resistant cases); (2) dapsone 100 to 200 mg once daily or TMP-SMX 80/400 to 160/800 mg daily for 2 to 3 years plus intramuscular kanamycin 15 mg/kg once daily for 2 weeks at the beginning of treatment, alternating with rest periods to reduce the risk for nephrotoxicity and ototoxicity¹⁰; (3) dapsone 1.5 mg/kg orally twice daily plus phosphomycin 500 mg once daily; (4) dapsone 1.5 mg/kg orally twice daily plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month, then the same dose every other day for 1 to 2 months monitoring for ototoxicity; and (5) TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years or rifampicin (15–20 mg/kg/d) plus streptomycin 1 g once daily (14 mg/kg/d) for 1 month at the beginning of treatment, then the same dose every other day for 2 to 3 months until a total dose of 60 g is administered, monitoring for ototoxicity.¹¹ Audiometric tests and creatinine levels must be performed every 5 weeks during the treatment to monitor toxicity.¹⁰

The best results for infections with A pelletieri, A madurae, and S somaliensis have been with streptomycin (1 g once daily in adults; 20 mg/kg once daily in children) until a total dose of 50 g is reached in combination with TMP-SMX or dapsone¹² (Figure 5). Alternatives for A madurae infections include streptomycin plus oral clofazimine (100 mg once daily), oral rifampicin (300 mg twice daily), oral tetracycline (1 g once daily), oral isoniazid (300–600 mg once daily), or oral minocycline (100 mg twice daily; also effective for A pelletieri).

More recently, other drugs have been used such as carbapenems (eg, imipenem, meropenem), which have wide-spectrum efficacy and are resistant to β-lactamases. Patients should be hospitalized to receive intravenous therapy with imipenem.² Carbapenems are effective against gram-positive and gram-negative as well as Nocardia species.^13,14 Mycetoma that is resistant, severe, or has visceral involvement can be treated with a combination of amikacin and imipenem.^15,16 Meropenem is a similar drug that is available as an oral formulation. Both imipenem and meropenem are recommended in cases with bone involvement.^17,18 Alternatives for resistant cases include amoxicillin–clavulanic acid 500/125 mg orally 3 times daily for 3 to 6 months or intravenous cefotaxime 1 g every 8 hours plus intramuscular amikacin 500 mg twice daily plus oral levamisole 300 mg once weekly for 4 weeks.^19-23

For resistant cases associated with Nocardia species, clindamycin plus quinolones (eg, ciprofloxacin, moxifloxacin, garenoxacin) at a dose of 25 mg/kg once daily for at least 3 months has been suggested in in vivo studies.²³

Overall, the cure rate for actinomycetoma treated with any of the prior therapies ranges from 60% to 90%. Treatment must be modified or stopped if there is clinical or laboratory evidence of drug toxicity.^13,24 Surgical treatment of actinomycetoma is contraindicated, as it may cause hematogenous dissemination.

Prognosis

Actinomycetomas of a few months’ duration and without bone involvement respond well to therapy. If no therapy is provided or if there is resistance, the functional and cosmetic prognosis is poor, mainly for the feet. There is a risk for spine involvement with mycetoma on the back and posterior head. Thoracic lesions may penetrate into the lungs. The muscular fascia impedes the penetration of abdominal lesions, but the inguinal canals can offer a path for intra-abdominal dissemination.⁴ Advanced cases lead to a poor general condition of patients, difficulty in using affected extremities, and in extreme cases even death.

The criteria used to guide the discontinuation of initial therapy for any mycetoma include a decrease in the volume of the lesion, closure of fistulae, 3 consecutive negative monthly cultures, imaging studies showing bone regeneration, lack of echoes and cavities on echography, and absence of grains on examination of fine-needle aspirates.¹¹ After the initial treatment protocol is finished, most experts recommend continuing treatment with dapsone 100 to 300 mg once daily for several years to prevent recurrence.¹²

Prevention

Mycetoma is a disease associated with poverty. It could be prevented by improving living conditions and by regular use of shoes in rural populations.²

Conclusion

Mycetoma is a chronic infection that develops after traumatic inoculation of the skin with either true fungi or aerobic actinomycetes. The resultant infections are known as eumycetoma or actinomycetoma, respectively. The etiologic agents can be found in the so-called grains. Black grains suggest a fungal infection, minute white grains suggest Nocardia, and red grains are due to A pelletieri. Larger white grains or yellow-white grains may be fungal or actinomycotic in origin.

Specific diagnosis requires direct examination, culture, and biopsy. The treatment of choice for actinomycetoma by N brasiliensis is a combination of dapsone 100 to 200 mg once daily and TMP-SMX 80/400 to 160/800 mg once daily for 2 to 3 years. Other effective treatments include aminoglycosides (eg, amikacine, streptomycin) and quinolones. More recently, some other agents have been used such as carbapenems and natural products of Streptomyces cattleya (imipenem), which have wide-spectrum efficacy and are resistant to β-lactamases.

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]

Updated lipid management guidelines include a category of “extreme risk” patients in whom LDL cholesterol should be lowered below 55 mg/dL, according to a summary by the American Association of Clinical Endocrinologists and American College of Endocrinology.

Achieving such a low LDL-cholesterol (LDL-C) level is possible with well-established medications such as a combination of simvastatin and ezetimibe and the newer, more clinically powerful agent PCSK9 inhibitors, Paul S. Jellinger, MD, chair of the guideline committee and professor of clinical medicine, University of Miami, said in an interview. The “extreme risk” category was derived largely from IMPROVE-IT and supporting meta-analyses.

Heterozygous hypercholesterolemia is more common than many physicians realize, affecting as it does 1 in 250 people, Dr. Jellinger noted.

“Supporting evidence for the ‘extreme risk’ category with an LDL-C of less than 55 mg/dL was recently announced with the top line results from the FOURIER CVD outcome trial utilizing PCSK9-inhibitor therapy, which met both its primary and secondary endpoints,” he stressed.

PCSK9 inhibitors are extremely expensive, said Dr. Jellinger. “In my view, payers should not be denying patients who clearly meet the Food and Drug Administration approved indications for PCSK9 inhibitors and those within the extreme risk criteria. Yet, I have been made aware that 80% of insurance claims for PCSK9 inhibitors in these extremely high-risk and vulnerable patients are being denied.”

Inclusion in the updated AACE lipid management guidelines should strengthen PCSK9 inhibitors’ place among lipid-lowering drugs that are acceptable to insurance companies by making it clear that PCSK9 is appropriate and indicated for select patients, according to Dr. Jellinger.

Aside from creation of the extreme risk category, the AACE lipid guidelines discuss the available tools for making a global risk assessment of having a cardiac, vascular, or stroke event in the next 10 years, without favoring any one risk score. Among the systems discussed, with links, are the Framingham, MESA (Multi-Ethnic Study of Atherosclerosis), Reynolds, and United Kingdom Prospective Diabetes Study risk scores.

The guidelines provide separate approaches to management of people at various ages. Another change from the 2012 guidelines is the establishment of acceptable and worrisome LDL-C levels in children: Acceptable is a level under 100 mg/dL, borderline is 100-129 mg/dL, and high is LDL-C at or above 130 mg/dL.

The guidelines, which will be published in full in the April issue of Endocrine Practice, are based largely on numerous clinical trials and studies, and in the end produced 87 recommendations, of which 45 are Grade A, 18 are Grade B, 15 are Grade C, and 9 are Grade D.

These are the first guidelines on lipid management from AACE since 2012. The executive summary of the guidelines is available at www.aace.com.

Dr. Jellinger reported receiving speakers honoraria from Amgen, AstraZeneca, BI-Lilly, Merck, and Novo Nordisk.
 

[email protected]