American College of Gastroenterology

Cases of Rare, Fatal Cancer Linked to Celiac Disease Increasing

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VANCOUVER, B.C.—The incidence of enteropathy-associated T-cell lymphoma—a rare and aggressive T-cell, non-Hodgkin lymphoma—is rising, according to data presented at the 2023 annual meeting of the American College of Gastroenterology.

The growing number of EATL cases could be connected to the increase in celiac disease, given the strong association between the two conditions, researchers said.

“Although [EATL is] rare, most of the cases that we see develop in patients with celiac disease,” said lead investigator Isabel Hujoel, MD, the clinic director of the Celiac Disease Center at UW Medical Center, in Seattle. “We don’t know why the incidence of EATL has steadily risen over the past two decades, but we suspect that it’s because celiac disease continues to increase in prevalence.”

The study, which used the Surveillance, Epidemiology, and End Results (SEER) program database, found 463 cases of EATL between 2000 and 2020, with an age-adjusted incidence rate of 0.014 per 100,000 people (abstract P1249). However, the incidence of EATL increased by 2.58% annually over this 20-year period.

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Poor Survival Outcomes

Findings from the study, which won Presidential Poster and Outstanding Research Awards, also showed that EATL was more common in men, and that the median age at diagnosis was 65 years. Most cases (42%) were treated with both surgery and chemotherapy.

Older age at the time of diagnosis was associated with a higher risk for death, while factors such as sex, race, year of diagnosis and time to treatment initiation showed no significant impact on survival.

Notably, despite medical advances over the past two decades, the data showed no change in survival over the study period. “Unfortunately, survival outcomes of patients with EATL have not improved over time,” Dr. Hujoel said. “Mean survival for this disease remains approximately six months.”

A separate, retrospective cohort analysis of 259 patients in the SEER database found that the majority of patients underwent surgical resection (69.9%), followed by chemotherapy (47.5%) (abstract P1594).

Investigator Sophia Dar, MD, a gastroenterology fellow at Southern Illinois University School of Medicine, in Springfield, told Gastroenterology & Endoscopy News that treatment with these methods was associated with improved survival rates compared with no treatment. Chemotherapy alone also decreased the hazard ratio when compared with no treatment.

“Patients in the chemotherapy group marginally outperformed their surgical counterparts, indicating perhaps chemotherapy as a more viable treatment option in certain scenarios,” Dr. Dar said. “Unfortunately, irrespective of treatment, 83.7% of patients died in the five-year follow-up period.”

Researchers from both studies emphasized the need for further study, especially considering the strong association between EATL and celiac disease.

“Better understanding of the factors contributing to the high mortality rate could help medical practitioners develop more efficient treatment plans for EATL,” Dr. Dar concluded.

Screen Only for Refractory Disease

Debra Silberg, MD, PhD, the chief scientific officer of the nonprofit Beyond Celiac, based in Ambler, Pa., told Gastroenterology & Endoscopy News that the research does not address whether the increase in EATL is accounted for by patients with celiac disease, but “since there has also been an annual increase in celiac disease diagnosis, it follows that there would be an increase in EATL. Therefore, the overall percentage of EATL in patients with celiac disease may not have changed—which is around 0.22 to 1.9 per 100,000—and is still extremely rare,” she added.

Regarding screening, Dr. Silberg referred to the American Gastroenterological Association guidelines for refractory celiac disease (Gastroenterology 2022;163[5]:1461-1469). If a patient is diagnosed with type 2 refractory celiac disease, which, she said, “is associated with clonal T-cell expansion, then small bowel imaging is recommended to exclude EATL and ulcerative jejunoileitis. Since EATL is still rare even with this increased incidence,” she added, “only patients with refractory celiac disease or a suspicion of a complication of celiac disease should be screened.”

Pancreatic Cancer Incidence Rising Sharply Among Young Women

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A “potentially alarming” trend is being seen in the increasing incidence of pancreatic cancer among younger women relative to younger men, according to researchers who presented population-based data at the 2021 annual meeting of the American College of Gastroenterology.

“If current trends persist, the incidence rate of pancreatic cancer in younger women is estimated to be 400% that of men by 2040,” said investigator Yazan Abboud, MD, a postdoctoral research fellow in the Pancreaticobiliary Program at Cedars-Sinai Medical Center, in Los Angeles.

According to senior investigator Srinivas Gaddam, MD, an assistant professor of medicine at Cedars-Sinai, this is the first report using current data showing pancreatic cancer is “increasing dramatically” in women younger than 50 years. “The findings are most dramatic in women younger than 35,” he noted.

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Changing Incidence Over 2 Decades

A modest increase in this malignancy has been noted for years, but data are limited on sex-based time trends. Dr. Abboud and his colleagues performed a time trend analysis of pancreatic cancer incidence rates (IRs) in the Surveillance, Epidemiology, and End Results (SEER) 21 database. They calculated IRs of the disease per 100,000 population for the years 2000 to 2018, stratified by age and sex (abstract P0009). They also estimated the annual percentage change (APC) and average APC (AAPC).

The researchers identified 283,817 cases of pancreatic cancer (50% women) and found that their AAPCs reflected a significant increase in IRs among women (0.72) and men (0.87) over the past two decades.

“The trends were parallel (P=0.28), suggesting that sex-specific IRs are increasing at the same rate. However, stratified analysis of different age groups showed a variation of trends between sexes,” Dr. Abboud said.

In the age group 50 years and older, the IR increase was greater in men than women, but the absolute AAPC difference was modest (0.26). However, in individuals younger than 50 years of age, this sex-based trend was reversed, and women showed a significantly larger increase in incidence compared with men, with a greater absolute AAPC difference (1.40).

“To evaluate the subgroup contributing to this reversal of trend, we analyzed the 15- to 34-year-old pancreatic cancer patients,” Dr. Abboud said. “Younger women were found to have a much greater increase than men (P=0.01). The magnitude of absolute AAPC difference was 3.48, suggesting a rapid increase in incidence,” he said, adding that persistence of this trend would amount to a 400% increase over men in 20 years.

Updated Numbers in Published Study

In a November issue of JAMA (2021;326[20]: 2075-2077), the investigators reported data showing changes among people aged 15 to 54 years, based on the notion that “younger” cancer patients usually are defined as those under 55, Dr. Gaddam pointed out.

In that analysis, the overall AAPC increased by 0.78% in women and 0.90% in men, reflecting no significant difference by sex. In contrast, In women younger than 55, the AAPC was 1.93% versus 0.77% in men, showing a significant difference, he said.

Additionally, the AAPC among women aged 35 to 54 years increased by 1.56%, compared with 0.65% in men in the same age group. The rate of change in women aged 15 to 34 was 7.68%, compared with 4.20% in men.

Possible Explanations

Dr. Gaddam speculated that the underlying reason for this rise may be some form of disproportionate exposure to environmental factors in women, or perhaps other unknown risk factors. He and his team are hoping to find some answers and solutions to stop the upward trend and are analyzing data from other large national databases.

Meanwhile, he cautioned that the incidence of this cancer is “still very low in younger people,” and emphasized that abdominal pain in young women is not likely to be pancreatic cancer.

Pancreatic cancer specialist Laleh Melstrom, MD, MS, the chief of the Division of Surgical Oncology at City of Hope, in Duarte, Calif., called the findings “very interesting and somewhat surprising.”

Pointing out that the median age of onset of pancreatic cancer remains in the 60s and 70s, she said, “this sharp increase in young women does not have a clear explanation and is very much hypothesis-generating.”

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Dr. Melstrom said that “the traditional risk factors of smoking, obesity and pancreatitis could perhaps be associated with a greater rise in younger women. However, this is not a clear association that has been at all established.” She added that the study results echo findings of increased colorectal cancer in younger age groups.

Assist Devices Boost Colonoscopy Quality

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Given the theoretical advantage of smoothing mucosal folds, devices that flatten the colon during endoscopy should reveal more polyps. But do they?

Two new studies—one retrospective, one randomized—show the gains from colonoscopy assist devices now available commercially are real. But, how much they will boost a skilled endoscopist’s ability to detect adenomas remains unclear.

Presented at the 2017 World Congress of Gastroenterology/American College of Gastroenterology, the randomized study compared unassisted conventional colonoscopy (CC) and colonoscopy assisted with the Olympus transparent cap (TC) or the Olympus Endocuff Vision (EV) (abstract 39). The retrospective analysis (abstract P1029) compared CC, EV and the Medivators AmplifEYE (AE).

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AmplifEYE from Medivators

The assist devices obey the same principle: Flattened mucosa should reveal polyps obscured by folds. All devices fit on the end of existing colonoscopes, but the technologies differ. The Olympus TC is designed to maintain an appropriate depth of field while preventing the scope from coming into direct contact with the mucosal membrane. The more sophisticated EV has finger-like projections that permit more controlled flattening of the mucosal folds. The AE device, which is the newest option, also has flexible extensions to stretch and flatten mucosal folds.

“The differences between the devices were not very striking, but our data show that using a device is much better than not using a device,” reported Talal Alkayali, MBBS, of the H.H. Chao Comprehensive Digestive Disease Center at the University of California, Irvine, who helped conduct the retrospective study. He called this analysis, which included data from 1,186 screening and surveillance colonoscopies performed by 32 colonoscopists, the first side-by-side comparison of EV and AE.

The study was based on colonoscopies conducted between September 2016 and May 2017. Of these, 520 were CC, 312 were performed with EV and 354 were performed with AE. There were some differences between groups. For example, the cecal intubation rate (CIR) was lower in the CC group (97.3%) than in the EV or AE groups (both >99%; P=0.012).

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Endocuff Vision from Olympus.

The adenoma detection rate (ADR) was 30% for CC, 54% for EV and 50% for AE, indicating significant superiority of the assist devices (P<0.001 for both vs. CC). The serrated polyp detection rate (SDR) was 7% for CC, 13% for EV (P=0.004 vs. CC) and 14% for AE (P=0.002 vs. CC). When stratified by sex, the detection rates were numerically greater and usually significantly greater for both assist devices relative to CC.

The other study, billed as the first randomized controlled trial to compare EV, TC and CC, enrolled 126 patients. Sooraj Tejaswi, MD, director of the Gastroenterology Fellowship Program at the University of California, Davis Medical Center, in Sacramento, led the trial (abstract 39).

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When performed by three experienced colonoscopists with baseline ADRs ranging from 43% to 55%, few differences between colonoscopy techniques reached statistical significance. The one exception was mean ADR, which was 1.7 in the EV group versus 1.1 for CC and 0.76 for TC (P=0.03 for EV vs. TC), but the higher mean ADR per positive colonoscopy was not significant for EV versus the other methods. EV was associated with a numerically higher ADR (54.8%) than CC (52.3%) or TC, but the ADR for CC was higher than for the cap (40.5%).

“There was no statistical difference with respect to ADR between EV and CC, which may be accounted for by the high prestudy baseline ADR with our experienced endoscopists,” said Joseph Marsano, MD, a GI fellow at UC Davis, who presented the data. The results do not rule out an advantage of EV for providers with lower ADRs, but more studies would be needed to evaluate that hypothesis, he said.

In the randomized study, patient demographics and procedure metrics, such as cecal intubation time, were similar in the three study arms. The ADR was 52% for CC, 40% for TC and 54% for EV. Other measured outcomes followed this same general pattern. For example, the ADR in the proximal colon was 45% for CC, 35% for TC and 50% for EV; the mean numbers of adenomas detected per positive colonoscopy were 2.08, 1.63 and 2.59 in the three arms. None of these differences was statistically significant. When the mean numbers of adenomas per colonoscopy were compared, the difference for EV (1.7) was significantly superior to TC (0.76; P=0.03) but not CC (1.1).

“An interesting finding of the randomized study was the numerically higher sessile serrated adenoma detection rate of 23.8% with EV compared to 16.7% for CC and 14.3% for TC,” Dr. Tejaswi said. Although the study was not adequately powered to confirm this difference, Dr. Tejaswi said future research should explore whether assist devices have an advantage in increasing the detection rate of this type of adenoma.

At Dr. Alkayali’s institution, the assist devices have been widely incorporated into routine practice. In the absence of clear differences between the attachments, experience or personal experience might be more important criteria for selecting one over another. “Further studies will give us verification of the results” and may distinguish relative advantages between available devices, he added.

Why the results of the two studies diverge is unclear. Although randomization provides greater objectivity for making a comparison, there are many variables, such as the skill of the endoscopist, that may be important in considering the utility of these devices in typical patient screening and for future comparative studies.

David Johnson, MD, chief of the Division of Gastroenterology at Eastern Virginia Medical School, in Norfolk, said although the attachments “may be helpful, particularly for less skilled endoscopists, the additional costs and willingness to invest into additional nonreimbursed equipment will be the challenge.”

More data are needed to demonstrate the specific advantage of assist devices for both the detection of adenomas and serrated polyps and their ability to lead to definitive resection, Dr. Johnson said. These kinds of potential technical improvements are welcome, but “clearly, at present, the operator-dependent skills remain the backbone in ADR detection.”

Hepatitis C Drug Sofosbuvir Still Effective at 24 Weeks.

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New data from 4 phase 3 trials with the hepatitis C (HCV) drug sofosbuvir (SOF) and ribavirin (RBV) show that a 12-week regimen is effective in treating HCV genotypes 1 through 6. Twenty-four-week sustained virologic response (SVR) is essentially identical to 12-week SVR, bolstering confidence that the drug combination represents a cure. Those with genotype 3 infections are better served with a 16-week course of treatment.

The new work extends the results of the studies out to 24 weeks after treatment cessation. Twenty-four weeks was the traditional milestone for HCV treatments, but in recent years, the US Food and Drug Administration and industry have gravitated toward the 12-week time point. However, with new drugs set to greatly affect HCV treatment, it is important to consider this older benchmark, according to Kris Kowdley, MD, director of the Liver Center of Excellence at the Digestive Disease Institute at the Virginia Mason Medical Center in Seattle, Washington, who presented the research here at the American College of Gastroenterology (ACG) 2013 Annual Scientific Meeting and Postgraduate Course.

“We’re in a brave new world of hepatitis C treatments, and we’re very quickly reaching all oral, interferon-free, short-duration regimens, so I think it remains valuable to continue following patients to 24 weeks, and possibly 48 weeks, posttreatment to see if the assumption [of a cure] really holds up. We can also learn more about late relapses and possible questions about resistance,” Dr. Kowdley told Medscape Medical News.

The research drew from 4 phase 3 studies: Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection (NEUTRINO), which enrolled treatment-naive patients with genotype (GT) 1, 4, 5, and 6 infection, each of whom received 12 weeks of SOF, peg-interferon (PEG), and ribavirin (RBV); Phase 3 Study of Sofosbuvir and Ribavirin (FISSION), which enrolled treatment-naive GT 2/3 patients to receive either 12 weeks of SOF+RBV or 24 weeks of PEG+RBV; GS-7977 + Ribavirin for 12 Weeks in Subjects With Chronic Genotype 2 or 3 HCV Infection Who Are Interferon Intolerant, Interferon Ineligible or Unwilling to Take Interferon (POSITRON), which enrolled GT 2/3 patients unable or unwilling to receive interferon, who were randomly assigned to receive 12 weeks of SOF+RBV or placebo; and Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION), which enrolled treatment-experienced GT2/3 patients who received 12 or 16 weeks of SOF+RBV.

For all studies, the primary end point was sustained virologic response (HCV RNA < 25 IU/mL) at 12 weeks posttreatment (SVR12).

In the studies, participants had a mean age of 53 years (range, 19 – 77 years) and a mean body mass index of 28 kg/m2 (range, 17 – 56 kg/m2). Demographics were consistent with those of the HCV-infected population in the United States. Six percent of the participants were receiving opioid replacement therapy.

Table 1. 12-Week SVR Rates

GT 1,4,5,6 GT 2 and 3
NEUTRINO FISSION POSITRON FUSION
SOF/PEG/RBV (n = 327) SOF/RBV (n = 253) PEG/RBV (n = 243) SOF/RBV (n = 207) Placebo (n = 71) SOF/RBV 12 week (n = 100) SOF/RBV 16 week (n = 95)
Overall 91% 67% 67% 78% 0% 50% 73%
GT 2 N/A 97% 78% 93% 0% 86% 94%
GT 3 N/A 56% 63% 61% 0% 30% 62%
Noncirrhotic 93% 72% 74% 81% 0% 61% 76%
Cirrhotic 80% 47% 38% 61% 0% 31% 66%

Compensated cirrhosis at baseline was found in 17% of patients in the NEUTRINO study, 21% in FISSION, 18% in POSITRON, and 33% in FUSION.

In all studies, SVR12 was higher in patients without cirrhosis. Patients with GT 2 experienced higher SVR12 rates than those with GT 3.

SVR 24 rates were similar to SVR 12 rates.

Table 2. SVR12 vs SVR24

SVR12 SVR24
Treatment-naïve patients
GT 1, 4, 5, 6 overall 91% 91%
GT 1 90% 90%
GT 4 96% 96%
GT 5 and GT 6 100% 100%
Treatment-naive and experienced GT 2, 3 patients
Treatment-naive 67% 67%
Interferon unable 78% 78%
Previously treated (12 week regimen) 51% 50%
Previously treated (16 week regimen) 73% 72%

The additional data back up the 12-week SVR. “In all the studies, the 24-week results are almost identical [to the 12-week SVR]. We detected durability of that response,” said Dr. Kowdley. The studies also suggest that interferon is not needed to achieve SVR in genotypes 2 and 3, although Dr. Kowdley said that trials of interferon-sparing regimens are underway.

The results further underscore the anticipation that physicians have toward sofosbuvir and other new drugs. “I think 2 years ago there was a standing-room only meeting in San Francisco, where Pharmasset (which originally developed sofosbuvir), dropped just unbelievable results, and we all thought this was too good to be true,” Tim Little, MD, a physician with Puget Sound Gastroenterology in Seattle, Washington, who attended the presentation, told Medscape Medical News.

“I don’t know that there’s anything incredibly new about (this study), but it’s confirmation that this dramatic result that this very small group of investigators presented is actually real, and I think we can all understand that this is as good as they said it was going to be, or almost as good,” Dr. Little said.

On October 25, an FDA advisory committee unanimously recommended approval of sofosbuvir based on the 12-week results. The FDA is expected to make a decision by December 8.

Source: American College of Gastroenterology (ACG)