Mary Ann Moon

Patients who quit smoking shortly before undergo­ing surgery are not at increased risk of postopera­tive complications, compared with those who continue to smoke, according to a report published online in the Archives of Internal Medicine.

“Until some new evidence of harm emerges, firm ad­vice to stop smoking and an offer of smoking cessation treatment to those who need it can be provided to presurgical patients at any time,” said Katie Myers, M.Sc., of Queen Mary, University of London and her associates.

<[stk -3]>Publication of a study in 1989 with 39 subjects sug­gested that “stopping smoking leads to a decrease in coughing and an increase in sputum production.” Al­though that article did not show a significant effect of smoking cessation on postoperative complications, it has continued to influence routine practice; in fact, some treatment guidelines recommend against smoking cessation in the 2 months prior to surgery “to minimize the increase in pulmonary complications in recent quitters.” <[etk]>

<[stk -2]>Ms. Myers and her colleagues reviewed the literature for all studies that allowed comparisons of postoperative complications in patients who stopped smoking 8 weeks or less before undergoing surgery (recent quitters) and patients who continued to smoke. They then performed a meta-analysis of the nine studies that did so, rating as “high quality” the three studies that also used biochem­ical testing to validate subjects’ self-report of their smok­ing status. These studies involved 889 subjects, including 448 recent quitters and 441 continuing smokers.<[etk]>

<[stk -3]>Only one of the studies showed a significant effect of smoking cessation, and that was in favor of recent quit­ting. When the results were pooled, there was “no ben­eficial or detrimental effect of quitting within 8 weeks before surgery compared with continued smoking.” <[etk]><[stk -2]>The results were the same in an analysis of the three high-quality studies, and likewise when the analysis was restricted to only pulmonary postoperative complications. <[etk]>

“In conclusion, there is currently no suggestion, ei­ther from any single study or from combinations of studies, that quitting smoking shortly before surgery increases postoperative complications,” the investigators said (Arch. Intern. Med. 2011 [doi:10.1001/archintern­med.2011.97]).

The reluctance to allow or encourage smoking ces­sation shortly before surgery is based on unconfirmed assumptions. Only one study in the literature has di­rectly examined mucociliary clearance in surgical pa­tients shortly after smoking cessation, and that study found no significant difference between surgical pa­tients who had recently quit and those who continued to smoke, Ms. Myers and her associates noted.

im, ob               embargoed until 4 pm 3/14

{Copy eds. -- I had to get some of my figures from charts and tables because they weren't in the text of the article. -- mam}

I have checked the following facts in my story:

NA     Drug names and dosages

NA     Lab test values and their units

MM     Nos. are correct and add up, and percentages based on those nos. are correct

MM/ew   Citation

MM/ew     Investigators’ names and affiliations

MM /ew    All other proper names (e.g., clinical trials; geographic, company, and test names)

MM     Investigators’ conflicts of interest and sponsor of study

Best contact number = 301-325-5890; email = The study is limited by its observational nature and by the small number of studies available for review.

Ms. Myers reported no conflicts.

********* UNDERSET  1  LINES *********

Patients who quit smoking shortly before undergo­ing surgery are not at increased risk of postopera­tive complications, compared with those who continue to smoke, according to a report published online in the Archives of Internal Medicine.

“Until some new evidence of harm emerges, firm ad­vice to stop smoking and an offer of smoking cessation treatment to those who need it can be provided to presurgical patients at any time,” said Katie Myers, M.Sc., of Queen Mary, University of London and her associates.

<[stk -3]>Publication of a study in 1989 with 39 subjects sug­gested that “stopping smoking leads to a decrease in coughing and an increase in sputum production.” Al­though that article did not show a significant effect of smoking cessation on postoperative complications, it has continued to influence routine practice; in fact, some treatment guidelines recommend against smoking cessation in the 2 months prior to surgery “to minimize the increase in pulmonary complications in recent quitters.” <[etk]>

<[stk -2]>Ms. Myers and her colleagues reviewed the literature for all studies that allowed comparisons of postoperative complications in patients who stopped smoking 8 weeks or less before undergoing surgery (recent quitters) and patients who continued to smoke. They then performed a meta-analysis of the nine studies that did so, rating as “high quality” the three studies that also used biochem­ical testing to validate subjects’ self-report of their smok­ing status. These studies involved 889 subjects, including 448 recent quitters and 441 continuing smokers.<[etk]>

<[stk -3]>Only one of the studies showed a significant effect of smoking cessation, and that was in favor of recent quit­ting. When the results were pooled, there was “no ben­eficial or detrimental effect of quitting within 8 weeks before surgery compared with continued smoking.” <[etk]><[stk -2]>The results were the same in an analysis of the three high-quality studies, and likewise when the analysis was restricted to only pulmonary postoperative complications. <[etk]>

“In conclusion, there is currently no suggestion, ei­ther from any single study or from combinations of studies, that quitting smoking shortly before surgery increases postoperative complications,” the investigators said (Arch. Intern. Med. 2011 [doi:10.1001/archintern­med.2011.97]).

The reluctance to allow or encourage smoking ces­sation shortly before surgery is based on unconfirmed assumptions. Only one study in the literature has di­rectly examined mucociliary clearance in surgical pa­tients shortly after smoking cessation, and that study found no significant difference between surgical pa­tients who had recently quit and those who continued to smoke, Ms. Myers and her associates noted.

im, ob               embargoed until 4 pm 3/14

{Copy eds. -- I had to get some of my figures from charts and tables because they weren't in the text of the article. -- mam}

I have checked the following facts in my story:

NA     Drug names and dosages

NA     Lab test values and their units

MM     Nos. are correct and add up, and percentages based on those nos. are correct

MM/ew   Citation

MM/ew     Investigators’ names and affiliations

MM /ew    All other proper names (e.g., clinical trials; geographic, company, and test names)

MM     Investigators’ conflicts of interest and sponsor of study

Best contact number = 301-325-5890; email = The study is limited by its observational nature and by the small number of studies available for review.

Ms. Myers reported no conflicts.

********* UNDERSET  1  LINES *********

Patients who quit smoking shortly before undergo­ing surgery are not at increased risk of postopera­tive complications, compared with those who continue to smoke, according to a report published online in the Archives of Internal Medicine.

“Until some new evidence of harm emerges, firm ad­vice to stop smoking and an offer of smoking cessation treatment to those who need it can be provided to presurgical patients at any time,” said Katie Myers, M.Sc., of Queen Mary, University of London and her associates.

<[stk -3]>Publication of a study in 1989 with 39 subjects sug­gested that “stopping smoking leads to a decrease in coughing and an increase in sputum production.” Al­though that article did not show a significant effect of smoking cessation on postoperative complications, it has continued to influence routine practice; in fact, some treatment guidelines recommend against smoking cessation in the 2 months prior to surgery “to minimize the increase in pulmonary complications in recent quitters.” <[etk]>

<[stk -2]>Ms. Myers and her colleagues reviewed the literature for all studies that allowed comparisons of postoperative complications in patients who stopped smoking 8 weeks or less before undergoing surgery (recent quitters) and patients who continued to smoke. They then performed a meta-analysis of the nine studies that did so, rating as “high quality” the three studies that also used biochem­ical testing to validate subjects’ self-report of their smok­ing status. These studies involved 889 subjects, including 448 recent quitters and 441 continuing smokers.<[etk]>

<[stk -3]>Only one of the studies showed a significant effect of smoking cessation, and that was in favor of recent quit­ting. When the results were pooled, there was “no ben­eficial or detrimental effect of quitting within 8 weeks before surgery compared with continued smoking.” <[etk]><[stk -2]>The results were the same in an analysis of the three high-quality studies, and likewise when the analysis was restricted to only pulmonary postoperative complications. <[etk]>

“In conclusion, there is currently no suggestion, ei­ther from any single study or from combinations of studies, that quitting smoking shortly before surgery increases postoperative complications,” the investigators said (Arch. Intern. Med. 2011 [doi:10.1001/archintern­med.2011.97]).

The reluctance to allow or encourage smoking ces­sation shortly before surgery is based on unconfirmed assumptions. Only one study in the literature has di­rectly examined mucociliary clearance in surgical pa­tients shortly after smoking cessation, and that study found no significant difference between surgical pa­tients who had recently quit and those who continued to smoke, Ms. Myers and her associates noted.

im, ob               embargoed until 4 pm 3/14

{Copy eds. -- I had to get some of my figures from charts and tables because they weren't in the text of the article. -- mam}

I have checked the following facts in my story:

NA     Drug names and dosages

NA     Lab test values and their units

MM     Nos. are correct and add up, and percentages based on those nos. are correct

MM/ew   Citation

MM/ew     Investigators’ names and affiliations

MM /ew    All other proper names (e.g., clinical trials; geographic, company, and test names)

MM     Investigators’ conflicts of interest and sponsor of study

Best contact number = 301-325-5890; email = The study is limited by its observational nature and by the small number of studies available for review.

Ms. Myers reported no conflicts.

********* UNDERSET  1  LINES *********

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

It has not yet been definitively established that nonalcoholic steatohepatitis can progress to hepatocellular carcinoma, but the evidence is mounting, Dr. Kohichiroh Yasui and colleagues reported in the May issue of Clinical Gastroenterology and Hepatology.

Case reports and case series, retrospective studies, and prospective studies have all suggested such a link, but most have examined only a small number of cases and have had limited duration of follow-up. Therefore, the incidence of hepatocellular carcinoma (HCC) among patients with nonalcoholic steatohepatitis (NASH), and the risk factors that may predispose patients with NASH to progress to HCC, are not yet clear.

Dr. Yasui and associates performed a cross-sectional study to characterize the features of NASH in 87 Japanese patients who went on to develop HCC. The investigators used data collected by the Japan NASH Study Group, which was begun in 2008 by the Ministry of Health, Labour, and Welfare of Japan to support research in liver disease.

Most of the study subjects were found to have HCC as they were being screened for the disease while attending one of 15 hepatology centers for evaluation of NASH. The screening included ultrasound and/or CT scanning of the liver and testing of serum alpha-fetoprotein levels.

These subjects reported negligible alcohol consumption and had no other liver disease to account for their NASH. There were 54 men and 33 women, with a median age of 72 years. The degree of steatosis was generally mild, as expected: grade 1 (5%-33%) in 60 patients, grade 2 (34%-66%) in 19 patients, and grade 3 (more than 66%) in 7 patients.

One patient who showed less than 5% steatosis was diagnosed as having "burn-out" NASH, meaning that steatosis had been more severe earlier in the course of the disease but had disappeared as NASH progressed to cirrhosis. A previous liver biopsy had been performed in this patient before the development of HCC, and it had demonstrated the typical histologic features of NASH.

This case serves as a reminder that many instances of NASH-associated hepatocellular carcinoma may be missed because of this disappearance of the tell-tale sign of steatosis, the investigators noted.

In 49 patients, liver cancer was verified on hepatic resection, and in 21 it was verified by ultrasound-guided tumor biopsy. In the remaining 17 patients, it was diagnosed via dynamic CT or MRI. Noncancerous liver tissue was collected from all 87 patients so that background liver tissue at the time of cancer diagnosis could be assessed.

The necroinflammatory grade was mild in 31 patients, moderate in 45, and severe in 11. The degree of fibrosis was stage 1 in 10 patients, stage 2 in 15, stage 3 in 18, and stage 4 (that is, cirrhosis) in 44.

"Interestingly, male patients developed hepatocellular carcinoma at a less advanced stage of fibrosis than female patients, and the prevalence of cirrhosis was significantly lower in males (39%) than in females (70%)," the researchers noted. The reason for these discrepancies aren’t yet clear, but they show that screening for liver cancer is crucial not just in NASH patients who have advanced fibrosis but also in those with milder fibrosis, particularly if they are men.

The median tumor size was 3 cm in diameter, which is equal to or smaller than the typical size reported in the literature. Three-fourths of the patients had only one tumor. It is likely that malignancies were small and singular in these study subjects because in most cases the cancer was discovered relatively early, during screening.

Men with NASH had higher rates of liver cancer than did women, at a ratio approaching 2:1. The reasons for this sex-related difference may lie in differences in exposure to risk factors. "Men are more likely than women to be infected with hepatitis B and C viruses, consume alcohol, smoke cigarettes, and have increased iron stores," Dr. Yasui and colleagues said. In addition, androgens are thought to play a role in the development of HCC.

"Consistent with the literature, more than half of our patients displayed obesity, diabetes, and hypertension. Obesity constitutes a significant risk factor for cancer mortality in general and is an increasingly recognized risk factor for hepatocellular carcinoma in particular," they noted.

The exact mechanism by which NASH might predispose patients to liver cancer is not yet known. "Further prospective studies with a longer follow-up time and larger cohorts are needed to determine the causal association of NASH with hepatocellular carcinoma," the investigators added.

This study was supported by the Ministry of Health, Labour, and Welfare of Japan. No conflicts of interest were reported.

Major Finding: Structured aerobic, resistance, or combined exercise training lowers HbA_1c by an average of 0.67% in patients with type 2 diabetes.

Data Source: A meta-analysis of 47 randomized controlled trials involving 8,538 patients with type 2 diabetes.

Disclosures: Mr. Umpierre's associates reported ties to Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharpe & Dohme, Servier, Abbott, Aventis, Bioassist, and Boehringer Ingelheim.

Structured exercise with aerobic, resistance, or combined training was associated with a 0.67% decrease in hemoglobin A_1c in patients with type 2 diabetes, a meta-analysis has shown.

This compares favorably with the HbA_1c reductions reported for combination treatment with noninsulin antidiabetic drugs and maximal doses of metformin, said Daniel Umpierre of the Hospital de Clinicas de Porto Alegre (Brazil) and his associates.

The investigators performed a meta-analysis of 47 randomized controlled trials that assessed the effects of 12 weeks or more of structured aerobic exercise training (848 subjects), structured resistance exercise training (261), combined aerobic and resistance training (404), or unstructured physical activity (7,025) on HbA_1c levels.

Structured exercise training was defined as an intervention in which patients engaged in a planned, individualized, and supervised exercise program.

“The general quality of the studies was low, reflecting increased risk of bias in some studies,” the investigators noted.

Eighteen studies demonstrated that structured aerobic exercise training was associated with an absolute reduction of 0.73% in HbA_1c level. Four studies showed that structured resistance exercise training was associated with an absolute reduction of 0.57%. And seven studies showed that combined aerobic plus resistance exercise training was associated with an absolute reduction of 0.51%.

These benefits were most marked when the exercise was performed for 150 min/wk or more (absolute reduction of 0.89% in HbA_1c), and less so when it was performed less often (absolute reduction of 0.36% in HbA_1c). Current guidelines recommend an exercise duration of at least 150 min/wk, Mr. Umpierre and his colleagues said (JAMA 2011;305:1790-9).

In contrast, 24 studies of physical activity demonstrated that it was associated with an absolute reduction of 0.43% in HbA_1c. However, physical activity alone did not reduce HbA_1c. It was effective only when combined with dietary advice, as shown in 12 studies in which HbA_1c level declined by 0.58%.

Major Finding: Structured aerobic, resistance, or combined exercise training lowers HbA_1c by an average of 0.67% in patients with type 2 diabetes.

Data Source: A meta-analysis of 47 randomized controlled trials involving 8,538 patients with type 2 diabetes.

Disclosures: Mr. Umpierre's associates reported ties to Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharpe & Dohme, Servier, Abbott, Aventis, Bioassist, and Boehringer Ingelheim.

Structured exercise with aerobic, resistance, or combined training was associated with a 0.67% decrease in hemoglobin A_1c in patients with type 2 diabetes, a meta-analysis has shown.

This compares favorably with the HbA_1c reductions reported for combination treatment with noninsulin antidiabetic drugs and maximal doses of metformin, said Daniel Umpierre of the Hospital de Clinicas de Porto Alegre (Brazil) and his associates.

The investigators performed a meta-analysis of 47 randomized controlled trials that assessed the effects of 12 weeks or more of structured aerobic exercise training (848 subjects), structured resistance exercise training (261), combined aerobic and resistance training (404), or unstructured physical activity (7,025) on HbA_1c levels.

Structured exercise training was defined as an intervention in which patients engaged in a planned, individualized, and supervised exercise program.

“The general quality of the studies was low, reflecting increased risk of bias in some studies,” the investigators noted.

Eighteen studies demonstrated that structured aerobic exercise training was associated with an absolute reduction of 0.73% in HbA_1c level. Four studies showed that structured resistance exercise training was associated with an absolute reduction of 0.57%. And seven studies showed that combined aerobic plus resistance exercise training was associated with an absolute reduction of 0.51%.

These benefits were most marked when the exercise was performed for 150 min/wk or more (absolute reduction of 0.89% in HbA_1c), and less so when it was performed less often (absolute reduction of 0.36% in HbA_1c). Current guidelines recommend an exercise duration of at least 150 min/wk, Mr. Umpierre and his colleagues said (JAMA 2011;305:1790-9).

In contrast, 24 studies of physical activity demonstrated that it was associated with an absolute reduction of 0.43% in HbA_1c. However, physical activity alone did not reduce HbA_1c. It was effective only when combined with dietary advice, as shown in 12 studies in which HbA_1c level declined by 0.58%.

Major Finding: Structured aerobic, resistance, or combined exercise training lowers HbA_1c by an average of 0.67% in patients with type 2 diabetes.

Data Source: A meta-analysis of 47 randomized controlled trials involving 8,538 patients with type 2 diabetes.

Disclosures: Mr. Umpierre's associates reported ties to Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharpe & Dohme, Servier, Abbott, Aventis, Bioassist, and Boehringer Ingelheim.

Structured exercise with aerobic, resistance, or combined training was associated with a 0.67% decrease in hemoglobin A_1c in patients with type 2 diabetes, a meta-analysis has shown.

This compares favorably with the HbA_1c reductions reported for combination treatment with noninsulin antidiabetic drugs and maximal doses of metformin, said Daniel Umpierre of the Hospital de Clinicas de Porto Alegre (Brazil) and his associates.

The investigators performed a meta-analysis of 47 randomized controlled trials that assessed the effects of 12 weeks or more of structured aerobic exercise training (848 subjects), structured resistance exercise training (261), combined aerobic and resistance training (404), or unstructured physical activity (7,025) on HbA_1c levels.

Structured exercise training was defined as an intervention in which patients engaged in a planned, individualized, and supervised exercise program.

“The general quality of the studies was low, reflecting increased risk of bias in some studies,” the investigators noted.

Eighteen studies demonstrated that structured aerobic exercise training was associated with an absolute reduction of 0.73% in HbA_1c level. Four studies showed that structured resistance exercise training was associated with an absolute reduction of 0.57%. And seven studies showed that combined aerobic plus resistance exercise training was associated with an absolute reduction of 0.51%.

These benefits were most marked when the exercise was performed for 150 min/wk or more (absolute reduction of 0.89% in HbA_1c), and less so when it was performed less often (absolute reduction of 0.36% in HbA_1c). Current guidelines recommend an exercise duration of at least 150 min/wk, Mr. Umpierre and his colleagues said (JAMA 2011;305:1790-9).

In contrast, 24 studies of physical activity demonstrated that it was associated with an absolute reduction of 0.43% in HbA_1c. However, physical activity alone did not reduce HbA_1c. It was effective only when combined with dietary advice, as shown in 12 studies in which HbA_1c level declined by 0.58%.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

Major Finding: The difference in the absolute risk of atypical femoral fracture between users and nonusers of bisphosponates was five cases per 10,000 patient-years; the number need to harm was 2,000 for every year of use.

Data Source: A nationwide cohort analysis of data on all 12,777 women aged 55 and older in Sweden who sustained a femoral fracture during 2008, and a population-based, case-control study of a subgroup of 322 of these patients.

Disclosures: This study was funded by the Swedish Research Council. Dr. Schilcher's associate reported ties to Eli Lilly and Amgen, and holds stock in AddBIO, a company that is attempting to commercialize a method for bisphosphonate coating of implants to be inserted in bone and that holds a patent on that method.

The magnitude of the absolute risk for atypical fractures of the femoral shaft among women taking bisphosphonates is small, according to a recent report.

The absolute risk remains small even though there is a high prevalence of use of the drugs in patients who develop such fractures. Moreover, that risk is small enough to be easily outweighed by bisphosphonates' benefit in preventing fractures, said Dr. Jörg Schilcher of Linköping (Sweden) University and his associates.

These findings, which come from nationwide population-based analyses of data on all 12,777 women in Sweden who were aged 55 and older and sustained a femoral fracture in 2008, “should be reassuring for bisphosphonate users,” they noted.

The American Society for Bone and Mineral Research has formed a task force report about the issue, ant the Food and Drug Administration has announced that it intends to monitor instances of such cases. There have also been several studies on the topic, but the authors of this report say that the studies were too small to establish or negate an association.

Another population-based study in longtime elderly bisphosphonate users in Ontario recently showed that the absolute risk of atypical fractures was 1 in 1,000 women (JAMA 2011;305:783-9).

The investigators first reviewed the radiographs of all femoral sub-trochanteric and shaft fractures that were treated throughout Sweden that year. They identified the 1,234 cases among older women that resulted from falls.

The researchers then identified 47 cases of typical stress fractures (transverse on the lateral side without intermediate fragments, plus a thickening of the lateral cortex at the fracture site and no involvement of the trochanteric or condylar areas).

A second group of 12 patients had suspected stress fractures with the same characteristics as the fractures in the first group, but either without a thickening of the lateral cortex or with an intermediate fragment.

In a case-control analysis, Dr. Schilcher and his associates compared the use of bisphosphonates between these 59 women and 263 women who were chosen as control subjects and did not have stress fractures but who did have breaks in similar locations.

The prevalence of bisphosphonate use was much higher among the subjects who had atypical stress fractures (78%) than it was among the control subjects (10%). However, the absolute risk of sustaining an atypical fracture while using bisphosphonates was small: five cases per 10,000 patient-years.

This translates to a number needed to harm of 2,000 for every year of use; that is, 2,000 patients would need to use bisphosphonate for one case of drug-related atypical fracture to occur per year, Dr. Schilcher and his colleagues reported (N. Engl. J. Med. 2011;364:1728-37).

Thus, “the benefits of fracture prevention with bisphosphonate use will greatly outweigh the risk of atypical femoral fracture,” they wrote.

The risk of these atypical femoral fractures also appeared to be unrelated to the use of systemic glucocorticoids and other medications that affect bone. “It has been proposed that glucocorticoids and proton pump inhibitors are likely to contribute to the risk of atypical fractures, but our data suggest that this is not the case,” they added.

The risk of atypical femoral fracture also was independent of coexisting conditions and of patient age in this study population.

Previous studies that suggested that bisphosphonates raised the absolute risk of atypical femoral fractures to an unacceptable degree “relied on registry data or hospital records,” whereas this study relied on direct examination and classification of fractures from radiographs.

“The specific radiographie classification is important, since our analysis shows that the rare atypical femoral fracture will be overshadowed by other types of fractures in registry studies, impeding the detection of their association with bisphosphonates,” the investigators noted.

This study was limited in that it did not assess long-term bisphosphonate use or bone density. It also included only women of Northern European ethnicity, so the results may not be generalizable to men and other ethnic groups, they added.

Major Finding: The short-term increase in risks of stroke, DVT, and pulmonary embolism did not persist over the long term after unopposed estrogen therapy; the equivalent risks of CHD, colorectal cancer, and total mortality did persist; the reduction in hip fracture risk did not persist; and the reduction in breast cancer risk did persist.

Data Source: Extended (10-year) follow-up of approximately 78% of subjects who participated in the Women's Health Initiative-Estrogen Alone trial (3,778 postmenopausal women who took conjugated equine estrogen and 3,867 who took matching placebo for a median of 6 years).

Disclosures: The WHI was funded by the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs. Dr. LaCroix reported ties to Warner Chilcott, Sanofi-Aventis, Amgen, and Pfizer. Her associates reported ties to numerous other industry sources.

The most recent findings from the Women's Health Initiative study of short-term unopposed estrogen therapy suggest that after 10 years, the treatment neither increases nor decreases risks for coronary heart disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.

This portion of the WHI study was halted early when interim analysis in 2004 showed an increased risk of stroke in women taking conjugated equine estrogens (CEE) compared with those taking placebo. “All previous reports of this trial were limited to outcomes occurring during the intervention phase. [Now] we report data on postintervention outcomes through a mean of 10.7 years of follow-up,” said Andrea Z. LaCroix, Ph.D., of Fred Hutchinson Cancer Research Center, Seattle, and her associates (JAMA 2011;305:1305-14).

In the estrogen-only portion of the WHI study, 10,739 postmenopausal women who had undergone hysterectomy had been randomly assigned to receive either CEE or placebo. They were followed during this intervention phase for a median of 6 years, but the median “adherent time” – the interval during which the women actually took more than 80% of their study pills – was only 3.5 years because more than half stopped taking the pills even before the early halt of the trial.

Approximately 78% of the surviving study subjects (3,778 who took CEE and 3,867 who took placebo) agreed to participate in the extended follow-up reported here.

The increased risks of stroke, deep vein thrombosis, and pulmonary embolism that had been noted during the intervention phase did not persist during extended follow-up. In addition, active treatment, which had showed no effect on CHD risks during the intervention, continued to show no effect on CHD risks. For all cardiovascular events, the cumulative hazard ratio was 2.26% with active treatment and 2.12% with placebo.

Colorectal cancer incidence did not differ between women who received CEE and those who received placebo during the intervention phase, and this lack of effect persisted during extended follow-up.

Hip fracture risk had been reduced with CEE therapy during the intervention phase, but this benefit did not persist during the extended follow-up. Numerically, hip fracture incidence was slightly higher in the CEE group than in the placebo group.

Total mortality risk remained similar between the two study groups both during the intervention and during extended follow-up.

Only one benefit of CEE therapy that was seen during the intervention phase persisted in the extended follow-up and became statistically significant: Breast cancer incidence was 0.27% with active treatment and 0.35% with placebo. These results differ from those of the other portion of the WHI trial in which subjects received combined estrogen-plus-progestin. In that study arm, active treatment impeded mammographic accuracy and was associated with significantly higher rates of breast cancer and breast cancer mortality, the researchers noted.

The women's age at commencing treatment showed a significant interaction with outcomes, both in the intervention phase and during extended follow-up. The results suggest there may be greater benefit and safety for women who start CEE in their early 50s, and less benefit with more potential harm for women who are older when they begin treatment.

View on the News

Findings Don't Agree With the Body of Evidence

“The lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger,” longstanding, corroborated body of evidence that the treatment generally elevates the risk of breast cancer, said Dr. Emily S. Jungheim and Dr. Graham A. Colditz.

One can question whether results in the WHI study population, in which nearly 70% of the subjects were older than 60 years at baseline, can even be applied to younger women, particularly with regard to breast cancer risk and hormone therapy.

In addition, the duration of CEE use in the WHI remains problematic since the median “adherent time” was 3.5 years. “Thus, the WHI results do not address the balance of risks and benefits associated with longer term estrogen use,” they said.

DR. JUNGHEIM and Dr. Colditz are at Washington University, St. Louis. These remarks were taken from their editorial comment accompanying Dr. LaCroix's report (JAMA 2011;305:1354-5). They reported no relevant financial disclosures.

Major Finding: The short-term increase in risks of stroke, DVT, and pulmonary embolism did not persist over the long term after unopposed estrogen therapy; the equivalent risks of CHD, colorectal cancer, and total mortality did persist; the reduction in hip fracture risk did not persist; and the reduction in breast cancer risk did persist.

Data Source: Extended (10-year) follow-up of approximately 78% of subjects who participated in the Women's Health Initiative-Estrogen Alone trial (3,778 postmenopausal women who took conjugated equine estrogen and 3,867 who took matching placebo for a median of 6 years).

Disclosures: The WHI was funded by the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs. Dr. LaCroix reported ties to Warner Chilcott, Sanofi-Aventis, Amgen, and Pfizer. Her associates reported ties to numerous other industry sources.

The most recent findings from the Women's Health Initiative study of short-term unopposed estrogen therapy suggest that after 10 years, the treatment neither increases nor decreases risks for coronary heart disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.

This portion of the WHI study was halted early when interim analysis in 2004 showed an increased risk of stroke in women taking conjugated equine estrogens (CEE) compared with those taking placebo. “All previous reports of this trial were limited to outcomes occurring during the intervention phase. [Now] we report data on postintervention outcomes through a mean of 10.7 years of follow-up,” said Andrea Z. LaCroix, Ph.D., of Fred Hutchinson Cancer Research Center, Seattle, and her associates (JAMA 2011;305:1305-14).

In the estrogen-only portion of the WHI study, 10,739 postmenopausal women who had undergone hysterectomy had been randomly assigned to receive either CEE or placebo. They were followed during this intervention phase for a median of 6 years, but the median “adherent time” – the interval during which the women actually took more than 80% of their study pills – was only 3.5 years because more than half stopped taking the pills even before the early halt of the trial.

Approximately 78% of the surviving study subjects (3,778 who took CEE and 3,867 who took placebo) agreed to participate in the extended follow-up reported here.

The increased risks of stroke, deep vein thrombosis, and pulmonary embolism that had been noted during the intervention phase did not persist during extended follow-up. In addition, active treatment, which had showed no effect on CHD risks during the intervention, continued to show no effect on CHD risks. For all cardiovascular events, the cumulative hazard ratio was 2.26% with active treatment and 2.12% with placebo.

Colorectal cancer incidence did not differ between women who received CEE and those who received placebo during the intervention phase, and this lack of effect persisted during extended follow-up.

Hip fracture risk had been reduced with CEE therapy during the intervention phase, but this benefit did not persist during the extended follow-up. Numerically, hip fracture incidence was slightly higher in the CEE group than in the placebo group.

Total mortality risk remained similar between the two study groups both during the intervention and during extended follow-up.

Only one benefit of CEE therapy that was seen during the intervention phase persisted in the extended follow-up and became statistically significant: Breast cancer incidence was 0.27% with active treatment and 0.35% with placebo. These results differ from those of the other portion of the WHI trial in which subjects received combined estrogen-plus-progestin. In that study arm, active treatment impeded mammographic accuracy and was associated with significantly higher rates of breast cancer and breast cancer mortality, the researchers noted.

The women's age at commencing treatment showed a significant interaction with outcomes, both in the intervention phase and during extended follow-up. The results suggest there may be greater benefit and safety for women who start CEE in their early 50s, and less benefit with more potential harm for women who are older when they begin treatment.

View on the News

Findings Don't Agree With the Body of Evidence

“The lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger,” longstanding, corroborated body of evidence that the treatment generally elevates the risk of breast cancer, said Dr. Emily S. Jungheim and Dr. Graham A. Colditz.

One can question whether results in the WHI study population, in which nearly 70% of the subjects were older than 60 years at baseline, can even be applied to younger women, particularly with regard to breast cancer risk and hormone therapy.

In addition, the duration of CEE use in the WHI remains problematic since the median “adherent time” was 3.5 years. “Thus, the WHI results do not address the balance of risks and benefits associated with longer term estrogen use,” they said.

DR. JUNGHEIM and Dr. Colditz are at Washington University, St. Louis. These remarks were taken from their editorial comment accompanying Dr. LaCroix's report (JAMA 2011;305:1354-5). They reported no relevant financial disclosures.

Major Finding: The short-term increase in risks of stroke, DVT, and pulmonary embolism did not persist over the long term after unopposed estrogen therapy; the equivalent risks of CHD, colorectal cancer, and total mortality did persist; the reduction in hip fracture risk did not persist; and the reduction in breast cancer risk did persist.

Data Source: Extended (10-year) follow-up of approximately 78% of subjects who participated in the Women's Health Initiative-Estrogen Alone trial (3,778 postmenopausal women who took conjugated equine estrogen and 3,867 who took matching placebo for a median of 6 years).

Disclosures: The WHI was funded by the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs. Dr. LaCroix reported ties to Warner Chilcott, Sanofi-Aventis, Amgen, and Pfizer. Her associates reported ties to numerous other industry sources.

The most recent findings from the Women's Health Initiative study of short-term unopposed estrogen therapy suggest that after 10 years, the treatment neither increases nor decreases risks for coronary heart disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.

This portion of the WHI study was halted early when interim analysis in 2004 showed an increased risk of stroke in women taking conjugated equine estrogens (CEE) compared with those taking placebo. “All previous reports of this trial were limited to outcomes occurring during the intervention phase. [Now] we report data on postintervention outcomes through a mean of 10.7 years of follow-up,” said Andrea Z. LaCroix, Ph.D., of Fred Hutchinson Cancer Research Center, Seattle, and her associates (JAMA 2011;305:1305-14).

In the estrogen-only portion of the WHI study, 10,739 postmenopausal women who had undergone hysterectomy had been randomly assigned to receive either CEE or placebo. They were followed during this intervention phase for a median of 6 years, but the median “adherent time” – the interval during which the women actually took more than 80% of their study pills – was only 3.5 years because more than half stopped taking the pills even before the early halt of the trial.

Approximately 78% of the surviving study subjects (3,778 who took CEE and 3,867 who took placebo) agreed to participate in the extended follow-up reported here.

The increased risks of stroke, deep vein thrombosis, and pulmonary embolism that had been noted during the intervention phase did not persist during extended follow-up. In addition, active treatment, which had showed no effect on CHD risks during the intervention, continued to show no effect on CHD risks. For all cardiovascular events, the cumulative hazard ratio was 2.26% with active treatment and 2.12% with placebo.

Colorectal cancer incidence did not differ between women who received CEE and those who received placebo during the intervention phase, and this lack of effect persisted during extended follow-up.

Hip fracture risk had been reduced with CEE therapy during the intervention phase, but this benefit did not persist during the extended follow-up. Numerically, hip fracture incidence was slightly higher in the CEE group than in the placebo group.

Total mortality risk remained similar between the two study groups both during the intervention and during extended follow-up.

Only one benefit of CEE therapy that was seen during the intervention phase persisted in the extended follow-up and became statistically significant: Breast cancer incidence was 0.27% with active treatment and 0.35% with placebo. These results differ from those of the other portion of the WHI trial in which subjects received combined estrogen-plus-progestin. In that study arm, active treatment impeded mammographic accuracy and was associated with significantly higher rates of breast cancer and breast cancer mortality, the researchers noted.

The women's age at commencing treatment showed a significant interaction with outcomes, both in the intervention phase and during extended follow-up. The results suggest there may be greater benefit and safety for women who start CEE in their early 50s, and less benefit with more potential harm for women who are older when they begin treatment.

View on the News

Findings Don't Agree With the Body of Evidence

“The lack of an adverse effect of unopposed estrogen when used for a short period in the WHI does not counter the larger,” longstanding, corroborated body of evidence that the treatment generally elevates the risk of breast cancer, said Dr. Emily S. Jungheim and Dr. Graham A. Colditz.

One can question whether results in the WHI study population, in which nearly 70% of the subjects were older than 60 years at baseline, can even be applied to younger women, particularly with regard to breast cancer risk and hormone therapy.

In addition, the duration of CEE use in the WHI remains problematic since the median “adherent time” was 3.5 years. “Thus, the WHI results do not address the balance of risks and benefits associated with longer term estrogen use,” they said.

DR. JUNGHEIM and Dr. Colditz are at Washington University, St. Louis. These remarks were taken from their editorial comment accompanying Dr. LaCroix's report (JAMA 2011;305:1354-5). They reported no relevant financial disclosures.