Citations

Objective Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. Design 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. Results The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. Conclusions AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.

Abstract Background. Autophagy maintains energy metabolism and enables tumor cell survival during cellular stress. Beclin 1 is involved in autophagosome formation during which membrane-bound LC3 binds to p62/sequestosome 1. We reported that ectopic p62 can promote 5-fluorouracil-induced cell death (JBC 286:40002-12, 2011). It is unknown whether these autophagy markers can predict clinical outcome. Materials & Methods. Beclin 1, LC3B, and p62 proteins were analyzed by immunohistochemistry in tissue microarrays containing stage II and III colon carcinomas (N=151) from patients receiving 5-FU or surgery alone. The mean weighted score (intensity x extent) was dichotomized for survival analysis using Cox models. Results. Increased levels of cytoplasmic LC3, Beclin 1, and p62 expression were detected in 21%, 14%, and 68% of cancers, respectively, and were not associated with tumor site, stage or grade. By multivariable analysis, increased LC3 was significantly associated with worse disease-free survival (DFS) (p=0.022), but not overall survival (OS) [p=0.069](Table). Beclin 1 was not prognostic, but increased p62 was significantly associated with improved DFS (p=0.038), but not OS (p= 0.176)[Table]. When restricted to 5-FU-treated patients, increased LC3 was associated with worse DFS [HR= 2.38 (1.19, 4.75, p=0.020), elevated Beclin 1 predicted worse OS [HR=2.83 (1.27, 6.34), p = 0.019], and p62 was not prognostic. Conclusion. LC3 and Beclin 1 overexpression were independently associated with adverse outcome. Increased p62 was associated with better outcome consistent with its ability to promote cell death. These data support strategies to inhibit autophagy for therapeutic advantage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4112. doi:1538-7445.AM2012-4112

Abstract Lung cancer is the most common cause of smoking-related mortality in worldwide. However, approximately 10 to 25 % cases are not attributable to smoking. Cumulative evidence suggests that lung cancer from never smokers (&lt;100 cigarettes lifetime) may develop via molecular mechanisms that are different from lung cancers in smokers. Recently, miRNAs have been identified as a new class of regulatory molecules that participate in a variety of biological processes. Because each miRNAs can potentially target a large set of mRNA making and therefore may play a critical role in lung tumorigenesis and patient outcome, we sought to examine the role of miRNA in lung adenocarcinoma among never smokers. A total of 298 samples were analyzed in this study including 168 fresh frozen (FF) tissues from 88 lung adenocarcinomas and 80 adjacent non-involved lung tissues; and 132 formalin-fixed paraffin embedded (FFPE) tissues from 68 tumors and 64 normal lung samples. Gene expression profiling was performed for miRNA and mRNA using Illumina Whole Genome DASL platform. We identified 20 miRNAs with the most significant expression changes between the tumor and normal in both FF and FFPE samples (Fold change &gt; 1.5, p &lt;0.01, FDR &lt;0.05). We also examined mRNA expression signature using 56 matched FF tumors and normal lung tissues. Cox proportional hazard analysis was performed independently for both FF and FFPE cohorts and showed that increased expression of mir-708 was strongly associated with an increased risk of patient death after adjusting for age, sex and tumor stage (FF cohort, HR =1.92; 95% CI =1.02–3.63; p &lt; 0.05 and FFPE cohort, HR=1.90; 95% CI=1.08–3.34; P &lt; 0.05). Candidate biological targets of mir-708 were identified using TargetScan and MicroCosm Targets databases. A total of 13 candidate genes were found and one of these genes, CMT11 (Candidate Mir-708 Target), was down-regulated 1.6 fold on average in tumors that were high in mir-708 expression. Based on the sequence, CMT11 is a novel transmembrane protein. In Cox analysis, reduced CMT11 expression was strongly correlated with an increased risk of death in patients (HR = 2.43, 95% CI = 1.17 − 5.26; P &lt;0.01). Functionally, overexpression of mir-708 in A549 and HEK293T cells significantly increased the rate of cellular proliferation and migration. Over expression of mir-708 in HEK293T cells also repressed ∼70% of the luciferase activity when the reporter RNA contained the 3′ UTR of CMT11. Recently, several studies have showed mir-708 is a potential squamous cell lung cancer marker and one of miRNAs that may predict the recurrence of Stage I lung cancer after surgical resection. Additional evidence also suggests that CMT11 is a negative regulator of Wnt-signaling pathway. Our data provides clinical and functional evidence supporting an important role of mir-708 in lung cancer progression and identifies CMT11 as a down stream target gene mediating this process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-346. doi:10.1158/1538-7445.AM2011-LB-346

Background —Noninvasive assessment of diastolic filling by Doppler echocardiography provides important information about left ventricular (LV) status in selected subsets of patients. This study was designed to assess whether mitral annular velocities as assessed by tissue Doppler imaging are associated with invasive measures of diastolic LV performance and whether additional information is gained over traditional Doppler variables. Methods and Results —One hundred consecutive patients referred for cardiac catheterization underwent simultaneous Doppler interrogation. Invasive measurements of LV pressures were obtained with micromanometer-tipped catheters, and the mean LV diastolic pressure (M-LVDP) was used as a surrogate for mean left atrial pressure. Doppler signals from the mitral inflow, pulmonary venous inflow, and TDI of the mitral annulus were obtained. Isolated parameters of transmitral flow correlated with M-LVDP only when ejection fraction <50%. The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/E′) showed a better correlation with M-LVDP than did other Doppler variables for all levels of systolic function. E/E′ <8 accurately predicted normal M-LVDP, and E/E′ >15 identified increased M-LVDP. Wide variability was present in those with E/E′ of 8 to 15. A subset of those patients with E/E′ 8 to 15 could be further defined by use of other Doppler data. Conclusions —The combination of tissue Doppler imaging of the mitral annulus and mitral inflow velocity curves provides better estimates of LV filling pressures than other methods (pulmonary vein, preload reduction). However, accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data.