AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.

AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.

AMSTERDAM – There is a “very, very rich pipeline” of drugs being developed for the treatment of nonalcoholic steatohepatitis (NASH), Jean-François Dufour, MD, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Berne (Switzerland) said at the International Liver Congress.

“We have many therapeutic options [under investigation],” Dr. Dufour noted at the Congress, which is sponsored by the European Association for the Study of the Liver (EASL). These include drugs that target metabolic homeostasis, insulin resistance, inflammation, oxidative stress, or fibrosis (Liver Int. 2017 May;37:634-47).

In fact, there is such a range of options that target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely that these drugs will be used in combination, Dr. Dufour observed as he gave an overview of the current trials that are underway in NASH.

There are currently five ongoing multicenter phase III trials being undertaken with four drugs. First, there is the REGENERATE trial with Intercept’s farnesoid X receptor obeticholic acid(Ocaliva). This is a placebo-controlled trial comparing two daily doses of obeticholic acid (10 and 25 mg) on top of the standard of care. The trial will recruit just over 2,000 patients with biopsy-proven stage 2-3 NASH fibrosis, and the primary endpoint is the resolution of NASH without fibrosis worsening or improvement in fibrosis without worsening of NASH at week 72.

Second there is the RESOLVE-IT trial with Genfit’s peroxisome proliferator-activated receptor alpha/delta agonist elafibranor. This randomized, double-blind trial hopes to recruit 2,000 patients with biopsy-proven NASH stage 1-3 fibrosis and will compare elafibranor 120 mg given once a day with placebo. The primary endpoint is the resolution of NASH without worsening of fibrosis at week 72.

Next, Tobira Therapeutics’ C-C chemokine receptor type 2 and 5 antagonist cenicriviroc is being studied in the AURORA trial. Again, recruiting around 2,000 patients is the target, but this time with stage 2-3 biopsy-proven NASH fibrosis. Cenicriviroc will be given daily at a dose of 150 mg and will be compared against placebo. The primary endpoint is the improvement of fibrosis by one or more stage with no worsening of steatohepatitis at 1 year.

Finally, there are the STELLA 3 and STELLA 4 trials with Gilead’s apoptosis signal-regulated kinase-1 inhibitor selonsertib. Target accrual in both studies is 800 patients with STELLA 3 recruiting patients with stage-3 NASH fibrosis and STELLA 4 recruiting those with compensated cirrhosis from NASH. Both trials will compared two daily doses of selonsertib (6 mg and 18 mg) versus placebo. The primary endpoints are the improvement of at least one or more fibrosis stage with no worsening of steatohepatitis at 48 weeks and event-free survival at week 240.

In addition, there are at least 20 phase 2b and 2a studies looking at a variety of other novel drugs with different therapeutic targets, Dr. Dufour said, and during separate presentations at the congress, results of several early trials with novel drugs being tested for NASH were given.

Eric J. Lawitz, MD, reported the promising results of a “proof of concept” open-label study in which the safety and efficacy of 12 weeks’ treatment with the oral acetyl-CoA carboxylase (ACC) inhibitor, GS-0976, was examined in 10 patients with a clinical diagnosis of nonalcoholic fatty liver disease (NAFLD).

“ACC catalyzes the rate-limiting step in de novo hepatic lipogenesis (DNL),” which is an underlying pathologic process in NASH, Dr. Lawitz, who is vice president of scientific and research development at the Texas Liver Institute, San Antonio, observed.

He reported that 12 weeks’ treatment with the ACC inhibitor GS-0976 suppressed DNL by 29%, compared with baseline (P = .022). There was also a 43% decrease in hepatic steatosis from baseline to 12 weeks (P = .006), as measured by the magnetic resonance imaging–proton-density fat fraction (MRI-PDFF), and a nonsignificant 9% reduction in liver stiffness measured using magnetic resonance elastography (MRE).

Two markers of fibrosis and cell death (TIMP-1 and CK18) were also improved, he said, noting that overall, the drug was well tolerated, bar a trend to an increase in triglycerides and reduction in high-density lipoprotein cholesterol that needs further follow up.

“There is a placebo-controlled phase II trial of GS-0976 in patients with NASH that is ongoing,” Dr. Lawitz said. Results of two phase II studies presented during the late-breaking abstracts session at the meeting showed similar promising results could be achieved with drugs mimicking the activity of different fibroblast growth factors.

“Fibroblast growth factor 21 (FGF21) is a nonmitogenic hormone produced in the liver that is an important regulator of energy metabolism,” said Arun J. Sanyal, MD, who presented the findings of a study with the FGF21 inhibitor BMS-986036.

”From a NASH perspective, it improves insulin sensitivity and by doing that, decreases lipogenesis, and it also has been shown to have some antifibrotic effects,” Dr. Sanyal of Virginia Commonwealth University in Richmond, added.

FGF21 has a short half-life, however, and BMS-986036 is a recombinant human analog of this hormone that could potentially allow it to be given up to once weekly.

The study involved 74 patients with stage 1-3 biopsy-proven NASH fibrosis and a hepatic fat fraction of 10% or greater measured by MRI-PDFF. Patients were randomized to treatment with BMS-986036 at subcutaneously administered doses of 10 mg given once daily or 20 mg given once weekly or to placebo for 16 weeks.

A significant reduction in the hepatic fat fraction was seen in patients treated with both the once-daily and once-weekly regimen of the active treatment relative to placebo, with absolute changes from baseline of –6.8% (P = .008) and –5.2% (P = .0004), respectively, and just –1.3% for placebo.

“Results suggest that BMS-986036 had beneficial effects on steatosis, liver injury, and fibrosis in NASH,” said Dr. Sanyal, who also noted that there were no deaths and no signal that there could be any safety concerns.

NGM282 is another recombinant human analog mimicking the action of an FGF, this time FGF19, and early data also suggest that it also reduces hepatic steatosis and key biomarkers of NASH. Dr. Stephen Harrison, MD, the medical director of Pinnacle Clinical Research in Live Oak, reported data on 82 patients with stage 1-3 NASH fibrosis who had been treated with NGM-282 3 mg or 6 mg subcutaneously once a day or placebo for 12 weeks.

“The primary endpoint [decrease in absolute liver fat content greater than or equal to 5%] was met in 79% of NGM-282-treated subjects, with over one-third of subjects achieving normalization of liver fat content with 12 weeks of therapy,” Dr. Harrison reported.

“There were significant and rapid reductions in multiple markers that are relevant to the resolution of NASH and improvement in fibrosis,” Dr. Harrison added.

One serious adverse event of acute pancreatitis occurred in a patient treated with FGF19, which was possibly thought to be treatment related, but otherwise adverse events were generally mild and included gastrointestinal effects such as diarrhea and nausea, and injection site reactions.

“These data strongly support the continued development of NGM282 in NASH,” Dr. Harrison said.

During his presentation at a symposium session on current and future approaches to NAFLD and NASH, Dr. Dufour was keen to point out that a combination of diet and exercise remains central to managing patients with NASH.

“We should not forget, that the first line of discussion with these patients should be about changing their lifestyles.” Improving diet and exercise is something that everybody can do, he said, it is widely available and inexpensive, associated with few side effects and can produce good results.

However, convincing some patients can be difficult and those with a low acceptance to lifestyle changes often prefer to take medication. That is likely to come at a cost, not just in terms of money but there are likely to be some side effects, and, of course, efficacy in NASH is yet to be proven in many cases, Dr. Dufour said.

Dr. Dufour disclosed he had been part of a number of advisory committees or received speaking and teaching fees from a host of pharmaceutical companies, many of whom have an interest in the development of treatments for NASH.

Gilead Sciences supported the study reported by Dr. Lawitz and he disclosed receiving research grants or other support from the company, as well as several other pharmaceutical companies.

The study presented by Dr. Sanyal was financed by Bristol-Myers Squibb and he disclosed research funding was provided to his institution. Dr. Sanyal also disclosed receiving research support and consulting fees from multiple other pharmaceutical companies.

Dr. Harrison acknowledged receiving research funding from and acting as a consultant to NGM Bio, who sponsored the study he presented. He also disclosed acting as an adviser or speaker, and receiving grants from other pharmaceutical companies in the past 12 months.

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

GENEVA – Patients with stage IV non–small cell lung cancer (NSCLC) who have disease progression following treatment with an immune checkpoint inhibitor have a 30% better chance of achieving at least a partial response with salvage chemotherapy compared with patients who had received prior chemotherapy but not immunotherapy, according to Swiss and U.S. investigators.

In a study of 82 patients with advanced NSCLC, 18 of 67 patients (27%) who had progressed on an inhibitor of programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) had a partial response to combination chemotherapy, compared with just 1 of 15 (7%) of patients who had not received a checkpoint inhibitor, reported Sacha Rothschild, MD, PhD, of University Hospital Basel, Switzerland, and colleagues.

“The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference, however, warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity,” the researchers wrote in a scientific poster presented at the European Lung Cancer Conference.

Immune checkpoint inhibitors have been shown to be active in patients with late-stage NSCLC who have experienced disease progression following chemotherapy. To see whether salvage chemotherapy could offer any additional benefit to patients who had disease progression on immunotherapy, the investigators conducted a retrospective case-control study. They reviewed 355 patient records, and identified 82 patients – 46 men and 36 women – who met the study criteria.

Of this group, 67 patients had received a PD-1/PD-L1 checkpoint inhibitor, either nivolumab (Opdivo, 56 patients), pembrolizumab (Keytruda, 7), or atezolizumab (Tecentriq, 4). These patients were designated as cases. The remaining 15 patients, who had received prior chemotherapy or chemoradiotherapy only, were designated as controls.

Of all 82 patients, 63 (77%) had adenocarcinomas, 18 (22%) had squamous cell carcinomas, and 1 (1%) had a large-cell carcinoma.

Cases had a mean of 2.37 chemotherapy regimens prior to salvage chemotherapy, and controls had a mean of 1.93. Drugs used in the salvage regimens were docetaxel in 62% of patients, pemetrexed in 20%, gemcitabine in 12%, and paclitaxel in 6%.

Cognitive behavioral therapy administered online can effectively treat symptoms of depression in older people with knee osteoarthritis, according to results from the first randomized trial of its kind.

The benefits of the 10-week program extended to improving pain, stiffness, physical functioning, and self-efficacy, reported Kathleen A. O’Moore, PsyD, of St. Vincent’s Hospital, Sydney, Australia, and her colleagues (Arthritis Care Res. 2017 April 20. doi: 10.1002/acr.23257).

The investigators became motivated to conduct the trial by the fact that about one in five older people with osteoarthritis (OA) experience depression, yet many do not seek treatment, and depression in this population has been associated with an increased use of pain medication, reduced adherence to treatment recommendations, and, when recommendations are followed, reduced treatment benefits.

Pixelheadphoto/Thinkstock

Cognitive behavioral therapy administered online can effectively treat symptoms of depression in older people with knee osteoarthritis, according to results from the first randomized trial of its kind.

The benefits of the 10-week program extended to improving pain, stiffness, physical functioning, and self-efficacy, reported Kathleen A. O’Moore, PsyD, of St. Vincent’s Hospital, Sydney, Australia, and her colleagues (Arthritis Care Res. 2017 April 20. doi: 10.1002/acr.23257).

The investigators became motivated to conduct the trial by the fact that about one in five older people with osteoarthritis (OA) experience depression, yet many do not seek treatment, and depression in this population has been associated with an increased use of pain medication, reduced adherence to treatment recommendations, and, when recommendations are followed, reduced treatment benefits.

Pixelheadphoto/Thinkstock

Cognitive behavioral therapy administered online can effectively treat symptoms of depression in older people with knee osteoarthritis, according to results from the first randomized trial of its kind.

The benefits of the 10-week program extended to improving pain, stiffness, physical functioning, and self-efficacy, reported Kathleen A. O’Moore, PsyD, of St. Vincent’s Hospital, Sydney, Australia, and her colleagues (Arthritis Care Res. 2017 April 20. doi: 10.1002/acr.23257).

The investigators became motivated to conduct the trial by the fact that about one in five older people with osteoarthritis (OA) experience depression, yet many do not seek treatment, and depression in this population has been associated with an increased use of pain medication, reduced adherence to treatment recommendations, and, when recommendations are followed, reduced treatment benefits.

Pixelheadphoto/Thinkstock

LAS VEGAS – Young people who sustain an intra-articular knee injury while participating in youth sports are not only at increased risk for early posttraumatic osteoarthritis 3-10 years later as young adults, but they also are more prone to develop obesity and other modifiable risk factors for osteoarthritis, according to Jackie Whittaker, PhD.

“It appears that some of these young active individuals, after sustaining an injury which is itself a risk factor for osteoarthritis, are going down a pathway where they’re developing a second risk factor for the disease. This may accelerate the rate at which they get the disease and may very well also accelerate the rate at which the disease progresses after its onset,” Dr. Whittaker of the University of Alberta, Edmonton, said at the World Congress on Osteoarthritis.

Dr. Jackie L. Whittaker of the University of Alberta in Edmonton, Canada.

“In Canada, we know that injury during sport and recreation is the No. 1 reason that youth between the ages of 11 and 18 seek medical attention, with an alarming one in three doing so. Knee injuries are among the most common of those injuries,” she said.

At follow-up, 29% of the group with a history of knee injury and 4% of controls already had OA as defined by MRI. The likelihood of MRI evidence of OA was 13.5-fold greater in patients who underwent knee surgery for their injury, compared with controls.

“We saw the highest risk, as expected, in patients with ACL [anterior cruciate ligament] and/or meniscal tears, but we also saw a twofold increased risk of OA in those with seemingly less severe injuries, like grade 1-3 medial and collateral ligament injuries,” said Dr. Whittaker.

“I don’t think we were really shocked that knee injury can lead to structural changes that can be associated with future symptomatic OA, but we were surprised to be seeing that as early as 3-10 years post injury. And we were also seeing greater adiposity, a higher rate of being overweight or obese, reduced physical activity, weaker knee muscular strength, and poorer performance on balance and physical function tests,” she continued.

Indeed, at follow-up the subjects with a history of a youth sports knee injury were 4.4-fold more likely to be in the top quartile of fat mass index, compared with uninjured controls, 5.7-fold more likely to be in the highest quartile for abdominal fat, 2.1 times more likely to be in the lowest quartile for total weekly physical activity, and 2.4-fold more likely to be overweight or obese by body mass index (BMI). They were significantly less aerobically fit as reflected in their performance on the 20-meter shuttle run. And they scored significantly worse on the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), particularly on the knee-related quality of life, pain, and symptom subscales.

“The study is ongoing, but it has already contributed to identification of who we’re probably going to need to target for secondary prevention strategies: obviously, individuals who have torn their ACL and/or their meniscus, as was already well known, but perhaps also individuals that have had less severe injuries, those who have a high BMI or some other indicator of adiposity, and those at risk of becoming physically inactive,” Dr. Whittaker said.

She added that a key take-away message from the study, for which she is coprincipal investigator, is that reduced physical activity on the part of someone with a history of a youth sports knee injury is a big red flag. These patients need to address their modifiable risk factors for OA via physical therapy and rehabilitation, along with receiving education reinforcing the importance of lifelong musculoskeletal health.

“Reduced physical activity is a warning sign. Don’t wait for knee pain,” she emphasized.

The Alberta Youth Prevention in Early OA study is funded by the Canadian Institutes of Health Research and nonprofit organizations. Dr. Whittaker reported having no financial conflicts.

[email protected]

LAS VEGAS – Young people who sustain an intra-articular knee injury while participating in youth sports are not only at increased risk for early posttraumatic osteoarthritis 3-10 years later as young adults, but they also are more prone to develop obesity and other modifiable risk factors for osteoarthritis, according to Jackie Whittaker, PhD.

“It appears that some of these young active individuals, after sustaining an injury which is itself a risk factor for osteoarthritis, are going down a pathway where they’re developing a second risk factor for the disease. This may accelerate the rate at which they get the disease and may very well also accelerate the rate at which the disease progresses after its onset,” Dr. Whittaker of the University of Alberta, Edmonton, said at the World Congress on Osteoarthritis.

Dr. Jackie L. Whittaker of the University of Alberta in Edmonton, Canada.

“In Canada, we know that injury during sport and recreation is the No. 1 reason that youth between the ages of 11 and 18 seek medical attention, with an alarming one in three doing so. Knee injuries are among the most common of those injuries,” she said.

At follow-up, 29% of the group with a history of knee injury and 4% of controls already had OA as defined by MRI. The likelihood of MRI evidence of OA was 13.5-fold greater in patients who underwent knee surgery for their injury, compared with controls.

“We saw the highest risk, as expected, in patients with ACL [anterior cruciate ligament] and/or meniscal tears, but we also saw a twofold increased risk of OA in those with seemingly less severe injuries, like grade 1-3 medial and collateral ligament injuries,” said Dr. Whittaker.

“I don’t think we were really shocked that knee injury can lead to structural changes that can be associated with future symptomatic OA, but we were surprised to be seeing that as early as 3-10 years post injury. And we were also seeing greater adiposity, a higher rate of being overweight or obese, reduced physical activity, weaker knee muscular strength, and poorer performance on balance and physical function tests,” she continued.

Indeed, at follow-up the subjects with a history of a youth sports knee injury were 4.4-fold more likely to be in the top quartile of fat mass index, compared with uninjured controls, 5.7-fold more likely to be in the highest quartile for abdominal fat, 2.1 times more likely to be in the lowest quartile for total weekly physical activity, and 2.4-fold more likely to be overweight or obese by body mass index (BMI). They were significantly less aerobically fit as reflected in their performance on the 20-meter shuttle run. And they scored significantly worse on the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), particularly on the knee-related quality of life, pain, and symptom subscales.

“The study is ongoing, but it has already contributed to identification of who we’re probably going to need to target for secondary prevention strategies: obviously, individuals who have torn their ACL and/or their meniscus, as was already well known, but perhaps also individuals that have had less severe injuries, those who have a high BMI or some other indicator of adiposity, and those at risk of becoming physically inactive,” Dr. Whittaker said.

She added that a key take-away message from the study, for which she is coprincipal investigator, is that reduced physical activity on the part of someone with a history of a youth sports knee injury is a big red flag. These patients need to address their modifiable risk factors for OA via physical therapy and rehabilitation, along with receiving education reinforcing the importance of lifelong musculoskeletal health.

“Reduced physical activity is a warning sign. Don’t wait for knee pain,” she emphasized.

The Alberta Youth Prevention in Early OA study is funded by the Canadian Institutes of Health Research and nonprofit organizations. Dr. Whittaker reported having no financial conflicts.

[email protected]

LAS VEGAS – Young people who sustain an intra-articular knee injury while participating in youth sports are not only at increased risk for early posttraumatic osteoarthritis 3-10 years later as young adults, but they also are more prone to develop obesity and other modifiable risk factors for osteoarthritis, according to Jackie Whittaker, PhD.

“It appears that some of these young active individuals, after sustaining an injury which is itself a risk factor for osteoarthritis, are going down a pathway where they’re developing a second risk factor for the disease. This may accelerate the rate at which they get the disease and may very well also accelerate the rate at which the disease progresses after its onset,” Dr. Whittaker of the University of Alberta, Edmonton, said at the World Congress on Osteoarthritis.

Dr. Jackie L. Whittaker of the University of Alberta in Edmonton, Canada.

“In Canada, we know that injury during sport and recreation is the No. 1 reason that youth between the ages of 11 and 18 seek medical attention, with an alarming one in three doing so. Knee injuries are among the most common of those injuries,” she said.

At follow-up, 29% of the group with a history of knee injury and 4% of controls already had OA as defined by MRI. The likelihood of MRI evidence of OA was 13.5-fold greater in patients who underwent knee surgery for their injury, compared with controls.

“We saw the highest risk, as expected, in patients with ACL [anterior cruciate ligament] and/or meniscal tears, but we also saw a twofold increased risk of OA in those with seemingly less severe injuries, like grade 1-3 medial and collateral ligament injuries,” said Dr. Whittaker.

“I don’t think we were really shocked that knee injury can lead to structural changes that can be associated with future symptomatic OA, but we were surprised to be seeing that as early as 3-10 years post injury. And we were also seeing greater adiposity, a higher rate of being overweight or obese, reduced physical activity, weaker knee muscular strength, and poorer performance on balance and physical function tests,” she continued.

Indeed, at follow-up the subjects with a history of a youth sports knee injury were 4.4-fold more likely to be in the top quartile of fat mass index, compared with uninjured controls, 5.7-fold more likely to be in the highest quartile for abdominal fat, 2.1 times more likely to be in the lowest quartile for total weekly physical activity, and 2.4-fold more likely to be overweight or obese by body mass index (BMI). They were significantly less aerobically fit as reflected in their performance on the 20-meter shuttle run. And they scored significantly worse on the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), particularly on the knee-related quality of life, pain, and symptom subscales.

“The study is ongoing, but it has already contributed to identification of who we’re probably going to need to target for secondary prevention strategies: obviously, individuals who have torn their ACL and/or their meniscus, as was already well known, but perhaps also individuals that have had less severe injuries, those who have a high BMI or some other indicator of adiposity, and those at risk of becoming physically inactive,” Dr. Whittaker said.

She added that a key take-away message from the study, for which she is coprincipal investigator, is that reduced physical activity on the part of someone with a history of a youth sports knee injury is a big red flag. These patients need to address their modifiable risk factors for OA via physical therapy and rehabilitation, along with receiving education reinforcing the importance of lifelong musculoskeletal health.

“Reduced physical activity is a warning sign. Don’t wait for knee pain,” she emphasized.

The Alberta Youth Prevention in Early OA study is funded by the Canadian Institutes of Health Research and nonprofit organizations. Dr. Whittaker reported having no financial conflicts.

[email protected]

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week^®.

In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.

“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”

The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.

This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.

The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.

These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.

The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.

Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).

An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.

When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.

There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.

Dr. Bell disclosed that he is a consultant for TORAX.

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]

On Twitter @Alz_gal

CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week^®.

In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.

“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”

The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.

This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.

The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.

These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.

The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.

Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).

An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.

When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.

There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.

Dr. Bell disclosed that he is a consultant for TORAX.

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]

On Twitter @Alz_gal

CHICAGO – Persistent reflux symptoms resolved in 93% of patients who underwent laparoscopic deployment of a circlet of magnet beads to the lower esophageal juncture, but in just 9% of those who doubled their dose of omeprazole, Reginald Bell, MD, said at the annual Digestive Disease Week^®.

In addition to bolstering positive device data, the results of this ongoing randomized study suggest that it may be time to rethink the treatment algorithm for patients who don’t respond optimally to medical therapy, Dr. Bell said in an interview.

“We found that relatively few patients respond well to the typical doubling of PPIs,” said Dr. Bell of the SOFI SurgOne Foregut Institute, Englewood, Colo. “In light of these strong results, it’s my opinion that we should consider going straight to surgery for at least some of these patients”

The LINX Reflux Management System (TORAX Medical; Shoreview, Minn.) is a small, flexible band of interlinked titanium beads with magnetic cores. The magnetic attraction between the beads keeps them joined when the lower esophageal sphincter is at rest. It exerts just enough resistance, however, to keep the sphincter from opening under gastric pressures of less than about 20 mm Hg, preventing reflux into the esophagus. Reflux typically occurs at an opening pressure of 10-12 mm Hg. Swallowing pressures, however, generally exceed 20 mm Hg, Dr. Bell said, allowing the circlet to expand enough to allow free passage of the bolus. The magnetic forces then bring the beads back together, again keeping the sphincter in a closed position.

This variable pressure is a big advantage over the Nissen fundoplication, which creates a pseudoflap that isn’t as yielding to intragastric pressure, Dr. Bell said. Nissen patients frequently have trouble belching or vomiting, and can experience bloating and distention from a reduced ability to vent gases. That is generally not a problem with LINX patients. And while some do initially experience dysphagia, this is typically transient. In the pivotal trial, bloating occurred in 7% of patients by 24 months.

The study comprised 150 patients with persistent symptoms of gastroesophageal reflux disease (GERD), despite at least 8 weeks of taking 20 mg omeprazole daily. These patients were randomized on a 2:1 scheme to either a doubling of omeprazole (20 mg twice a day) or surgery with LINX. Dr. Bell reported 6-month outcomes on 80 patients, 25 of whom had the LINX procedure and 55 of whom began double-dose omeprazole.

These patients were a mean of 47 years old, and had used a proton pump inhibitor (PPI) for a mean of 8 years. Baseline work-ups confirmed moderate to severe GERD, with about 12% of gastric measurement times at less than pH 4. The mean DeMeester Score was about 40. On the GERD Health-Related Quality of Life Questionnaire, patients scored about 24 while on medical therapy and 31 while off. They reported moderate to severe heartburn and regurgitation.

The study’s primary endpoint was relief of moderate to severe regurgitation. This was reached in 93% of the LINX group and 9% of the double-dose PPI group – a significant difference. Significantly more LINX patients also achieved at least a 50% reduction in their baseline GERD-HRQL score (90% vs.7%). The mean score dropped from about 32-5 in the LINX group and 30-24 in the PPI group.

Mean scores on the Reflux Disease Questionnaire improved significantly more in the LINX group than in the PPI group, including regurgitation (4.2.-1.4; 4.4 at both time points), and heartburn (3.4-1.6; 3.6-3.9).

An independent, blinded laboratory conducted pH/impedance testing on the cohort; the normal values were less than 57 reflux episodes/24 hours. At 6 months, the LINX group experienced a mean of 30 episodes vs. 70 in the PPI group.

When the investigators examined a combined measure of the number of reflux episodes and the change in DeMeester scores, they found normal reflux in 92% of the LINX group and 36% of the PPI group.

There was one adverse event related to the LINX procedure. A 66-year-old man was hospitalized and medically treated for esophageal spasms. The incident resolved with no sequelae, Dr. Bell said. So far, one LINX patient has needed to add PPI therapy; other studies typically show that 2%-3% of patients with the device do so.

Dr. Bell disclosed that he is a consultant for TORAX.

Digestive Disease Week^® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

[email protected]

On Twitter @Alz_gal

Maternal antibody concentrations continue to affect children’s immune response to their first and later vaccine doses as late as age 2 years, according to study findings.

Greater spacing between doses did not eliminate the maternal antibody effects, the research published in JAMA Pediatrics showed.

copyright itsmejust/Thinkstock

Maternal antibody concentrations continue to affect children’s immune response to their first and later vaccine doses as late as age 2 years, according to study findings.

Greater spacing between doses did not eliminate the maternal antibody effects, the research published in JAMA Pediatrics showed.

copyright itsmejust/Thinkstock

Maternal antibody concentrations continue to affect children’s immune response to their first and later vaccine doses as late as age 2 years, according to study findings.

Greater spacing between doses did not eliminate the maternal antibody effects, the research published in JAMA Pediatrics showed.

copyright itsmejust/Thinkstock

A different measurement tool than body mass index (BMI) z scores was more accurate in assessing adolescents’ body fat percentage than BMI z scores, a study found.

More than twice as many adolescents aged 8-17 years were misclassified as overweight using BMI z scores than using triponderal mass index (TMI), which uses a formula for calculating a weight-to-height ratio, researchers reported. Obesity was similarly overreported with BMI z scores, compared with TMI scores.

Michail_Petrov-96/Thinkstock

A different measurement tool than body mass index (BMI) z scores was more accurate in assessing adolescents’ body fat percentage than BMI z scores, a study found.

More than twice as many adolescents aged 8-17 years were misclassified as overweight using BMI z scores than using triponderal mass index (TMI), which uses a formula for calculating a weight-to-height ratio, researchers reported. Obesity was similarly overreported with BMI z scores, compared with TMI scores.

Michail_Petrov-96/Thinkstock

A different measurement tool than body mass index (BMI) z scores was more accurate in assessing adolescents’ body fat percentage than BMI z scores, a study found.

More than twice as many adolescents aged 8-17 years were misclassified as overweight using BMI z scores than using triponderal mass index (TMI), which uses a formula for calculating a weight-to-height ratio, researchers reported. Obesity was similarly overreported with BMI z scores, compared with TMI scores.

Michail_Petrov-96/Thinkstock

BIRMINGHAM, ENGLAND – Researchers in the United Kingdom are looking at how smartphone technology can help to improve how patients with rheumatoid arthritis (RA) monitor their disease at home and between clinic visits.

As part of the Remote Monitoring of Rheumatoid Arthritis (REMORA) study, a team led by Will Dixon, MD, at the University of Manchester (England), has developed an app that links directly into electronic patient records to help collect information from patients between their regular clinic visits for both self-monitoring and research purposes.

“REMORA is motivated by the need to learn about what happens to patients in between clinic visits, and that’s both for clinical care and for research but also to have the opportunity to support self-management, so we’ve designed the study to meet those three needs,” Dr. Dixon, professor and chair of digital epidemiology in Manchester University’s division of musculoskeletal and dermatological sciences, said in an interview at the British Society for Rheumatology annual conference.

Sara Freeman/Frontline Medical News

Using built-in accelerometer for research

Another approach to harnessing smartphone technology is being taken by researchers at the University of Southampton (England), where engineering postgraduate student Jimmy Caroupapoulle and his collaborators are working on an app that continually uses the built-in sensors in a phone to detect movements, and thus how physically active someone is.

“What we are trying to achieve is to develop an application that can just run in the background so people do not have to do too much,” Mr. Caroupapoulle explained in an interview around his poster presentation.

Using the app, called RApp, patients will be able to answer daily questions based on existing tools (RAPID3 and MDHAQ) to record their levels of pain, joint inflammation, and physical activity. The latter would be recorded via the phone’s onboard accelerometer to give a more objective view of whether the patient is moving around, as well as the patient’s speed in getting up from a seated position. The app collects data using the 28-joint Disease Activity Score so an indication of the severity of joint pain or inflammation can be assessed.

The aim is to give the patients the power to monitor themselves but also to facilitate discussion with their physicians. Data from the app will be integrated into an online portal so that patients and their doctors can see the information provided.

So far, 5 patients with RA have tested the application and the next stage is to release the application to a wider group, perhaps 20 patients, Mr. Caroupapoulle said.

“There are lots of apps out there, but this is something that looks at the quality of movement.” consultant rheumatologist Christopher Edwards, MD, a member of the team behind the RApp, said in an interview.

As opposed to pedometers or other devices that monitor physical activity to varying degrees of accuracy, RApp looks at how people accelerate as they stand up or move, which can be important for those with arthritis, and how that relates to their disease activity, said Dr. Edwards, professor of rheumatology at the University of Southampton.

“You can’t guarantee that someone always had their phone in their hand or in their bag,” Dr. Edwards said, “so what you want to do is get a sample from time during the day that gives you an overall representation, even if that is a very short period, just once during the day, then we’ll see if that makes a difference over time and whether that correlates with someone’s disease activity.”

The REMORA study is sponsored by Arthritis Research UK and the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care Greater Manchester. RApp is being developed without commercial funding. Dr. Austin, Dr. Dixon, Mr. Caroupapoulle, and Dr. Edwards stated they had no conflicts of interest.

[email protected]

BIRMINGHAM, ENGLAND – Researchers in the United Kingdom are looking at how smartphone technology can help to improve how patients with rheumatoid arthritis (RA) monitor their disease at home and between clinic visits.

As part of the Remote Monitoring of Rheumatoid Arthritis (REMORA) study, a team led by Will Dixon, MD, at the University of Manchester (England), has developed an app that links directly into electronic patient records to help collect information from patients between their regular clinic visits for both self-monitoring and research purposes.

“REMORA is motivated by the need to learn about what happens to patients in between clinic visits, and that’s both for clinical care and for research but also to have the opportunity to support self-management, so we’ve designed the study to meet those three needs,” Dr. Dixon, professor and chair of digital epidemiology in Manchester University’s division of musculoskeletal and dermatological sciences, said in an interview at the British Society for Rheumatology annual conference.

Sara Freeman/Frontline Medical News

Using built-in accelerometer for research

Another approach to harnessing smartphone technology is being taken by researchers at the University of Southampton (England), where engineering postgraduate student Jimmy Caroupapoulle and his collaborators are working on an app that continually uses the built-in sensors in a phone to detect movements, and thus how physically active someone is.

“What we are trying to achieve is to develop an application that can just run in the background so people do not have to do too much,” Mr. Caroupapoulle explained in an interview around his poster presentation.

Using the app, called RApp, patients will be able to answer daily questions based on existing tools (RAPID3 and MDHAQ) to record their levels of pain, joint inflammation, and physical activity. The latter would be recorded via the phone’s onboard accelerometer to give a more objective view of whether the patient is moving around, as well as the patient’s speed in getting up from a seated position. The app collects data using the 28-joint Disease Activity Score so an indication of the severity of joint pain or inflammation can be assessed.

The aim is to give the patients the power to monitor themselves but also to facilitate discussion with their physicians. Data from the app will be integrated into an online portal so that patients and their doctors can see the information provided.

So far, 5 patients with RA have tested the application and the next stage is to release the application to a wider group, perhaps 20 patients, Mr. Caroupapoulle said.

“There are lots of apps out there, but this is something that looks at the quality of movement.” consultant rheumatologist Christopher Edwards, MD, a member of the team behind the RApp, said in an interview.

As opposed to pedometers or other devices that monitor physical activity to varying degrees of accuracy, RApp looks at how people accelerate as they stand up or move, which can be important for those with arthritis, and how that relates to their disease activity, said Dr. Edwards, professor of rheumatology at the University of Southampton.

“You can’t guarantee that someone always had their phone in their hand or in their bag,” Dr. Edwards said, “so what you want to do is get a sample from time during the day that gives you an overall representation, even if that is a very short period, just once during the day, then we’ll see if that makes a difference over time and whether that correlates with someone’s disease activity.”

The REMORA study is sponsored by Arthritis Research UK and the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care Greater Manchester. RApp is being developed without commercial funding. Dr. Austin, Dr. Dixon, Mr. Caroupapoulle, and Dr. Edwards stated they had no conflicts of interest.

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BIRMINGHAM, ENGLAND – Researchers in the United Kingdom are looking at how smartphone technology can help to improve how patients with rheumatoid arthritis (RA) monitor their disease at home and between clinic visits.

As part of the Remote Monitoring of Rheumatoid Arthritis (REMORA) study, a team led by Will Dixon, MD, at the University of Manchester (England), has developed an app that links directly into electronic patient records to help collect information from patients between their regular clinic visits for both self-monitoring and research purposes.

“REMORA is motivated by the need to learn about what happens to patients in between clinic visits, and that’s both for clinical care and for research but also to have the opportunity to support self-management, so we’ve designed the study to meet those three needs,” Dr. Dixon, professor and chair of digital epidemiology in Manchester University’s division of musculoskeletal and dermatological sciences, said in an interview at the British Society for Rheumatology annual conference.

Sara Freeman/Frontline Medical News

Using built-in accelerometer for research

Another approach to harnessing smartphone technology is being taken by researchers at the University of Southampton (England), where engineering postgraduate student Jimmy Caroupapoulle and his collaborators are working on an app that continually uses the built-in sensors in a phone to detect movements, and thus how physically active someone is.

“What we are trying to achieve is to develop an application that can just run in the background so people do not have to do too much,” Mr. Caroupapoulle explained in an interview around his poster presentation.

Using the app, called RApp, patients will be able to answer daily questions based on existing tools (RAPID3 and MDHAQ) to record their levels of pain, joint inflammation, and physical activity. The latter would be recorded via the phone’s onboard accelerometer to give a more objective view of whether the patient is moving around, as well as the patient’s speed in getting up from a seated position. The app collects data using the 28-joint Disease Activity Score so an indication of the severity of joint pain or inflammation can be assessed.

The aim is to give the patients the power to monitor themselves but also to facilitate discussion with their physicians. Data from the app will be integrated into an online portal so that patients and their doctors can see the information provided.

So far, 5 patients with RA have tested the application and the next stage is to release the application to a wider group, perhaps 20 patients, Mr. Caroupapoulle said.

“There are lots of apps out there, but this is something that looks at the quality of movement.” consultant rheumatologist Christopher Edwards, MD, a member of the team behind the RApp, said in an interview.

As opposed to pedometers or other devices that monitor physical activity to varying degrees of accuracy, RApp looks at how people accelerate as they stand up or move, which can be important for those with arthritis, and how that relates to their disease activity, said Dr. Edwards, professor of rheumatology at the University of Southampton.

“You can’t guarantee that someone always had their phone in their hand or in their bag,” Dr. Edwards said, “so what you want to do is get a sample from time during the day that gives you an overall representation, even if that is a very short period, just once during the day, then we’ll see if that makes a difference over time and whether that correlates with someone’s disease activity.”

The REMORA study is sponsored by Arthritis Research UK and the National Institute of Health Research Collaboration for Leadership in Applied Health Research and Care Greater Manchester. RApp is being developed without commercial funding. Dr. Austin, Dr. Dixon, Mr. Caroupapoulle, and Dr. Edwards stated they had no conflicts of interest.

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In retrospect, the founding of the American Association for Thoracic Surgery (AATS) in 1917 may seem surprisingly optimistic, given the status of cardiothoracic surgery as a discipline at that time. While important strides had been made in dealing with open chest wounds, to the modern eye, the field in the second decade of the 20th century seems more characterized by what was not yet possible rather than by what was.

One of the most critical issues holding back the development of cardiothoracic surgery in this early period was the problem of acute pneumothorax that occurred whenever the chest was opened.

As Willy Meyer (1858-1932), second president of the AATS, described the problem at the first AATS annual meeting in 1917: “What is it that happens when the thorax is opened, let us say [for example] by a stab wound in an intercostal space in an affray on the street? Immediately air rushes into the pleural cavity and this normal atmospheric pressure, being greater than the normal pressure within ... the lung contracts to a very small organ around its hilum. Air fills the space formerly occupied by the lung. This condition, with its immediate clinical pathologic consequences, is called ‘acute pneumothorax.’ It has been the stumbling block for almost a century to the proper development of the surgery of the chest. … Carbonic acid is retained in the blood … The accumulation of CO, with its deleterious effect increases, finally ending in the patient’s death.”

But in the first decade of the 20th century, two major and competing techniques evolved to solve the problem, each one represented by the first and second presidents of the fledgling AATS. For a short period of time a controversy seemed to separate the two men, but their views were expressly reconciled at the first annual meeting of the AATS.

Wikimedia Commons/Public domain

Wikimedia Commons/Public domain

Sources

Meltzer, S. J., 1917. First President’s Address. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/First-Presidents-Address.cgi

Meyer, W., 1917. Surgery Within the Past Fourteen Years. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/A-Review-of-the-Evolution-of-Thoracic-Surgery-Within-the-Pas.cgi

Nissen, R., Wilson, R.H.L. Pages in the History of Chest Surgery. Springfield, IL: Charles C. Thomas, 1960.
 

[email protected]

In retrospect, the founding of the American Association for Thoracic Surgery (AATS) in 1917 may seem surprisingly optimistic, given the status of cardiothoracic surgery as a discipline at that time. While important strides had been made in dealing with open chest wounds, to the modern eye, the field in the second decade of the 20th century seems more characterized by what was not yet possible rather than by what was.

One of the most critical issues holding back the development of cardiothoracic surgery in this early period was the problem of acute pneumothorax that occurred whenever the chest was opened.

As Willy Meyer (1858-1932), second president of the AATS, described the problem at the first AATS annual meeting in 1917: “What is it that happens when the thorax is opened, let us say [for example] by a stab wound in an intercostal space in an affray on the street? Immediately air rushes into the pleural cavity and this normal atmospheric pressure, being greater than the normal pressure within ... the lung contracts to a very small organ around its hilum. Air fills the space formerly occupied by the lung. This condition, with its immediate clinical pathologic consequences, is called ‘acute pneumothorax.’ It has been the stumbling block for almost a century to the proper development of the surgery of the chest. … Carbonic acid is retained in the blood … The accumulation of CO, with its deleterious effect increases, finally ending in the patient’s death.”

But in the first decade of the 20th century, two major and competing techniques evolved to solve the problem, each one represented by the first and second presidents of the fledgling AATS. For a short period of time a controversy seemed to separate the two men, but their views were expressly reconciled at the first annual meeting of the AATS.

Wikimedia Commons/Public domain

Wikimedia Commons/Public domain

Sources

Meltzer, S. J., 1917. First President’s Address. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/First-Presidents-Address.cgi

Meyer, W., 1917. Surgery Within the Past Fourteen Years. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/A-Review-of-the-Evolution-of-Thoracic-Surgery-Within-the-Pas.cgi

Nissen, R., Wilson, R.H.L. Pages in the History of Chest Surgery. Springfield, IL: Charles C. Thomas, 1960.
 

[email protected]

In retrospect, the founding of the American Association for Thoracic Surgery (AATS) in 1917 may seem surprisingly optimistic, given the status of cardiothoracic surgery as a discipline at that time. While important strides had been made in dealing with open chest wounds, to the modern eye, the field in the second decade of the 20th century seems more characterized by what was not yet possible rather than by what was.

One of the most critical issues holding back the development of cardiothoracic surgery in this early period was the problem of acute pneumothorax that occurred whenever the chest was opened.

As Willy Meyer (1858-1932), second president of the AATS, described the problem at the first AATS annual meeting in 1917: “What is it that happens when the thorax is opened, let us say [for example] by a stab wound in an intercostal space in an affray on the street? Immediately air rushes into the pleural cavity and this normal atmospheric pressure, being greater than the normal pressure within ... the lung contracts to a very small organ around its hilum. Air fills the space formerly occupied by the lung. This condition, with its immediate clinical pathologic consequences, is called ‘acute pneumothorax.’ It has been the stumbling block for almost a century to the proper development of the surgery of the chest. … Carbonic acid is retained in the blood … The accumulation of CO, with its deleterious effect increases, finally ending in the patient’s death.”

But in the first decade of the 20th century, two major and competing techniques evolved to solve the problem, each one represented by the first and second presidents of the fledgling AATS. For a short period of time a controversy seemed to separate the two men, but their views were expressly reconciled at the first annual meeting of the AATS.

Wikimedia Commons/Public domain

Wikimedia Commons/Public domain

Sources

Meltzer, S. J., 1917. First President’s Address. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/First-Presidents-Address.cgi

Meyer, W., 1917. Surgery Within the Past Fourteen Years. http://t.aats.org/annualmeeting/Program-Books/50th-Anniversary-Book/A-Review-of-the-Evolution-of-Thoracic-Surgery-Within-the-Pas.cgi

Nissen, R., Wilson, R.H.L. Pages in the History of Chest Surgery. Springfield, IL: Charles C. Thomas, 1960.
 

[email protected]