Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering “druggable” molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation. Cancer Res; 75(22); 4852–62. ©2015 AACR.

Background: Inconsistent results have been reported regarding mortality predictors of malignant pleural effusion (MPE). Objective: We aim to describe prognostic features of MPE in patients evaluated over 5 years in a referral center. Methods: All consecutive MPEs (confirmed by pleural cytology or biopsy) from January 2009 to July 2014 were included in this retrospective cohort study. Clinical data were collected from medical registries. Overall survival (OS) rate was calculated with Kaplan-Meier method and compared by the log-rank test. Hazard ratios (HRs) were calculated by the Cox proportional regression model. Results: A total of 110 patients were identified. Mean OS was 8.3 months (range: 25-426 days). No difference in OS was noted based on tumor type. Patients with MPE <50% had a significant better survival than those with malignant pleural effusion ≥50% (median OS: 15.7 vs 5.7 months; HR: 1.71; 95% confidence interval [CI]: 1.06-2.78; P = .0026). After adjusting for confounding variables, MPE size was independently associated with mortality (HR: 1.78; 95% CI: 1.11-2.91; P < .001). No association between glucose or pH in pleural fluid and OS was noted. Conclusion: Our study showed that MPE size, as determined by chest X-ray, is significantly associated with mortality.

We have previously shown that amino acid changes in the human Kruppel-Like Factor (KLF) 11 protein is associated with the development of maturity onset diabetes of the young VII, whereas complete inactivation of this pathway by the −331 human insulin mutation causes neonatal diabetes mellitus. Here, we report that Klf11−/− mice have decreased circulating insulin levels, alterations in the control of blood glucose and body weight, as well as serum dyslipidemia, but do not develop diabetes. Functional assays using ex vivo liver tissue sections demonstrate that Klf11−/− mice display increased insulin sensitivity. Genome-wide experiments validated by pathway-specific quantitative PCR arrays reveal that the Klf11−/− phenotype associates to alterations in the regulation of gene networks involved in lipid metabolism, in particular those regulated by peroxisome proliferator-activated receptor-γ. Combined, these results demonstrate that the major phenotype given by the whole-body deletion of Klf11 in mouse is not diabetes but increased insulin sensitivity, likely due to altered transcriptional regulation in target tissues. The absence of diabetes in the Klf11−/− mouse either indicates an interspecies difference for the role of this transcription factor in metabolic homeostasis between mouse and humans, or potentially highlights the fact that other molecular factors can compensate for its absence. Nevertheless, the data of this study, gathered at the whole-organism level, further support a role for KLF11 in metabolic processes like insulin sensitivity, which regulation is critical in several forms of diabetes.

Purpose: To report the use of an investigational stent-graft to treat an ascending aortic aneurysm in a patient with a heart transplant. Case Report: A 48-year-old man presented with a 3.5×1.5-cm saccular aneurysm in the mid anterior ascending aorta, abutting the sternum. The patient’s history was notable for placement of a left ventricular assist device followed by orthotopic heart transplantation 2 years prior to treat end-stage familial dilated cardiomyopathy. Under compassionate use, a custom-designed ascending aortic stent-graft (Zenith Ascend) was successfully delivered via an 18-F system and deployed just distal to the origin of the left main coronary artery under pulmonary artery catheter–guided rapid ventricular pacing. The patient was discharged the next day, and 6-month follow-up was unremarkable. Imaging at 5 months showed an excluded aneurysm sac with no endoleak or migration. Conclusion: The ideal ascending aortic stent-graft should be low profile, conformable to the arch anatomy, with short tip delivery system and a stepwise deployment mechanism that allows precise placement relative to the ostia of the coronary arteries and the innominate artery. This case illustrates the advancement of endovascular techniques to the most challenging segment of the aorta to decrease morbidity and mortality in high-risk patients.

ABSTRACTPurposeTo assess the role of temporal bone characteristics in transcranial Doppler (TCD) insonation failures in Amerindians living in rural Ecuador.MethodsWe evaluated thickness and texture of temporal bones in community‐dwelling Amerindians ≥65 years old undergoing TCD. Using receiver operator characteristics curve analysis and generalized estimating equations, we investigated factors associated with insonation failures.ResultsOf 65 participants (mean age 74.7 ± 6.7 years, 60% women), 32 (49%) had uni‐ or bilateral insonation failure through temporal windows. Considering temporal bones independently, 57 of 130 (44%) had poor insonation. Mean thickness was higher (4.7 ± 1.2 versus 2.7 ± 0.9, p < 0.0001), and texture more often heterogeneous (93% versus 22%, p < 0.0001) in bones with poor acoustic windows. Thickness, better predicting poor insonation, was ≥3.6 mm if used alone, and ≥2.7 mm if used together with heterogeneous texture. For every millimeter of increase in thickness, subjects were 2.9 times more likely to have insonation failures. Per se, heterogeneous texture increased by 3.2 times the odds for poor insonation. In all models, being woman increased the odds for poor insonation by six to nine times.ConclusionsTemporal bone thickness and texture are independent predictors of TCD insonation failure in Amerindians. © 2015 Wiley Periodicals, Inc. J Clin Ultrasound 44:55–60, 2016

Abstract Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow‐up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa‐associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty‐five per cent of the patients were female. The median age at diagnosis was 62 (range 28–88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression‐free survival ( p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long‐term disease‐free survival for patients with localized disease. Systemic treatment, including alkylating‐containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.

Diabetic ketoacidosis is a life-threatening acute metabolic complication of uncontrolled diabetes. Severe cases of DKA (pH ≤ 7.00, bicarbonate level ≤ 10.0, anion gap > 12, positive ketones, and altered mental status) are commonly encountered in patients with type 1 diabetes and are thought to carry an ominous prognosis. There is not enough information on the clinical course of severely acidotic type 2 diabetes (pH ≤ 6.9) patients with DKA, possibly because this condition is rarely seen in developed countries. In this series, we present 18 patients with type 2 diabetes, DKA, and a pH ≤ 6.9 that presented to a tertiary university hospital over the past 11 years. The objective was to describe their clinical characteristics, the triggering cause, and emphasis on treatment, evolution, and outcomes. The majority of the patients were female (61%). Mean age was 40.66 years (23–59). The patients had been first diagnosed with type 2 diabetes on average 5.27 ± 3.12 years before admission. Glutamic acid decarboxylase (GAD65) antibodies were negative in all patients. The origin of DKA could be attributed to two main causes: treatment omission in 8 (44.4%) patients and infections in 7 (38.8%) patients. The most common symptoms described were general malaise, dyspnea, altered mental status, and abdominal pain. Mean serum glucose on admission was 613.8 ± 114.5 mg/dL. Mean venous pH was 6.84 ± 0.03 with an anion gap of 30.3 ± 2.9 and a venous HCO3level of 3.62 ± 1.35 mmol/L. All patients had acute renal failure on admission, with a mean serum creatinine of 1.57 ± 0.35 mg/dL compared to 0.55 ± 0.21 mg/dL at discharge. All patients received regular insulin infusion, aggressive fluid repletion, and 12 patients (66%) received bicarbonate infusion. Mean total insulin infusion dose was 181.7 ± 90.4 U (on average 0.14 ± 0.05 U/Kg/h). Mean time on infusion was 24.4 ± 12.6 hours. We recorded no mortality in this case series. Mean in-hospital stay was 5.0 ± 4.1 days. In conclusion, very severe DKA in type 2 diabetes is not uncommon in our population, shares many features with non-very-severe cases of DKA (bicarbonate therapy did not make a difference in mortality), and can be managed following standard published or institutional guidelines.

ABSTRACT Background: Diagnosis of cerebral small vessel disease (SVD) is a challenge in remote areas where magnetic resonance imaging (MRI) is not available. Hospital-based studies in high-risk or stroke patients have found an association between the pulsatility index (PI) of intracranial arteries - as derived from transcranial Doppler (TCD) - and white matter hyperintensities (WMH) of presumed vascular origin. We aimed to assess the reliability of cerebral pulsatility indices to identify candidates for MRI screening in population-based studies assessing prevalence of SVD. Methods: A representative sample of stroke-free Atahualpa residents aged ≥65 years investigated with MRI underwent TCD. Using generalized linear models, we evaluated whether the PI of major intracranial arteries correlate with WMH (used as a proxy of diffuse SVD), after adjusting for demographics and cardiovascular risk factors. Results: Out of 70 participants (mean age 70.6 ± 4.6 years, 57% women), 28 (40%) had moderate-to-severe WMH. In multivariate models, there were no differences across categories of WMH in the mean PI of middle cerebral arteries (1.10 ± 0.16 vs. 1.22 ± 0.24, β: 0.065, 95% confidence interval (CI): −0.084-0.177, P = 0.474) or vertebrobasilar arteries (1.11 ± 0.16 vs. 1.29 ± 0.27, β: 0.066, 95% CI: −0.0024-0.156, P = 0.146). Conclusions: Cerebral PI should not be used to identify candidates for MRI screening in population-based studies assessing the burden of SVD.