Distinct Presentation of Autoimmune Hepatitis in the Elderly

Distinct Presentation of Autoimmune Hepatitis in the Elderly

Dual-vaccine therapy prolonged survival in pancreatic cancer

SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le. A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients. The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology. In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines. “This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. “Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy.” Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient. “Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone,” Dr. Le noted. GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response. CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells. The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin. Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy. They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable. With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03). The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le. In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Low hospital readmission rates apply across diagnoses

ST LOUIS (MD Consult) - Hospitals with lower 30-day readmission rates have a lower number of readmissions across a wide range of diagnoses and throughout the post-discharge period, reports a study in the January 11, 2014, British Medical Journal. The researchers analyzed data on Medicare beneficiaries aged 65 or older who were readmitted within 30 days after admission for heart failure, acute myocardial infarction, or pneumonia from 2007 to 2009. Readmission diagnoses were classified using a modified version of the Centers for Medicare and Medicaid Services' condition categories, and the timing of readmission was classified by day since discharge. Based on 30-day risk-standardized readmission rates over the 3 years studied, hospitals were classified as having high, average, or low readmission performance for each condition. The range of readmission diagnoses and median times to readmission were compared for high-, average-, and low-performing hospitals. The lead author was Kumar Dharmarajan of Columbia University Medical Center. The analysis included about 320,000 readmissions after 1.3 million admissions for heart failure at 4,041 hospitals, 103,000 readmissions after 516,000 admissions for acute myocardial infarction at 2,378 hospitals, and 208,000 readmissions after 1.1 million admissions for pneumonia at 4,328 hospitals. For all 3 index conditions, the range of readmission diagnoses was similar at hospitals with high, average, and low readmission rates. For heart failure and acute myocardial infarction, median time to readmission was similar across the 3 hospital performance groups. For pneumonia, median time to readmission was 1.4 days longer among high-performing hospitals, compared to low-performing hospitals. The patterns were similar after adjustment for additional hospital factors potentially affecting readmission rates. Thirty-day readmission rates vary substantially among U.S. hospitals. There are few data on how hospital readmission rates are related to the diagnoses and timing of readmissions. This information could have implications for identifying the effective strategies followed by the best-performing hospitals. For the 3 index diagnoses studied, hospitals with low 30-day readmission rates have proportionately fewer readmissions, with similar readmission diagnoses and timing. The results may help to explain why studies evaluating "broad based and longitudinal" interventions for lowering readmissions have higher reported higher success rates, compared to "disease specific or time limited interventions."

Never exceed dose of constipation drugs containing sodium phosphate, FDA warns

ST LOUIS (MD Consult) - On January 8, 2014, the US Food and Drug Administration (FDA) issued an alert concerning the use of over-the-counter (OTC) sodium phosphate drugs to treat constipation. The agency is warning that using more than 1 dose in 24 hours of such drugs can cause rare but serious harm to the kidneys and heart, and even death. These drug products include oral solutions and enemas. They are marketed under the brand-name Fleet, and as store brands and generic products. They are available as single-ingredient drug products, containing either sodium biphosphate or sodium phosphate, and as combination drug products containing both ingredients. The FDA reviewed the Adverse Event Reporting System database from 1969 through 2012 and the medical literature from 1957 through August 2013 for cases describing serious adverse events associated with the of over-the-counter (OTC) sodium phosphate drug products used to treat constipation. The agency identified 54 cases describing serious adverse events in 25 adults and in 29 children. These reports described severe dehydration and changes in serum electrolytes levels associated with taking more than the recommended dose of OTC sodium phosphate products, resulting in serious adverse effects on organs (eg, kidneys and heart) and in some cases resulting in death. These serum electrolytes include calcium, sodium, and phosphate. According to the reports, most cases of serious harm occurred with a single dose of sodium phosphate that was larger than recommended or with more than 1 dose in a day. Some persons may be at higher risk for potential adverse events when the recommended dose of OTC sodium phosphate is exceeded. This includes young children, persons older than 55 years, patients with dehydration, kidney disease, bowel obstruction, or bowel inflammation, and patients who receive medications that may affect kidney function. These medications include diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers used to treat hypertension, as well as nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, and naproxen. Health care professionals should use caution when recommending an oral dose of these products for children 5 years and younger. The rectal form of these products should never be given to children younger than 2 years.

Resecting residual gastrointestinal stromal tumors improved survival

SAN FRANCISCO (IMNG)– Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients. After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations. The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. “It’s really hard to conduct a prospective study of this design,” said Dr. Park of Asan Medical Center, Seoul, South Korea. He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months. “This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery,” he said. Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival. In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said. The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group). As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases. Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.