SAN DIEGO – Diabetes (not recent onset), obesity, and gallstone disease were associated with the occurrence of sporadic pancreatic neuroendocrine tumors (PNET) in the prospective, case-control European EpiNet study.

Cigarette smoking, first-degree family history of cancer, and alcohol consumption were not significantly associated with PNET in this study, which was reported at the annual Digestive Disease Week.

“This is the first prospective multicenter study investigating risk factors for the occurrence of PNET. We confirmed that diabetes, obesity and gallstone disease are significantly associated with PNET. The role of obesity is confirmed for the first time. However, the study failed to confirm an association with family history of cancer, smoking cigarettes, alcohol consumption, hormonal reproductive factors, or allergies. This is different from pancreatic cancer,” said lead author Dr. Roberto Valente, Sapienza University of Rome, Italy.

Alice Goodman/Frontline Medical News

PNET is a rare tumor, comprising 1% of all pancreatic tumors and 10% of all pancreatic neoplasms.

“The incidence of PNET is rising over time and we don’t know why. Thus far, risk factors for PNET have been poorly investigated. Many factors associated with pancreatic cancer have not been previously studied in PNET, including allergies, use of aspirin, and reproductive/gynecologic factors in women,” he said.

Previous case-control studies in small samples identified diabetes, smoking, alcohol consumption, and a family history of cancer as potential risk factors. Dr. Valente and coinvestigators sought to evaluate risk and protective factors for PNET in a more rigorous study.

Participants were drawn from five European countries. The study included 201 cases of sporadic, histologically proven PNET diagnosed within 24 months of the initiation of the study, and 603 controls matched for age and sex. For both cases and controls, about 50% were male, mean age was 59 years, and 97% were Caucasian. Among cases, 76.6% had nonfunctioning PNET that were equally distributed anatomically.

Participants responded to standardized questionnaires about demographics, and environmental, and familial risk factors using a predefined standard questionnaire.

Obesity (defined as body mass index [BMI] greater than 30) was significantly more prevalent in cases than controls (26.5% versus 19.26%, respectively, P = .03). Diabetes was also significantly more prevalent in cases than controls (18.5% versus 12.5%, respectively P = .003).

No differences were found between cases and controls in family history of any cancer, alcohol consumption, coffee drinking, or cigarette smoking.

Looking at previous medical history, only gallstone disease was strongly associated with PNET, but this was of borderline statistical significance (19.2% versus 13.2%, respectively, P = .06).

The investigators looked at previously uninvestigated potentially protective factors such as allergies (asthma, eczema, hay fever), and use of aspirin. None of these was significantly more prevalent in cases compared with controls.

Reproductive/hormonal factors were analyzed in 98 cases and 294 controls. None of these factors was significantly different in cases or controls.

Univariate regression analysis adjusted for age found that diabetes (P = .02), diabetes for more than 1 year (P = .002), obesity (P = .02), and previous gallstone disease (P = .04) were significant risk factors for PNET.

Multivariate logistic regression analysis confirmed diabetes as a significant risk factor (P = .009), and obesity and gallstone disease were of borderline significance (P = .09 and P = .07, respectively).

“The reported risk factors partially overlap with those reported for pancreatic adenocarcinoma, thus suggesting a possible organ-specific carcinogenic effect,” Dr Valente noted.

SAN DIEGO – Diabetes (not recent onset), obesity, and gallstone disease were associated with the occurrence of sporadic pancreatic neuroendocrine tumors (PNET) in the prospective, case-control European EpiNet study.

Cigarette smoking, first-degree family history of cancer, and alcohol consumption were not significantly associated with PNET in this study, which was reported at the annual Digestive Disease Week.

“This is the first prospective multicenter study investigating risk factors for the occurrence of PNET. We confirmed that diabetes, obesity and gallstone disease are significantly associated with PNET. The role of obesity is confirmed for the first time. However, the study failed to confirm an association with family history of cancer, smoking cigarettes, alcohol consumption, hormonal reproductive factors, or allergies. This is different from pancreatic cancer,” said lead author Dr. Roberto Valente, Sapienza University of Rome, Italy.

Alice Goodman/Frontline Medical News

PNET is a rare tumor, comprising 1% of all pancreatic tumors and 10% of all pancreatic neoplasms.

“The incidence of PNET is rising over time and we don’t know why. Thus far, risk factors for PNET have been poorly investigated. Many factors associated with pancreatic cancer have not been previously studied in PNET, including allergies, use of aspirin, and reproductive/gynecologic factors in women,” he said.

Previous case-control studies in small samples identified diabetes, smoking, alcohol consumption, and a family history of cancer as potential risk factors. Dr. Valente and coinvestigators sought to evaluate risk and protective factors for PNET in a more rigorous study.

Participants were drawn from five European countries. The study included 201 cases of sporadic, histologically proven PNET diagnosed within 24 months of the initiation of the study, and 603 controls matched for age and sex. For both cases and controls, about 50% were male, mean age was 59 years, and 97% were Caucasian. Among cases, 76.6% had nonfunctioning PNET that were equally distributed anatomically.

Participants responded to standardized questionnaires about demographics, and environmental, and familial risk factors using a predefined standard questionnaire.

Obesity (defined as body mass index [BMI] greater than 30) was significantly more prevalent in cases than controls (26.5% versus 19.26%, respectively, P = .03). Diabetes was also significantly more prevalent in cases than controls (18.5% versus 12.5%, respectively P = .003).

No differences were found between cases and controls in family history of any cancer, alcohol consumption, coffee drinking, or cigarette smoking.

Looking at previous medical history, only gallstone disease was strongly associated with PNET, but this was of borderline statistical significance (19.2% versus 13.2%, respectively, P = .06).

The investigators looked at previously uninvestigated potentially protective factors such as allergies (asthma, eczema, hay fever), and use of aspirin. None of these was significantly more prevalent in cases compared with controls.

Reproductive/hormonal factors were analyzed in 98 cases and 294 controls. None of these factors was significantly different in cases or controls.

Univariate regression analysis adjusted for age found that diabetes (P = .02), diabetes for more than 1 year (P = .002), obesity (P = .02), and previous gallstone disease (P = .04) were significant risk factors for PNET.

Multivariate logistic regression analysis confirmed diabetes as a significant risk factor (P = .009), and obesity and gallstone disease were of borderline significance (P = .09 and P = .07, respectively).

“The reported risk factors partially overlap with those reported for pancreatic adenocarcinoma, thus suggesting a possible organ-specific carcinogenic effect,” Dr Valente noted.

SAN DIEGO – Diabetes (not recent onset), obesity, and gallstone disease were associated with the occurrence of sporadic pancreatic neuroendocrine tumors (PNET) in the prospective, case-control European EpiNet study.

Cigarette smoking, first-degree family history of cancer, and alcohol consumption were not significantly associated with PNET in this study, which was reported at the annual Digestive Disease Week.

“This is the first prospective multicenter study investigating risk factors for the occurrence of PNET. We confirmed that diabetes, obesity and gallstone disease are significantly associated with PNET. The role of obesity is confirmed for the first time. However, the study failed to confirm an association with family history of cancer, smoking cigarettes, alcohol consumption, hormonal reproductive factors, or allergies. This is different from pancreatic cancer,” said lead author Dr. Roberto Valente, Sapienza University of Rome, Italy.

Alice Goodman/Frontline Medical News

PNET is a rare tumor, comprising 1% of all pancreatic tumors and 10% of all pancreatic neoplasms.

“The incidence of PNET is rising over time and we don’t know why. Thus far, risk factors for PNET have been poorly investigated. Many factors associated with pancreatic cancer have not been previously studied in PNET, including allergies, use of aspirin, and reproductive/gynecologic factors in women,” he said.

Previous case-control studies in small samples identified diabetes, smoking, alcohol consumption, and a family history of cancer as potential risk factors. Dr. Valente and coinvestigators sought to evaluate risk and protective factors for PNET in a more rigorous study.

Participants were drawn from five European countries. The study included 201 cases of sporadic, histologically proven PNET diagnosed within 24 months of the initiation of the study, and 603 controls matched for age and sex. For both cases and controls, about 50% were male, mean age was 59 years, and 97% were Caucasian. Among cases, 76.6% had nonfunctioning PNET that were equally distributed anatomically.

Participants responded to standardized questionnaires about demographics, and environmental, and familial risk factors using a predefined standard questionnaire.

Obesity (defined as body mass index [BMI] greater than 30) was significantly more prevalent in cases than controls (26.5% versus 19.26%, respectively, P = .03). Diabetes was also significantly more prevalent in cases than controls (18.5% versus 12.5%, respectively P = .003).

No differences were found between cases and controls in family history of any cancer, alcohol consumption, coffee drinking, or cigarette smoking.

Looking at previous medical history, only gallstone disease was strongly associated with PNET, but this was of borderline statistical significance (19.2% versus 13.2%, respectively, P = .06).

The investigators looked at previously uninvestigated potentially protective factors such as allergies (asthma, eczema, hay fever), and use of aspirin. None of these was significantly more prevalent in cases compared with controls.

Reproductive/hormonal factors were analyzed in 98 cases and 294 controls. None of these factors was significantly different in cases or controls.

Univariate regression analysis adjusted for age found that diabetes (P = .02), diabetes for more than 1 year (P = .002), obesity (P = .02), and previous gallstone disease (P = .04) were significant risk factors for PNET.

Multivariate logistic regression analysis confirmed diabetes as a significant risk factor (P = .009), and obesity and gallstone disease were of borderline significance (P = .09 and P = .07, respectively).

“The reported risk factors partially overlap with those reported for pancreatic adenocarcinoma, thus suggesting a possible organ-specific carcinogenic effect,” Dr Valente noted.

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

ORLANDO – Matrilin-2 – a matrix protein found in peritumoral stroma – reliably distinguished invasive basal cell carcinoma from the often difficult-to-distinguish basaloid follicular hamartoma (BFH), in a study that evaluated the protein as a marker in this setting.

The protein marked 41 of 42 cancers and none of the hamartomas, Dr. Renato Goreshi reported at the annual meeting of the American College of Mohs Surgery. The one cancer it failed to identify was a superficial basal cell tumor – a finding that makes sense, since dermal fibroblasts appear to secrete matrilin-2 as a response to invasive skin tumors, said Dr. Goreshi of the Roger Williams Cancer Center, Providence, R.I.

Mohs surgery typically employs hematoxylin and eosin staining to delineate tumor boundary. But, Dr. Goreshi said, that stain doesn’t always reliably differentiate adnexal tumors from basal cell carcinomas. “Basaloid follicular hamartoma can be particularly difficult to distinguish from basal cell carcinoma,” he said.

BFH typically presents as individual or linearly arranged, small skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk (Arch Pathol Lab Med. 2010 Aug;134[8]:1215-9). These are often stable for many years. The differential diagnosis includes basal cell carcinoma and trichoepithelioma.

BFH sometimes occurs near a BCC, although there are no data on how often this happens.

Dr. Goreshi cited a 2007 case report of a young woman that illustrates this problem. The patient presented with a basal cell carcinoma on the side of her nose. The adjacent BFH was unrecognized, however. She underwent a multiple-stage Mohs that was unnecessarily extended because tumor margins included sections of the BFH.

“The lesion was interpreted as malignancy by both the Mohs surgeon and the dermatopathologist, but was later determined to have been a hamartoma. This highlights the importance of finding an effective marker,” Dr. Goreshi said.

He and his fellowship director, Dr. Satori Iwamoto, chief of Mohs micrographic surgery at Roger Williams, looked for a reliable way to differentiate these tumors, capitalizing on the invasive nature of BCC. The peritumoral stroma plays a role in tumor growth and invasion. It involves fibroblasts, inflammatory and endothelial cells, and extracellular matrix proteins. Matrilin-2, which is involved in the formation of filamentous networks, was a promising candidate and the initial investigations looked good, said Dr. Goreshi said.

Their confirmatory study comprised 42 BCC and seven BFH sections that were obtained during Mohs surgery. All were stained for matrilin-2 and scored for location and intensity of staining by two reviewers. The investigators also conducted flow cytometry to determine the source of the protein.

The BCC set consisted of 11 morpheaform/infiltrative BCCs, 25 nodular BCCs, and 6 superficial BCCs. With the exception of one superficial lesion, all of these stained positive for matrilin-2 in the peritumoral stroma. None of the BFH sections stained positive for the protein, however. Flow cytometry determined that the protein was coming from dermal fibroblasts in the stroma.

This is actually a key point, Dr. Goreshi noted. “Matrilin-2 is not acting as a conventional tumor marker would, but as a marker of invasion.”

This was again played out in the variation of staining intensity in the tumor subtypes. It was most intense around the infiltrative subtypes. There was also adnexal staining, but it was significantly less than what was seen in the peritumoral stroma. There was virtually no staining in or around the hamartoma.

Staining was not as intense around the superficial BCC subtypes. In fact, it was not significantly different from what was seen in the adnexal structures. Again, however, there was no staining in or around the hamartoma.

“Now we are looking at the staining patterns of other lesions, including melanoma and squamous cell carcinoma, and trying to figure out why the dermal fibroblasts are secreting matrilin-2,” Dr. Goreshi said.

The study was the winner of the 2016 Theodore Tromovitch Award, presented for original research conducted by a fellow-in-training during his or her year of training.

Neither Dr. Goreshi nor Dr. Iwamoto had any relevant financial disclosures.

[email protected]

Black patients with hepatocellular carcinoma (HCC) have shorter survival and more adverse clinical features at diagnosis than do non-Hispanic whites and other races, according to a single-center review.

Blacks were at a 33% increased risk of death because of HCC, compared with non-Hispanic whites, and were diagnosed at a later stage with larger tumors. Thus, they were less likely to be eligible for curative transplantation, said Dr. Patricia D. Jones of the University of Miami, who presented her findings during a teleconference in advance of the annual Digestive Disease Week.

“We found that race was the strongest predictor of survival in a diverse sample of patients diagnosed with HCC,” said lead author Dr. Jones, who is also on the staff of the Sylvester Comprehensive Cancer Center at the university.

“Most research on racial disparity in medical illness comes from large retrospective databases such as SEER [Surveillance, Epidemiology, and End Results], which represents 28% of the U.S. population. Florida is excluded from the SEER database, but Florida has a diversity of patients as well as a diversity of practitioners. More than 50% of our study sample was born outside of the U.S.,” Dr. Jones explained.

The study included 999 patients diagnosed with HCC at the University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospitals between 2005 and 2014.

Based on a review of patient records, median survival following a diagnosis of HCC was 301 days for black patients, compared with 534 days for non-Hispanic whites and 437 days for Hispanics.

An analysis showed that median tumor size in blacks was 5.2 cm, compared with 3.9 cm in whites. “This seems like a small difference, but tumor size greater than 5 cm excludes a patient from transplantation, which is curative,” she said. “Larger tumor size also suggests inadequate screening and lack of access to medical care.”

After adjustment for factors such as alcohol use, tobacco use, insurance, and age at diagnosis, non-Hispanic whites had a 25% reduced risk of death and Hispanics, a 21% reduced risk of death, compared with black patients. Black patients were also significantly more likely to have hepatitis B virus (HBV), compared with non-Hispanic whites (24.1% vs. 7%, respectively; P less than .01), which increases the risk of developing HCC.

“Hepatitis B virus can be prevented by vaccination. This may be an underlying issue in this population,” according to Dr. Jones.

Patients who were eligible for and went on to have a liver transplant had a 66% reduction in death, compared with those who did not. Only 11.9% of black patients had a liver transplant, compared with 33.3% of non-Hispanic whites. When adjusted for transplant, the survival gap between races was narrowed. Among transplant recipients, non-Hispanic whites had an 8% reduction in risk of death and Hispanics, a 7% reduction, compared with blacks.

Dr. Jones and her coinvestigators plan to conduct further research to explore risk factors for HCC among their diverse patient population and identify opportunities to maximize education and screening.

One limitation of this study, she said, is that some information may be missing in studies based on records, and the severity of underlying liver disease was not known.

“Because this is a single-center study, we have the ability to go back and get more detailed information to understand racial disparities. For example, we can continue to review the charts of these patients to determine medical conditions and comorbidities,” she said. “So far, the factors that have emerged are socioeconomic, related to access to care and insurance.”

Dr. Jones had no relevant financial disclosures.

Black patients with hepatocellular carcinoma (HCC) have shorter survival and more adverse clinical features at diagnosis than do non-Hispanic whites and other races, according to a single-center review.

Blacks were at a 33% increased risk of death because of HCC, compared with non-Hispanic whites, and were diagnosed at a later stage with larger tumors. Thus, they were less likely to be eligible for curative transplantation, said Dr. Patricia D. Jones of the University of Miami, who presented her findings during a teleconference in advance of the annual Digestive Disease Week.

“We found that race was the strongest predictor of survival in a diverse sample of patients diagnosed with HCC,” said lead author Dr. Jones, who is also on the staff of the Sylvester Comprehensive Cancer Center at the university.

“Most research on racial disparity in medical illness comes from large retrospective databases such as SEER [Surveillance, Epidemiology, and End Results], which represents 28% of the U.S. population. Florida is excluded from the SEER database, but Florida has a diversity of patients as well as a diversity of practitioners. More than 50% of our study sample was born outside of the U.S.,” Dr. Jones explained.

The study included 999 patients diagnosed with HCC at the University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospitals between 2005 and 2014.

Based on a review of patient records, median survival following a diagnosis of HCC was 301 days for black patients, compared with 534 days for non-Hispanic whites and 437 days for Hispanics.

An analysis showed that median tumor size in blacks was 5.2 cm, compared with 3.9 cm in whites. “This seems like a small difference, but tumor size greater than 5 cm excludes a patient from transplantation, which is curative,” she said. “Larger tumor size also suggests inadequate screening and lack of access to medical care.”

After adjustment for factors such as alcohol use, tobacco use, insurance, and age at diagnosis, non-Hispanic whites had a 25% reduced risk of death and Hispanics, a 21% reduced risk of death, compared with black patients. Black patients were also significantly more likely to have hepatitis B virus (HBV), compared with non-Hispanic whites (24.1% vs. 7%, respectively; P less than .01), which increases the risk of developing HCC.

“Hepatitis B virus can be prevented by vaccination. This may be an underlying issue in this population,” according to Dr. Jones.

Patients who were eligible for and went on to have a liver transplant had a 66% reduction in death, compared with those who did not. Only 11.9% of black patients had a liver transplant, compared with 33.3% of non-Hispanic whites. When adjusted for transplant, the survival gap between races was narrowed. Among transplant recipients, non-Hispanic whites had an 8% reduction in risk of death and Hispanics, a 7% reduction, compared with blacks.

Dr. Jones and her coinvestigators plan to conduct further research to explore risk factors for HCC among their diverse patient population and identify opportunities to maximize education and screening.

One limitation of this study, she said, is that some information may be missing in studies based on records, and the severity of underlying liver disease was not known.

“Because this is a single-center study, we have the ability to go back and get more detailed information to understand racial disparities. For example, we can continue to review the charts of these patients to determine medical conditions and comorbidities,” she said. “So far, the factors that have emerged are socioeconomic, related to access to care and insurance.”

Dr. Jones had no relevant financial disclosures.

Black patients with hepatocellular carcinoma (HCC) have shorter survival and more adverse clinical features at diagnosis than do non-Hispanic whites and other races, according to a single-center review.

Blacks were at a 33% increased risk of death because of HCC, compared with non-Hispanic whites, and were diagnosed at a later stage with larger tumors. Thus, they were less likely to be eligible for curative transplantation, said Dr. Patricia D. Jones of the University of Miami, who presented her findings during a teleconference in advance of the annual Digestive Disease Week.

“We found that race was the strongest predictor of survival in a diverse sample of patients diagnosed with HCC,” said lead author Dr. Jones, who is also on the staff of the Sylvester Comprehensive Cancer Center at the university.

“Most research on racial disparity in medical illness comes from large retrospective databases such as SEER [Surveillance, Epidemiology, and End Results], which represents 28% of the U.S. population. Florida is excluded from the SEER database, but Florida has a diversity of patients as well as a diversity of practitioners. More than 50% of our study sample was born outside of the U.S.,” Dr. Jones explained.

The study included 999 patients diagnosed with HCC at the University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospitals between 2005 and 2014.

Based on a review of patient records, median survival following a diagnosis of HCC was 301 days for black patients, compared with 534 days for non-Hispanic whites and 437 days for Hispanics.

An analysis showed that median tumor size in blacks was 5.2 cm, compared with 3.9 cm in whites. “This seems like a small difference, but tumor size greater than 5 cm excludes a patient from transplantation, which is curative,” she said. “Larger tumor size also suggests inadequate screening and lack of access to medical care.”

After adjustment for factors such as alcohol use, tobacco use, insurance, and age at diagnosis, non-Hispanic whites had a 25% reduced risk of death and Hispanics, a 21% reduced risk of death, compared with black patients. Black patients were also significantly more likely to have hepatitis B virus (HBV), compared with non-Hispanic whites (24.1% vs. 7%, respectively; P less than .01), which increases the risk of developing HCC.

“Hepatitis B virus can be prevented by vaccination. This may be an underlying issue in this population,” according to Dr. Jones.

Patients who were eligible for and went on to have a liver transplant had a 66% reduction in death, compared with those who did not. Only 11.9% of black patients had a liver transplant, compared with 33.3% of non-Hispanic whites. When adjusted for transplant, the survival gap between races was narrowed. Among transplant recipients, non-Hispanic whites had an 8% reduction in risk of death and Hispanics, a 7% reduction, compared with blacks.

Dr. Jones and her coinvestigators plan to conduct further research to explore risk factors for HCC among their diverse patient population and identify opportunities to maximize education and screening.

One limitation of this study, she said, is that some information may be missing in studies based on records, and the severity of underlying liver disease was not known.

“Because this is a single-center study, we have the ability to go back and get more detailed information to understand racial disparities. For example, we can continue to review the charts of these patients to determine medical conditions and comorbidities,” she said. “So far, the factors that have emerged are socioeconomic, related to access to care and insurance.”

Dr. Jones had no relevant financial disclosures.

SAN DIEGO – A panel of four fecal bacteria can reliably discriminate between colorectal cancer (CRC) patients and controls. Combining these four biomarkers with the fecal immunochemical test (FIT) further increases the sensitivity and specificity for CRC.

“This study establishes a reliable platform for a convenient translational approach of using new markers identified by a metagenomics approach. This panel, in combination with other modalities, may be useful for a noninvasive method of diagnosing CRC. Our data look most promising for the combination of FIT plus the four biomarkers,” Dr. Jessie Qiaoyi Liang said at a presentation during the annual Digestive Disease Week.

In this study, FIT had a sensitivity of 70.3% and a specificity of 98.3%. Using the four biomarkers led to a sensitivity of 83.8% and a specificity of 83.2%, while combining them with FIT achieved a sensitivity of 92.8% and a specificity of 81.5%.

The four bacteria included Fusobacterium nucleatum (Fn, a previously identified biomarker), as well as three newly described candidates: Bacteroides clarus (Bc), Clostridium hathewayi (Ch), and one undefined species (in-house label ‘m7’).

The study evaluated the utility of fecal bacterial marker candidates by metagenomic sequencing for the diagnosis of CRC using the simple, cost-effective and targeted method of quantitative PCR.

A strong correlation was observed between qPCR assays and the metagenomic approach for these candidate bacteria. The four bacteria were selected from 21 candidate bacteria. Each of the four candidates was analyzed separately and in combination to determine their utility for the diagnosis of CRC.

The four biomarkers were validated in stool samples from two cohorts of patients prior to undergoing colonoscopy: a Hong Kong cohort of 370 patients (170 found to have CRC and 200 controls) and a second cohort of Shanghai patients (total 69, 33 CRC patients and 36 controls).

All four were found to significantly discriminate between CRC and controls in both cohorts of patients

Next, the researchers looked at these four bacteria and compared them with Fn, m7, and Bc in a cohort of 230 subjects from Hong Kong – 111 with CRC and 119 controls. The four-bacteria panel was significantly better than the three-bacteria panel.

In that same cohort of patients, they compared FIT alone, the four bacteria panel alone, and the combination of the two. The four markers had higher sensitivity compared to FIT alone for stage 1 colorectal cancer, but sensitivity was similar to FIT for stages II, III, and IV.

Using both FIT and the four-bacteria panel increased the sensitivity from 70.3% for FIT to 92.8%.

“At this time, we can say this is promising research. The panel cannot be used in the clinical setting. We plan further studies. The combination of FIT plus the four biomarkers looks the most promising,” said Dr. Liang, a research assistant professor at the Chinese University of Hong Kong.

She noted that the panel is not discriminatory enough for adenoma patients. “We are still looking for other markers for adenomas,” she said.

Commenting on the state of the art for biomarkers in gastrointestinal cancer, Dr. Joseph Sung, Chinese University of Hong Kong, said that there are thousands of biomarkers under study.

“Combinations of biomarkers will turn out to be more useful. They should be used in combination with other diagnostic modules. Cancer biomarkers require large validation studies in different populations.

“We are unlikely to find a single magic bullet,” he said. “The list of biomarkers will continue to grow. All are undergoing larger-scale validation in centers in China, but we need to be cognizant that populations around the world will not have the same biomarkers. The real issue in microbiome markers is geographic variation,” he stated.

SAN DIEGO – A panel of four fecal bacteria can reliably discriminate between colorectal cancer (CRC) patients and controls. Combining these four biomarkers with the fecal immunochemical test (FIT) further increases the sensitivity and specificity for CRC.

“This study establishes a reliable platform for a convenient translational approach of using new markers identified by a metagenomics approach. This panel, in combination with other modalities, may be useful for a noninvasive method of diagnosing CRC. Our data look most promising for the combination of FIT plus the four biomarkers,” Dr. Jessie Qiaoyi Liang said at a presentation during the annual Digestive Disease Week.

In this study, FIT had a sensitivity of 70.3% and a specificity of 98.3%. Using the four biomarkers led to a sensitivity of 83.8% and a specificity of 83.2%, while combining them with FIT achieved a sensitivity of 92.8% and a specificity of 81.5%.

The four bacteria included Fusobacterium nucleatum (Fn, a previously identified biomarker), as well as three newly described candidates: Bacteroides clarus (Bc), Clostridium hathewayi (Ch), and one undefined species (in-house label ‘m7’).

The study evaluated the utility of fecal bacterial marker candidates by metagenomic sequencing for the diagnosis of CRC using the simple, cost-effective and targeted method of quantitative PCR.

A strong correlation was observed between qPCR assays and the metagenomic approach for these candidate bacteria. The four bacteria were selected from 21 candidate bacteria. Each of the four candidates was analyzed separately and in combination to determine their utility for the diagnosis of CRC.

The four biomarkers were validated in stool samples from two cohorts of patients prior to undergoing colonoscopy: a Hong Kong cohort of 370 patients (170 found to have CRC and 200 controls) and a second cohort of Shanghai patients (total 69, 33 CRC patients and 36 controls).

All four were found to significantly discriminate between CRC and controls in both cohorts of patients

Next, the researchers looked at these four bacteria and compared them with Fn, m7, and Bc in a cohort of 230 subjects from Hong Kong – 111 with CRC and 119 controls. The four-bacteria panel was significantly better than the three-bacteria panel.

In that same cohort of patients, they compared FIT alone, the four bacteria panel alone, and the combination of the two. The four markers had higher sensitivity compared to FIT alone for stage 1 colorectal cancer, but sensitivity was similar to FIT for stages II, III, and IV.

Using both FIT and the four-bacteria panel increased the sensitivity from 70.3% for FIT to 92.8%.

“At this time, we can say this is promising research. The panel cannot be used in the clinical setting. We plan further studies. The combination of FIT plus the four biomarkers looks the most promising,” said Dr. Liang, a research assistant professor at the Chinese University of Hong Kong.

She noted that the panel is not discriminatory enough for adenoma patients. “We are still looking for other markers for adenomas,” she said.

Commenting on the state of the art for biomarkers in gastrointestinal cancer, Dr. Joseph Sung, Chinese University of Hong Kong, said that there are thousands of biomarkers under study.

“Combinations of biomarkers will turn out to be more useful. They should be used in combination with other diagnostic modules. Cancer biomarkers require large validation studies in different populations.

“We are unlikely to find a single magic bullet,” he said. “The list of biomarkers will continue to grow. All are undergoing larger-scale validation in centers in China, but we need to be cognizant that populations around the world will not have the same biomarkers. The real issue in microbiome markers is geographic variation,” he stated.

SAN DIEGO – A panel of four fecal bacteria can reliably discriminate between colorectal cancer (CRC) patients and controls. Combining these four biomarkers with the fecal immunochemical test (FIT) further increases the sensitivity and specificity for CRC.

“This study establishes a reliable platform for a convenient translational approach of using new markers identified by a metagenomics approach. This panel, in combination with other modalities, may be useful for a noninvasive method of diagnosing CRC. Our data look most promising for the combination of FIT plus the four biomarkers,” Dr. Jessie Qiaoyi Liang said at a presentation during the annual Digestive Disease Week.

In this study, FIT had a sensitivity of 70.3% and a specificity of 98.3%. Using the four biomarkers led to a sensitivity of 83.8% and a specificity of 83.2%, while combining them with FIT achieved a sensitivity of 92.8% and a specificity of 81.5%.

The four bacteria included Fusobacterium nucleatum (Fn, a previously identified biomarker), as well as three newly described candidates: Bacteroides clarus (Bc), Clostridium hathewayi (Ch), and one undefined species (in-house label ‘m7’).

The study evaluated the utility of fecal bacterial marker candidates by metagenomic sequencing for the diagnosis of CRC using the simple, cost-effective and targeted method of quantitative PCR.

A strong correlation was observed between qPCR assays and the metagenomic approach for these candidate bacteria. The four bacteria were selected from 21 candidate bacteria. Each of the four candidates was analyzed separately and in combination to determine their utility for the diagnosis of CRC.

The four biomarkers were validated in stool samples from two cohorts of patients prior to undergoing colonoscopy: a Hong Kong cohort of 370 patients (170 found to have CRC and 200 controls) and a second cohort of Shanghai patients (total 69, 33 CRC patients and 36 controls).

All four were found to significantly discriminate between CRC and controls in both cohorts of patients

Next, the researchers looked at these four bacteria and compared them with Fn, m7, and Bc in a cohort of 230 subjects from Hong Kong – 111 with CRC and 119 controls. The four-bacteria panel was significantly better than the three-bacteria panel.

In that same cohort of patients, they compared FIT alone, the four bacteria panel alone, and the combination of the two. The four markers had higher sensitivity compared to FIT alone for stage 1 colorectal cancer, but sensitivity was similar to FIT for stages II, III, and IV.

Using both FIT and the four-bacteria panel increased the sensitivity from 70.3% for FIT to 92.8%.

“At this time, we can say this is promising research. The panel cannot be used in the clinical setting. We plan further studies. The combination of FIT plus the four biomarkers looks the most promising,” said Dr. Liang, a research assistant professor at the Chinese University of Hong Kong.

She noted that the panel is not discriminatory enough for adenoma patients. “We are still looking for other markers for adenomas,” she said.

Commenting on the state of the art for biomarkers in gastrointestinal cancer, Dr. Joseph Sung, Chinese University of Hong Kong, said that there are thousands of biomarkers under study.

“Combinations of biomarkers will turn out to be more useful. They should be used in combination with other diagnostic modules. Cancer biomarkers require large validation studies in different populations.

“We are unlikely to find a single magic bullet,” he said. “The list of biomarkers will continue to grow. All are undergoing larger-scale validation in centers in China, but we need to be cognizant that populations around the world will not have the same biomarkers. The real issue in microbiome markers is geographic variation,” he stated.

The Vascular Annual Meeting – affectionately known as VAM – is in little over a week. For those who haven’t registered yet, what are you waiting for?

When registration hits 1,485 – the number of people registered in 2015 BEFORE VAM opened – all registrants are entered into a drawing to win a new iPad Pro.

Don’t wait -- register today.

The Vascular Annual Meeting – affectionately known as VAM – is in little over a week. For those who haven’t registered yet, what are you waiting for?

When registration hits 1,485 – the number of people registered in 2015 BEFORE VAM opened – all registrants are entered into a drawing to win a new iPad Pro.

Don’t wait -- register today.

The Vascular Annual Meeting – affectionately known as VAM – is in little over a week. For those who haven’t registered yet, what are you waiting for?

When registration hits 1,485 – the number of people registered in 2015 BEFORE VAM opened – all registrants are entered into a drawing to win a new iPad Pro.

Don’t wait -- register today.

FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.

Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.

Mitchel L. Zoler/Frontline Medical News

This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.

The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.

Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.

The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.

But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.

“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”

Mitchel L. Zoler/Frontline Medical News

Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”

She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.

Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.

The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m².

In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.

Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.

Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.

Mitchel L. Zoler/Frontline Medical News

This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.

The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.

Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.

The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.

But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.

“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”

Mitchel L. Zoler/Frontline Medical News

Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”

She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.

Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.

The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m².

In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.

Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.

[email protected]

On Twitter @mitchelzoler

FLORENCE, ITALY – In patients with moderate to severe central sleep apnea, an implanted device that stimulates the phrenic nerve to optimize diaphragm-driven breathing met its efficacy and safety goals, based on results from a multicenter, controlled trial with 151 patients.

Among the 68 patients randomized to active treatment with the device and available for follow-up after 6 months on treatment, 35 patients (51%) had a 50% or better reduction in their apnea-hypopnea index compared with 8 of 73 patients (11%) who had this level of response following device implantation but without its active use.

Mitchel L. Zoler/Frontline Medical News

This statistically significant difference in response to the study’s primary endpoint should pave the way for the device’s approval, Dr. Maria Rosa Costanzo said at a meeting held by the Heart Failure Association of the European Society of Cardiology.

Although the trial enrolled patients with a mix of disorders that caused their central sleep apnea, the majority, 80 patients, had heart failure. Other enrollees had their breathing disorder secondary to atrial fibrillation, hypertension, and other diseases, suggesting that the implanted device, called the remede System, is suitable for patients with moderate to severe central sleep apnea regardless of the etiology, said Dr. Costanzo, medical director for heart failure at the Advocate Medical Group in Naperville, Ill. Among the 80 heart failure patients in the trial, the percentage of patients on active treatment who had a 50% or better reduction in their apnea-hypopnea index closely matched the rate in the entire study group.

The results also demonstrated the treatment’s safety, with a 9% rate of serious adverse events secondary to either the device’s implantation or function during the 12 months following placement in all 151 patients enrolled. Patients in the control arm had a device implanted but not turned on during the first 6 months of the study. The device was turned on and they received active treatment during the next 6 months. The trial’s prespecified safety goal, developed in conjunction with the Food and Drug Administration, was a 1-year rate of freedom from a serious adverse event of at least 80%; the actual rate achieved was 91%.

Successful implantation of the device by electrophysiology cardiologists occurred in 97% of enrolled patients, a procedure that took an average of nearly 3 hours. Need for a lead revision, one of the serious adverse events tallied during follow-up, occurred in 3% of patients. No patients in the study died during 1-year follow-up. Most other serious adverse events involved lead reposition (but not revision) to better optimize the phrenic nerve stimulation. Dr. Costanzo likened the complexity of implanting and operating the device to placement and use of a cardiac resynchronization device.

The efficacy and safety of the device shown in this pivotal trial “should be plenty” for obtaining FDA approval, predicted Dr. Costanzo, the study’s lead investigator, which would make it the first approved intervention for central sleep apnea. “I think this is a game changer,” she said in an interview.

But coming less than a year after a report of an unexpected excess-mortality rate in heart failure patients treated for central sleep apnea with an adaptive servo-ventilation device (N Engl J Med. 2015 Sept 17;373[12]:1095-1105), heart-failure specialists are now more demanding about the data needed to prove safety and clinical benefit from an intervention that targets central sleep apnea and sleep-disordered breathing.

“I think we need an endpoint that involves hospitalizations and death” to more clearly demonstrate meaningful clinical benefit and safety, said Dr. Mariell Jessup, a professor of medicine and heart failure specialist at the University of Pennsylvania in Philadelphia. Following the experience with increased mortality from servo-ventilation “we now need to demand” more comprehensive safety data in sleep trials. Also, the approach tested in this study involves “putting a device into patients, so it’s not completely benign,” she said in an interview. “A lot of things that we thought made a lot of sense, like treating a heart-failure patient’s sleep apnea, turned out to cause things we didn’t expect. We need to be cautious.”

Mitchel L. Zoler/Frontline Medical News

Dr. Costanzo agreed that there is need for additional studies of the phrenic-nerve stimulating device in larger number of heart failure patients that involve heart-failure-specific endpoints. But she also stressed how life changing this intervention was for some of the patients in the study. “The transformation of their lives was unbelievable. They said things like ‘I feel I have my life back.’ ”

She also stressed that the mechanism of action of phrenic nerve stimulation is dramatically different from more traditional sleep-apnea treatments that have relied on positive air pressure devices.

Phrenic nerve stimulation causes contraction of a patient’s diaphragm that creates negative pressure within the chest cavity in a manner similar to that of natural breathing. The stimulation is adjusted to make it imperceptible to patients, and stimulation does not occur when a patient is standing or sitting, only when lying down. “With positive airway pressure in patients with advanced heart failure you reduce venous return, and when a patient’s heart is sick and depends on preload this can hurt the patient. Phrenic nerve stimulation does the opposite. It contracts the diaphragm and creates negative pressure, so it anything it facilitates venous return,” she explained.

The trial, run at 31 centers, mostly in the United States with the others in Europe, enrolled patients with moderate to severe central sleep apnea with an average apnea-hypopnea index of 45 episodes per hour while sleeping. The average age was 65 years, about 90% of the patients were men, and average body mass index was 31 kg/m².

In addition to the primary efficacy endpoint of reduced apnea-hypopnea index, the patients on active treatment also showed statistically significant reductions compared with baseline in central apnea episodes and in daytime sleepiness measured on the Epworth Sleepiness Scale and an improvement in the patients’ global assessment of their condition. The changes did not occur in the control patients. In the treated patients central apnea episodes fell from an average of 32 episodes per hour at baseline to an average of 6 central episodes an hour after 6 months on treatment.

Dr. Costanzo is a consultant to and has received research support from Respicardia, the company developing the tested phrenic-nerve stimulation device. Dr. Jessup had no disclosures.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – A retrospective study provides insight as to why some patients have a milder versus a more severe course of inflammatory bowel disease (IBD) after liver transplant for primary sclerosing cholangitis (PSC).

Recurrent PSC, prolonged use of steroids, and cancer development after liver transplant were associated with a milder course of IBD, but tacrolimus use was associated with increased IBD flare post transplant.

Alice Goodman/Frontline Medical News

“The course of IBD is highly variable after liver transplant for PSC. PSC is associated with IBD in 60% to 90% of patients, and IBD worsens in about 30% of PSC-IBD patients after transplant. We wanted to explore the risk factors for worsening IBD in this setting,” Dr. Mohamad Mouchli of the Mayo Clinic in Rochester, Minn., explained at the annual Digestive Disease Week.

For purposes of this study, progression of IBD was defined as the need for escalation of medical therapy, compared with before liver transplant, or need for colectomy for medically refractory IBD.

The study population included patients with PSC-IBD who underwent liver transplant for noncholangiocarcinoma indications at the Mayo Clinic from 1998 to 2012. Patients were followed through February 2015.

The investigators screened 373 patients: After exclusions for cancer, no IBD at transplant, and pretransplant colectomy, 151 patients with an intact colon were left and formed the basis of further analysis.

Median age at transplant was 46 years and two-thirds of the patients were male. Transplant-related variables included the following: 23% experienced allograft failure, 36% had recurrent PSC, 25.2% had CMV infection, 19.2% were retransplanted, 22.5% developed cancer after liver transplant, and 52.3% had acute cellular rejection.

Before transplant, 69 patients had quiescent IBD with no therapy and 62 were maintained on 5-aminosalicylates. Post transplant, despite transplant-related immunosuppression, 56 patients (37.1%) required escalation of therapy, 87 patients (57.6%) had a stable course, and 8 patients (5.3%) improved.

Risk of IBD progression at 1, 5, and 10 years was 4%, 18.5%, and 25.5%, respectively. Thirty-five patients underwent colectomy after transplant: the 1-, 5-, and 10-year risks of colectomy were 2%, 9.3%, and 17.2%, respectively. Fourteen percent of patients required anti–tumor necrosis factor therapy after transplant.

On multivariate analysis, tacrolimus exposure emerged as a risk factor for progression of IBD. Tacrolimus immunosuppression was twice as likely as cyclosporine-based immunosuppression to lead to IBD progression. By contrast, recurrent PSC, use of steroids for longer than 6 months, and cancer development after liver transplant were protective of IBD progression.

No association was found between progression of IBD and transplant-related infection or mismatch, immunosuppression with mycophenolate or azathioprine, or IBD-related factors such as pretransplant IBD status or empirical initiation of 5-aminosalicylates within 4 months of liver transplant. During the question-and-answer session following his presentation, Dr. Mouchli was asked whether these results justify prophylactic colectomy. He said that could be considered in patients with active IBD before transplant, but on a case-by-case basis.

SAN DIEGO – A retrospective study provides insight as to why some patients have a milder versus a more severe course of inflammatory bowel disease (IBD) after liver transplant for primary sclerosing cholangitis (PSC).

Recurrent PSC, prolonged use of steroids, and cancer development after liver transplant were associated with a milder course of IBD, but tacrolimus use was associated with increased IBD flare post transplant.

Alice Goodman/Frontline Medical News

“The course of IBD is highly variable after liver transplant for PSC. PSC is associated with IBD in 60% to 90% of patients, and IBD worsens in about 30% of PSC-IBD patients after transplant. We wanted to explore the risk factors for worsening IBD in this setting,” Dr. Mohamad Mouchli of the Mayo Clinic in Rochester, Minn., explained at the annual Digestive Disease Week.

For purposes of this study, progression of IBD was defined as the need for escalation of medical therapy, compared with before liver transplant, or need for colectomy for medically refractory IBD.

The study population included patients with PSC-IBD who underwent liver transplant for noncholangiocarcinoma indications at the Mayo Clinic from 1998 to 2012. Patients were followed through February 2015.

The investigators screened 373 patients: After exclusions for cancer, no IBD at transplant, and pretransplant colectomy, 151 patients with an intact colon were left and formed the basis of further analysis.

Median age at transplant was 46 years and two-thirds of the patients were male. Transplant-related variables included the following: 23% experienced allograft failure, 36% had recurrent PSC, 25.2% had CMV infection, 19.2% were retransplanted, 22.5% developed cancer after liver transplant, and 52.3% had acute cellular rejection.

Before transplant, 69 patients had quiescent IBD with no therapy and 62 were maintained on 5-aminosalicylates. Post transplant, despite transplant-related immunosuppression, 56 patients (37.1%) required escalation of therapy, 87 patients (57.6%) had a stable course, and 8 patients (5.3%) improved.

Risk of IBD progression at 1, 5, and 10 years was 4%, 18.5%, and 25.5%, respectively. Thirty-five patients underwent colectomy after transplant: the 1-, 5-, and 10-year risks of colectomy were 2%, 9.3%, and 17.2%, respectively. Fourteen percent of patients required anti–tumor necrosis factor therapy after transplant.

On multivariate analysis, tacrolimus exposure emerged as a risk factor for progression of IBD. Tacrolimus immunosuppression was twice as likely as cyclosporine-based immunosuppression to lead to IBD progression. By contrast, recurrent PSC, use of steroids for longer than 6 months, and cancer development after liver transplant were protective of IBD progression.

No association was found between progression of IBD and transplant-related infection or mismatch, immunosuppression with mycophenolate or azathioprine, or IBD-related factors such as pretransplant IBD status or empirical initiation of 5-aminosalicylates within 4 months of liver transplant. During the question-and-answer session following his presentation, Dr. Mouchli was asked whether these results justify prophylactic colectomy. He said that could be considered in patients with active IBD before transplant, but on a case-by-case basis.

SAN DIEGO – A retrospective study provides insight as to why some patients have a milder versus a more severe course of inflammatory bowel disease (IBD) after liver transplant for primary sclerosing cholangitis (PSC).

Recurrent PSC, prolonged use of steroids, and cancer development after liver transplant were associated with a milder course of IBD, but tacrolimus use was associated with increased IBD flare post transplant.

Alice Goodman/Frontline Medical News

“The course of IBD is highly variable after liver transplant for PSC. PSC is associated with IBD in 60% to 90% of patients, and IBD worsens in about 30% of PSC-IBD patients after transplant. We wanted to explore the risk factors for worsening IBD in this setting,” Dr. Mohamad Mouchli of the Mayo Clinic in Rochester, Minn., explained at the annual Digestive Disease Week.

For purposes of this study, progression of IBD was defined as the need for escalation of medical therapy, compared with before liver transplant, or need for colectomy for medically refractory IBD.

The study population included patients with PSC-IBD who underwent liver transplant for noncholangiocarcinoma indications at the Mayo Clinic from 1998 to 2012. Patients were followed through February 2015.

The investigators screened 373 patients: After exclusions for cancer, no IBD at transplant, and pretransplant colectomy, 151 patients with an intact colon were left and formed the basis of further analysis.

Median age at transplant was 46 years and two-thirds of the patients were male. Transplant-related variables included the following: 23% experienced allograft failure, 36% had recurrent PSC, 25.2% had CMV infection, 19.2% were retransplanted, 22.5% developed cancer after liver transplant, and 52.3% had acute cellular rejection.

Before transplant, 69 patients had quiescent IBD with no therapy and 62 were maintained on 5-aminosalicylates. Post transplant, despite transplant-related immunosuppression, 56 patients (37.1%) required escalation of therapy, 87 patients (57.6%) had a stable course, and 8 patients (5.3%) improved.

Risk of IBD progression at 1, 5, and 10 years was 4%, 18.5%, and 25.5%, respectively. Thirty-five patients underwent colectomy after transplant: the 1-, 5-, and 10-year risks of colectomy were 2%, 9.3%, and 17.2%, respectively. Fourteen percent of patients required anti–tumor necrosis factor therapy after transplant.

On multivariate analysis, tacrolimus exposure emerged as a risk factor for progression of IBD. Tacrolimus immunosuppression was twice as likely as cyclosporine-based immunosuppression to lead to IBD progression. By contrast, recurrent PSC, use of steroids for longer than 6 months, and cancer development after liver transplant were protective of IBD progression.

No association was found between progression of IBD and transplant-related infection or mismatch, immunosuppression with mycophenolate or azathioprine, or IBD-related factors such as pretransplant IBD status or empirical initiation of 5-aminosalicylates within 4 months of liver transplant. During the question-and-answer session following his presentation, Dr. Mouchli was asked whether these results justify prophylactic colectomy. He said that could be considered in patients with active IBD before transplant, but on a case-by-case basis.

Clinical question: What are the current recommendations for antithrombotic therapy in various venous thromboembolism (VTE) scenarios?

Background: VTE is commonly encountered with a multitude of therapeutic options. Selecting the optimal anticoagulant is as important as making the diagnosis and requires knowledge of individual patient characteristics to initiate the correct therapy. These factors include malignancy, location of thrombus, and history of recurrent VTE despite anticoagulation.

Study design: Guideline.

Setting: Expert panel.

Synopsis: For VTE patients without cancer, non-vitamin K oral anticoagulants (NOAC) are now suggested over vitamin K antagonists (Grade 2B). However, there remains no strong evidence to favor one NOAC over another.

Better evidence now supports the prior recommendation to discourage IVC filters for VTE that is being treated with anticoagulation (Grade 1B).

In pulmonary embolism of the subsegmental type without proximal DVT, clinical surveillance is favored over anticoagulation in lower-risk patients (Grade 2C).

Low-molecular-weight heparin (LMWH) is advised in recurrent VTE treated with non-LMWH, and for recurrences on LMWH, a dose increase of LMWH is advised (Grade 2C).

Finally, routine use of compression stockings for post-thrombotic syndrome prevention is not routinely recommended (Grade 2B).

Limitations include only 20 of the 54 total recommendations being of strong Grade 1 criteria. Additionally, none of the 54 statements are drawn from high-quality evidence.

Further study is needed to continually update our practice in caring for VTE disease as more experience and comparison data are obtained with the use of NOAC drugs.

Bottom line: Anticoagulant therapy recommendations have been updated, but few are strong recommendations and none are based on high-quality evidence.

Citation: Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.

Clinical question: What are the current recommendations for antithrombotic therapy in various venous thromboembolism (VTE) scenarios?

Background: VTE is commonly encountered with a multitude of therapeutic options. Selecting the optimal anticoagulant is as important as making the diagnosis and requires knowledge of individual patient characteristics to initiate the correct therapy. These factors include malignancy, location of thrombus, and history of recurrent VTE despite anticoagulation.

Study design: Guideline.

Setting: Expert panel.

Synopsis: For VTE patients without cancer, non-vitamin K oral anticoagulants (NOAC) are now suggested over vitamin K antagonists (Grade 2B). However, there remains no strong evidence to favor one NOAC over another.

Better evidence now supports the prior recommendation to discourage IVC filters for VTE that is being treated with anticoagulation (Grade 1B).

In pulmonary embolism of the subsegmental type without proximal DVT, clinical surveillance is favored over anticoagulation in lower-risk patients (Grade 2C).

Low-molecular-weight heparin (LMWH) is advised in recurrent VTE treated with non-LMWH, and for recurrences on LMWH, a dose increase of LMWH is advised (Grade 2C).

Finally, routine use of compression stockings for post-thrombotic syndrome prevention is not routinely recommended (Grade 2B).

Limitations include only 20 of the 54 total recommendations being of strong Grade 1 criteria. Additionally, none of the 54 statements are drawn from high-quality evidence.

Further study is needed to continually update our practice in caring for VTE disease as more experience and comparison data are obtained with the use of NOAC drugs.

Bottom line: Anticoagulant therapy recommendations have been updated, but few are strong recommendations and none are based on high-quality evidence.

Citation: Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.

Clinical question: What are the current recommendations for antithrombotic therapy in various venous thromboembolism (VTE) scenarios?

Background: VTE is commonly encountered with a multitude of therapeutic options. Selecting the optimal anticoagulant is as important as making the diagnosis and requires knowledge of individual patient characteristics to initiate the correct therapy. These factors include malignancy, location of thrombus, and history of recurrent VTE despite anticoagulation.

Study design: Guideline.

Setting: Expert panel.

Synopsis: For VTE patients without cancer, non-vitamin K oral anticoagulants (NOAC) are now suggested over vitamin K antagonists (Grade 2B). However, there remains no strong evidence to favor one NOAC over another.

Better evidence now supports the prior recommendation to discourage IVC filters for VTE that is being treated with anticoagulation (Grade 1B).

In pulmonary embolism of the subsegmental type without proximal DVT, clinical surveillance is favored over anticoagulation in lower-risk patients (Grade 2C).

Low-molecular-weight heparin (LMWH) is advised in recurrent VTE treated with non-LMWH, and for recurrences on LMWH, a dose increase of LMWH is advised (Grade 2C).

Finally, routine use of compression stockings for post-thrombotic syndrome prevention is not routinely recommended (Grade 2B).

Limitations include only 20 of the 54 total recommendations being of strong Grade 1 criteria. Additionally, none of the 54 statements are drawn from high-quality evidence.

Further study is needed to continually update our practice in caring for VTE disease as more experience and comparison data are obtained with the use of NOAC drugs.

Bottom line: Anticoagulant therapy recommendations have been updated, but few are strong recommendations and none are based on high-quality evidence.

Citation: Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.

Clinical question: Is tamsulosin efficacious as an expulsive therapy for distal ureter stones ≤10 mm in diameter?

Background: Ureteric calculi are a common reason for hospital admission, and use of medical expulsive therapy during observation periods for small caliber stones has gained much attention recently. Specifically, tamsulosin has been suggested as a medical therapy for small stones.

Study design: Randomized, double-blind, placebo-controlled study.

Setting: Five EDs in Australia.

Synopsis: A total of 403 patients participated in the study, based on inclusion criteria of age older than 18 years with symptoms and CT evidence of ureteric stones Exclusion criteria included fever, glomerular filtration rate <60, and calculi >10 mm. Patients were randomized to placebo or 0.4 mg tamsulosin daily for 28 days. The outcome was stone expulsion demonstrated by absence of calculi on repeat CT. Stone passage in the entire group occurred in 87% of the tamsulosin arm and 81.9% of the placebo, with a 95% CI of -3.0% to 13%, which was not a significant difference with P=0.22.

Interestingly, in a subgroup analysis of larger stones 5–10 mm, 83% of tamsulosin subjects compared to 61% of placebo subjects had stone passage that was significant at a 22% difference and P=.03.

Limitations included compliance in both groups, applicability to other populations given study based in Australia, and the lack of follow-through with CT scan at 28 days in 17% of the original group, resulting in missing outcome data.

Bottom line: Patients with ureteric stones 5–10 mm in size demonstrate increased spontaneous stone expulsion with the addition of tamsulosin and should thus be offered this therapy.

Citation: Furyk J, Chu K, Banks C, et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med. 2016;67(1):86-95.e2.

Short Take

Low Diagnostic Yield of Blood Cultures in Hospitalized Medical Patients

Prospective cohort study of patients hospitalized on a medical service demonstrated a true positive rate of blood cultures that was lower than previously studied. Using objective clinical predictors may improve likelihood of true positive blood cultures.

Citation: Linsenmeyer K, Gupta K, Strymish JM, Dhanani M, Brecher SM, Breu AC. Culture if spikes? Indications and yield of blood cultures in hospitalized medical patients [published online ahead of print January 13, 2016]. J Hosp Med. doi:10.1002/jhm.2541.

Clinical question: Is tamsulosin efficacious as an expulsive therapy for distal ureter stones ≤10 mm in diameter?

Background: Ureteric calculi are a common reason for hospital admission, and use of medical expulsive therapy during observation periods for small caliber stones has gained much attention recently. Specifically, tamsulosin has been suggested as a medical therapy for small stones.

Study design: Randomized, double-blind, placebo-controlled study.

Setting: Five EDs in Australia.

Synopsis: A total of 403 patients participated in the study, based on inclusion criteria of age older than 18 years with symptoms and CT evidence of ureteric stones Exclusion criteria included fever, glomerular filtration rate <60, and calculi >10 mm. Patients were randomized to placebo or 0.4 mg tamsulosin daily for 28 days. The outcome was stone expulsion demonstrated by absence of calculi on repeat CT. Stone passage in the entire group occurred in 87% of the tamsulosin arm and 81.9% of the placebo, with a 95% CI of -3.0% to 13%, which was not a significant difference with P=0.22.

Interestingly, in a subgroup analysis of larger stones 5–10 mm, 83% of tamsulosin subjects compared to 61% of placebo subjects had stone passage that was significant at a 22% difference and P=.03.

Limitations included compliance in both groups, applicability to other populations given study based in Australia, and the lack of follow-through with CT scan at 28 days in 17% of the original group, resulting in missing outcome data.

Bottom line: Patients with ureteric stones 5–10 mm in size demonstrate increased spontaneous stone expulsion with the addition of tamsulosin and should thus be offered this therapy.

Citation: Furyk J, Chu K, Banks C, et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med. 2016;67(1):86-95.e2.

Short Take

Low Diagnostic Yield of Blood Cultures in Hospitalized Medical Patients

Prospective cohort study of patients hospitalized on a medical service demonstrated a true positive rate of blood cultures that was lower than previously studied. Using objective clinical predictors may improve likelihood of true positive blood cultures.

Citation: Linsenmeyer K, Gupta K, Strymish JM, Dhanani M, Brecher SM, Breu AC. Culture if spikes? Indications and yield of blood cultures in hospitalized medical patients [published online ahead of print January 13, 2016]. J Hosp Med. doi:10.1002/jhm.2541.

Clinical question: Is tamsulosin efficacious as an expulsive therapy for distal ureter stones ≤10 mm in diameter?

Background: Ureteric calculi are a common reason for hospital admission, and use of medical expulsive therapy during observation periods for small caliber stones has gained much attention recently. Specifically, tamsulosin has been suggested as a medical therapy for small stones.

Study design: Randomized, double-blind, placebo-controlled study.

Setting: Five EDs in Australia.

Synopsis: A total of 403 patients participated in the study, based on inclusion criteria of age older than 18 years with symptoms and CT evidence of ureteric stones Exclusion criteria included fever, glomerular filtration rate <60, and calculi >10 mm. Patients were randomized to placebo or 0.4 mg tamsulosin daily for 28 days. The outcome was stone expulsion demonstrated by absence of calculi on repeat CT. Stone passage in the entire group occurred in 87% of the tamsulosin arm and 81.9% of the placebo, with a 95% CI of -3.0% to 13%, which was not a significant difference with P=0.22.

Interestingly, in a subgroup analysis of larger stones 5–10 mm, 83% of tamsulosin subjects compared to 61% of placebo subjects had stone passage that was significant at a 22% difference and P=.03.

Limitations included compliance in both groups, applicability to other populations given study based in Australia, and the lack of follow-through with CT scan at 28 days in 17% of the original group, resulting in missing outcome data.

Bottom line: Patients with ureteric stones 5–10 mm in size demonstrate increased spontaneous stone expulsion with the addition of tamsulosin and should thus be offered this therapy.

Citation: Furyk J, Chu K, Banks C, et al. Distal ureteric stones and tamsulosin: a double-blind, placebo-controlled, randomized, multicenter trial. Ann Emerg Med. 2016;67(1):86-95.e2.

Short Take

Low Diagnostic Yield of Blood Cultures in Hospitalized Medical Patients

Prospective cohort study of patients hospitalized on a medical service demonstrated a true positive rate of blood cultures that was lower than previously studied. Using objective clinical predictors may improve likelihood of true positive blood cultures.

Citation: Linsenmeyer K, Gupta K, Strymish JM, Dhanani M, Brecher SM, Breu AC. Culture if spikes? Indications and yield of blood cultures in hospitalized medical patients [published online ahead of print January 13, 2016]. J Hosp Med. doi:10.1002/jhm.2541.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how BET inhibitors fight hematologic malignancies.

Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.

The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.

The findings have been published in Leukaemia.

Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).

The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.

“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.

“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”

The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.

These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.

“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how BET inhibitors fight hematologic malignancies.

Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.

The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.

The findings have been published in Leukaemia.

Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).

The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.

“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.

“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”

The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.

These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.

“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.

Drug release in a cancer cell

Image courtesy of PNAS

Researchers say they have determined how BET inhibitors fight hematologic malignancies.

Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.

The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.

The findings have been published in Leukaemia.

Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).

The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.

“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.

“This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”

The researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.

These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.

“Understanding how the drugs work gives us the opportunity to investigate new treatments—for example, by using combination therapies or altering the dosage and timing of treatment to prevent drug resistance from emerging,” Dr Glaser said.