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SummaryBackgroundCurrent diagnostic guidelines recommend that eosinophilic oesophagitis (EoE) should be diagnosed only after GERD is excluded by a lack of response to a trial of acid suppression. There is limited information available providing outcome data about the effectiveness of this approach.AimTo examine the impact of double‐dose proton pump inhibitor (PPI) therapy on symptoms, endoscopic and histological features in patients with documented oesophageal eosinophilia consistent with EoE (≥15 eosinophils/high‐power field).MethodsSixty consecutive symptomatic patients with documented oesophageal eosinophilia received open‐label omeprazole 20 mg orally twice daily before meals for 8 weeks. Clinical, endoscopic and histological (resolution: 0–5 eosinophils/HPF, partial improvement: 5–14 eosinophils/HPF), or no improvement: (≥15 eosinophils/HPF) evaluation was repeated at the end of this period. An expert GI pathologist, unaware of the study aims, reviewed all slides.ResultsClinical improvement occurred in 43 (71.6%), endoscopic signs were reduced in 34 (61.8%) and normalised in 12 (21.8%), and histologically, 34 (56.6%) improved, while 15 (25%) obtained complete resolution. Overall, 22 patients (36.7%) obtained both complete clinical and histological remission.ConclusionsMore than 50% of patients with documented oesophageal eosinophilic infiltration in the EoE range improved when treated with a double‐dose PPI trial for 8 weeks. These findings support the published guidelines recommending a PPI trial prior to diagnosing EoE, and confirm the existence of an eosinophilic oesophageal infiltrationPPI‐responsive population.

Object Conventional deep brain stimulation (DBS) devices continue to rely on an open-loop system in which stimulation is independent of functional neural feedback. The authors previously proposed that as the foundation of a DBS “smart” device, a closed-loop system based on neurochemical feedback, may have the potential to improve therapeutic outcomes. Alterations in neurochemical release are thought to be linked to the clinical benefit of DBS, and fast-scan cyclic voltammetry (FSCV) has been shown to be effective for recording these evoked neurochemical changes. However, the combination of FSCV with conventional DBS devices interferes with the recording and identification of the evoked analytes. To integrate neurochemical recording with neurostimulation, the authors developed the Mayo Investigational Neuromodulation Control System (MINCS), a novel, wirelessly controlled stimulation device designed to interface with FSCV performed by their previously described Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS). Methods To test the functionality of these integrated devices, various frequencies of electrical stimulation were applied by MINCS to the medial forebrain bundle of the anesthetized rat, and striatal dopamine release was recorded by WINCS. The parameters for FSCV in the present study consisted of a pyramidal voltage waveform applied to the carbon-fiber microelectrode every 100 msec, ramping between −0.4 V and +1.5 V with respect to an Ag/AgCl reference electrode at a scan rate of either 400 V/sec or 1000 V/sec. The carbon-fiber microelectrode was held at the baseline potential of −0.4 V between scans. Results By using MINCS in conjunction with WINCS coordinated through an optic fiber, the authors interleaved intervals of electrical stimulation with FSCV scans and thus obtained artifact-free wireless FSCV recordings. Electrical stimulation of the medial forebrain bundle in the anesthetized rat by MINCS elicited striatal dopamine release that was time-locked to stimulation and increased progressively with stimulation frequency. Conclusions Here, the authors report a series of proof-of-principle tests in the rat brain demonstrating MINCS to be a reliable and flexible stimulation device that, when used in conjunction with WINCS, performs wirelessly controlled stimulation concurrent with artifact-free neurochemical recording. These findings suggest that the integration of neurochemical recording with neurostimulation may be a useful first step toward the development of a closed-loop DBS system for human application.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Amyloid deposits that characteristically form in the pancreatic islets of patients with non-insulin-dependent diabetes mellitus (NIDDM) and in insulinomas are both derived from islet amyloid polypeptide (IAPP). Evidence from previous studies has suggested that deposition of IAPP-derived amyloid is related to inherent amyloidogenic sequences present within normal human IAPP, together with an increased production and local concentration of IAPP. However, whether the aggregation of IAPP to form amyloid fibrils is primarily an intra- or extracellular event is not clear. To address this question, we studied 20 human insulinomas by light and electron microscopy. By light microscopy, amyloid deposits were demonstrated in 13 of 20 (65%) human insulinomas. Furthermore, evaluation of Congo red-stained tumor sections showed small, globular or irregular, congophilic amyloid deposits within the cytoplasm of many tumor cells in 10 of 13 (77%) amyloid-containing insulinomas. Dense, punctate areas of IAPP immunoreactivity within tumor cells corresponded with the congophilic intracellular deposits. Ubiquitin immunoreactivity also was observed as punctate intracellular labeling and within large extracellular amyloid deposits. Among the 10 insulinomas available for electron microscopic evaluation, pathological IAPP-immunoreactive (immunogold) deposits were found in 3 of 5 insulinomas in which amyloid was demonstrated by light microscopy and in none of 5 tumors found negative for amyloid by light microscopy. Morphology of IAPP-immunoreactive deposits varied from those with the classical distinct 7- to 10-nm diameter nonbranching fibrils to those with distinct but faint fibrillarity to those without discernable fibrils. In each of the 3 tumors with ultrastructurally demonstrable amyloid deposits, intracellular aggregates of IAPP-immunoreactive amyloid fibrils were observed either free in the cytoplasmic matrix or in membrane-bound structures. Intracellular IAPP-immunoreactive deposits were up to 10 urn in the greatest dimension. Free intracellular aggregates of amyloid fibrils sometimes contained degenerating secretory vesicles and fragments of membranous organelles. These observations suggest that IAPP-derived amyloid deposits are initially formed intracellularly and are subsequently released to the extracellular space by exocytosis of the membrane-bound structures and/or after necrosis of the tumor cells. Our observations raise the possibility that IAPP-derived islet amyloid deposits (characteristically present in NIODM patients) also may be initially formed within the cytoplasm of β-cells, thus leading to β-cell necrosis and a reduction of β-cell mass as seen in NIDDM.

The importance of portal insulin delivery in the regulation of postprandial carbohydrate metabolism is uncertain. To address this question, three groups of dogs were studied: one group in which pancreatic venous drainage was transected and reanastomosed (portal insulin delivery), one in which the pancreatic drainage was transected and anastomosed to the inferior vena cava (peripheral insulin delivery), and one that received only a sham operation. Plasma insulin was greater (P &lt; 0.05) during peripheral insulin delivery than in either the portal or sham groups, respectively, before and after meal ingestion. On the other hand, C-peptide concentrations did not differ between groups, resulting in a higher (P &lt; 0.001) insulin to C-peptide ratio in the peripheral group. This indicated that the hyperinsulinemia in the peripheral group was due to decreased insulin clearance rather than increased insulin secretion. Isotopically determined splanchnic uptake of ingested glucose, postprandial suppression of hepatic glucose release, incorporation of CO2 into glucose (a qualitative measure of gluconeogenesis), and total-body glucose uptake were virtually identical in all groups. Similarly, plasma lipid, β-hydroxybutyrate, and lactate concentrations did not differ between groups. Our data indicate that, despite differences in systemic insulin concentration, portal and peripheral insulin delivery comparably regulate hepatic and extrahepatic carbohydrate metabolism after meal ingestion.

Rapid axonal transport was studied by several methods in rats with serum glucose levels above 300 mg/dl as a result of treatment with streptozotocin (45–50 mg/kg) 3 days, 1 wk, 4 wk, 8 wk, or 4 mo earlier. With untreated age-matched rats as controls, rapid anterograde axonal transport in the sciatic nerves of diabetic rats appeared entirely normal. Statistically significant differences were never observed between experimental and control nerves in the basal content of acetylcholinesterase (AChE) and dopamine-β-hydroxylase (DBH) activity or in the rate of accumulation of these enzymes proximal or distal to a ligature. Therefore, the basic capacity for rapid anterograde and retrograde axonal transport of proteins was probably unimpaired in the diabetic nerves. The accumulation of labeled glycoproteins proximal to ligatures on the contralateral nerves of the same rats after injection of the L5 dorsal root ganglion with 3H-fucose was likewise normal. However, rats with 1, 4, and 8 wk of diabetes did show reduced accumulation of fucose-labeled protein distal to nerve ligations, indicating a long-lasting abnormality of retrograde axonal transport. Furthermore, this abnormality was reversed by daily insulin treatment during the second half of an 8-wk experimental period. It is therefore unlikely that the depression of retrograde transport reflects direct toxic effects of streptozotocin. We conclude that streptozotocin-induced diabetes leads to: (1) abnormal delay in the turnaround of transported proteins in distal nerve regions, perhaps combined with (2) an abnormal metabolism of glycoproteins. A delayed onset of retrograde transport is consistent with present observations of reduced accumulation of 125I-labeled nerve growth factor (NGF) below a midthigh ligature on the sciatic nerve after injection of this protein into the hindfoot of rats with 3–5 wk of diabetes. Further work on the factors controlling rapid retrograde transport of proteins in diabetic nerve is warranted.

BACKGROUNDThe management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed.METHODSTwelve institutions contributed deidentified clinicopathologic and outcome data for patients diagnosed with PM from 1953 through 2008.RESULTSOverall survival (OS) data were reported for 365 patients with invasive PM who had adequate follow‐up data. The mean age of the patients was 16 years (range 1 year‐21 years). The 10‐year OS rate, 80.6%, tended to vary by patient age: 100% for those aged birth to 10 years, 69.7% for those aged > 10 years to 15 years, and 79.5% for those aged > 15 years to 20 years (P = .147). Patients with melanomas measuring ≤ 1 mm had a favorable prognosis (10‐year OS rate of 97%), whereas survival was lower but similar for patients with melanomas measuring > 1 mm to 2 mm, > 2 mm to 4 mm, and > 4 mm (70%, 78%, and 80%, respectively; P = .0077). Ulceration and lymph node metastasis were found to be correlated with worse survival (P = .022 and P = .017, respectively). The 10‐year OS rate was 94.1% for patients with American Joint Committee on Cancer stage I disease, 79.6% for those with stage II disease, and 77.1% for patients with stage III disease (P < .001).CONCLUSIONSTumor thickness, ulceration, lymph node status, and stage were found to be significant predictors of survival in patients with PM, similar to adult melanoma. There is a trend toward increased survival in children aged ≤ 10 years versus adolescents aged > 10 years. Further analyses are needed to probe for potential biological and behavioral differences in pediatric versus adult melanoma. Cancer 2013;119:4012–4019. © 2013 American Cancer Society.

AbstractBackgroundLow basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal.MethodsPatients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal.Key ResultsA total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%).Conclusions & InferencesIn GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1‐week treatment period.