No Evidence of Cancer Risk from Long-Term PPI Therapy.

Hormonal and histologic changes observed with long-term use of proton-pump inhibitors do not seem to translate into an elevated risk for mucosal gland atrophy or cancer.

Prolonged use of proton-pump inhibitors (PPIs) has been associated with an increase in serum gastrin levels, which could drive proliferation of enterochromaffin-like (ECL) cells in the gastric mucosa and contribute to mucosal gland atrophy in the presence of Helicobacter pylori infection. Two recent studies evaluated the long-term effects of PPI use on gastric mucosa.

In a multicenter study, Fiocca and colleagues randomized 554 patients with chronic gastroesophageal reflux to receive 20 mg of esomeprazole daily or undergo laparoscopic antireflux surgery. Gastric biopsies and serum samples for gastrin and chromogranin A were taken at baseline and at 1, 3, and 5 years. Biopsies from each time point were available for 338 participants. In the esomeprazole arm, ECL cell hyperplasia increased between time points, mucosal inflammation decreased (only in those with H. pylori infection), and serum gastrin and chromogranin A levels increased moderately. No atrophy or intestinal metaplasia occurred. The authors concluded that despite moderate increases in gastrin and chromogranin A levels, 5 years of esomeprazole therapy did not cause dysplastic or neoplastic changes and decreased inflammation in patients with H. pylori infection.

Brunner and colleagues report the longest follow-up results to date of efficacy, safety, and tolerability in 142 patients who received pantoprazole for a mean of 9.2 years to treat peptic ulcers or reflux esophagitis. Gastric biopsies and serum gastrin levels were obtained at baseline, during healing (until week 12), every 6 months during the first 5 years, and annually during the subsequent 10 years. The ECL cell density increased moderately during the first 3 years and then stabilized. Investigators observed no clinically relevant changes in the gastric mucosa or increase in intestinal metaplasia. Serum gastrin levels rose to moderate levels and subsequently remained constant but showed high variability between patients. In patients with H. pylori infection, antral gastritis regressed after eradication of the infection. The authors concluded that maintenance therapy with pantoprazole for up to 15 years is well tolerated, with no evidence of increased risk for gastric cancer.

Comment: Both studies confirm that long-term PPI treatment increases serum gastrin levels and is associated with an increase in ECL cells. Serum gastrin levels rose to a moderate level early in treatment and then remained constant for the duration of follow-up. The absence of histologic evidence of intestinal metaplasia or other precancerous mucosal changes suggests that the risk for gastric cancer is probably not increased by PPI therapy. However, both of these prospective studies were small and underpowered to detect a small increase in risk.

Source: Journal Watch Gastroenterology


When Should a Patient Be Referred for Epilepsy Surgery Evaluation?

A new Web-based tool is available to help clinicians decide when to refer a patient for evaluation.

Evidence suggests that the low rate of referral for epilepsy surgery evaluation is in part caused by clinicians’ doubts about patient eligibility. To improve the rate of appropriate referrals, researchers have now developed and tested a Web-based decision-making tool.

A clinician panel that included epilepsy specialists and general neurologists surveyed the literature to identify eligibility criteria for entrance into epilepsy surgery studies, which they used to create a systematic, stepwise decision-making tool. The criteria were based on magnetic resonance imaging and electroencephalography findings, frequency of disabling seizures, presence of adverse effects related to antiepileptic drug (AED) use, and number of AEDs tried. The panel then used the tool to rate 2646 clinical scenarios as “appropriate,” “inappropriate,” or “uncertain” to refer the described patient for epilepsy surgery evaluation. The reviewers rated 62% of scenarios as inappropriate for surgery evaluation referral, 21% as appropriate, and 17% as uncertain. The reviewers disagreed in only 0.8% of cases, all of which involved either incomplete clinical investigations or nondisabling seizures. The Web-based tool is published at

Comment: The panel developed this tool because of the persistent, frustrating absence of improvement in the relative number and timely referral of appropriate candidates for epilepsy surgery evaluation, despite decades of accumulating evidence and excellent guidelines supporting the efficacy and relatively low risks of epilepsy surgery. Astonishingly, time to surgical evaluation and treatment for adults remains approximately 20 years (CNS Spectr 2004; 9:136).

Regardless of any limitations in the data and methods used to develop this tool, it can aid in changing practice. Notably, the authors used only variables important in considering referral for epilepsy surgery evaluation, not the more extensive data points necessary for determining actual surgery candidacy. As the authors emphasize, the tool must be validated and, most importantly, updated as new pertinent knowledge becomes available. This should not be difficult, and the tool is easy to use. The challenge will be making target physicians aware of the tool and its importance.

Source: Journal Watch Neurology


T-DM1 Prolongs Survival in Advanced HER2-Positive Breast Cancer.

The drug-antibody conjugate was more effective and less toxic than lapatinib plus capecitabine in patients previously treated with trastuzumab and a taxane.

We can expect that the next breast cancer drug soon to be approved by the FDA will be trastuzumab emtansine (T-DM1), an antibody-drug conjugate combining trastuzumab with a derivative of the cytotoxic maytansine via a stable linker molecule (JW Oncol Hematol Oct 2 2012). T-DM1 is more than just another new agent. It represents vindication for those who have worked on fusion molecules for the last 2 decades. Previous efforts with such molecules were often derailed because the linker was either unstable (resulting in systemic exposure to the toxin) or cytotoxic (resulting in prohibitive adverse effects). With T-DM1, intracellular drug delivery only to human epidermal growth factor receptor 2 (HER2)–overexpressing tumor cells has been observed.

Now, investigators report the results of the EMILIA study, an industry-sponsored, phase III, randomized, open-label trial involving 991 patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane. Patients received either T-DM1 or lapatinib plus capecitabine (LC) and were stratified by world region, number of prior chemotherapy regimens for advanced disease, and presence or absence of visceral disease. Primary endpoints were progression-free survival (PFS), overall survival (OS), and safety; secondary endpoints included objective response rate, duration of response, and time to symptom progression.

Median PFS was significantly longer with T-DM1 versus LC (9.6 vs. 6.4 months; hazard ratio, 0.65; P<0.001), as was median OS (30.9 vs. 25.1 months; HR, 0.68; P<0.001). Overall response rate was also superior with T-DM1 versus LC (43.6% vs. 30.8%; P<0.001), as were results for all secondary endpoints. Rates of grade 3 or 4 adverse events were 40.8% with T-DM1 and 57.0% with LC.

Comment: The excitement surrounding the anticipated FDA approval of T-DM1 is justified given that the drug successfully targets HER2-overexpressing disease with potent antitumor activity minus the full complement of adverse effects associated with typical chemotherapy partnered with trastuzumab. Of course, the stage is set for exploring T-DM1 in combination with other anti-HER2 agents, including pertuzumab (JW Oncol Hematol Jan 24 2012). Because the toxicity of T-DM1 is quite modest, adjuvant trials are under way to compare the use of this compound with standard trastuzumab-based regimens.

Source: Journal Watch Oncology and Hematology


Widespread Screening for Type 2 Diabetes Might Not Lower 10-Year Mortality.

In a population-based U.K. study, screening all middle-aged high-risk patients did not help.

Early diagnosis of type 2 diabetes can improve clinical outcomes, and mathematical models have suggested that widespread screening might lower diabetes-related mortality. To test this hypothesis, researchers cluster-randomized 33 general practices in eastern England to offer either a single round of formal screening to all middle-aged patients (age range, 40–69) considered to be at high risk for diabetes according to specified clinical characteristics (28 practices with approximately 16,000 high-risk patients) or to continue diagnosing diabetes in such patients through routine clinical assessment (5 practices with approximately 4000 high-risk patients).

Overall, 73% of invited patients participated in screening, and 3% of patients in both groups received diabetes diagnoses. After a median 9.6 years of follow-up, overall mortality among high-risk patients was similar in the screening and no-screening practices (10.5 and 9.9 deaths per 1000 person-years, respectively). Rates of cardiovascular- and cancer-related mortality also were similar in the two groups.

Comment: The study population was of above-average socioeconomic status; these results might not be generalizable to less-affluent populations in which the prevalence of undiagnosed diabetes might be higher. In addition, multiple rounds of screening and longer follow-up might be necessary to detect mortality differences attributable to screening. Furthermore, important outcomes other than mortality might be modifiable by screening. Regardless, these data suggest that population screening for diabetes might be less effective than expected and should be evaluated carefully before widespread implementation.

Source: Journal Watch General Medicine