Limited studies investigated clinicopathological and prognostic significance of histologic and molecular subgroups of gastric cancer concurrently. We retrospectively enrolled 1,248 patients with ...gastric cancer who received radical gastrectomy with lymphadenectomy and classified these cases into the Epstein–Barr virus (EBV)‐associated and microsatellite instability (MSI)‐associated subtypes by EBV‐encoded small RNA in situ hybridization and immunohistochemical stains for DNA mismatch repair proteins, respectively. The remaining cases were categorized as the Lauren intestinal and diffuse/mixed subtypes. The clinicopathological and prognostic significance of the subtypes was examined by statistical analysis. In total, 65 (5.2%), 116 (9.3%), 496 (39.7%), 431 (34.5%) and 140 (11.2%) cases were identified as EBV‐associated, MSI‐associated, intestinal, diffuse and mixed subtypes, respectively. The EBV‐associated, MSI‐associated, intestinal and diffuse/mixed subtypes exhibited distinctive clinicopathological characteristics, including differences in age, gender, stump cancer, gastric location, tumor size, TNM stage, margin involvement, lymphatic/perineural invasion, HER2 status and recurrence pattern. The log‐rank test showed survival discrimination (p < 0.001), and the multivariate analysis identified EBV‐associated and MSI‐associated cases demonstrated better outcomes than the diffuse/mixed subtype (EBV, HR 0.464, 95% CI 0.296–0.727, p = 0.001; MSI, HR 0.590, 95% CI 0.407–0.856, p = 0.005). EBV‐associated lymphoepithelioma‐like carcinoma cases had the most favorable outcome (HR 0.138, 95% CI 0.033–0.565, p = 0.006). In different clinical groups, the subtypes exhibited survival discrepancies. The EBV‐associated and diffuse/mixed cases exhibited more favorable response to chemotherapy. In conclusion, this combined classification, in parallel with the molecular subtypes specified in the Cancer Genome Atlas study, has implications for the clinical management of gastric cancer.
What's new?
Gastric cancer is a heterogeneous disease from histologic and molecular viewpoints. Stratifying gastric cancer into Epstein–Barr virus‐positive, microsatellite instability‐associated and Lauren intestinal and diffuse/mixed subtypes demonstrates significant clinicopathological and prognostic discrimination, which is relevant to current genetic knowledge and clinical management. This combined molecular and histologic classification, correspondent to the molecular subtyping specified in the Cancer Genome Atlas study, is practically implementable with etiologic insight and therapeutic implications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Asprosin is a novel fasting-induced glucogenic and orexigenic protein hormone. The clinical function of asprosin in obesity is currently unknown. This study investigated the association between ...asprosin abundance and the outcome of bariatric surgery.
Patients with body mass index more than 35 kg/m
were recruited for the Obesity and Clock for Elegant Aging Registry in 2011-2016. Body weight changes, blood sugar, and asprosin were assessed in 117 patients receiving bariatric surgery and 57 non-obese subjects as normal control. Primary outcomes of excess weight loss percentage at 6 months after bariatric surgery were determined at follow-up.
Asprosin levels were significantly higher in obese patients than in non-obese subjects (2360 ± 5094 vs. 307 ± 832 ng/ml, p < 0.0001). Multivariate analyses showed a significant association of asprosin abundance with excess body weight loss percentage at 6 months after surgery (p < 0.0001). After adjusted for age, sex, smoking, HbA1c, cholesterol, and triglyceride, serum asprosin level was the only independent predictor of 6 months excess weight loss percentage after bariatric surgery. Asprosin levels decreased significantly 6 months after bariatric surgery (162.2 ± 169.1 ng/ml). Furthermore, there was no association between asprosin and serum glucose levels in our study.
This study provides novel evidence that higher asprosin concentrations before bariatric surgery were associated with the weight reduction magnitude at 6 months after surgery. Further studies are warranted to investigate whether asprosin has direct functions to modulate body weight regulation in humans after bariatric surgery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary Background D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient ...outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II–IIIB gastric cancer. Methods The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II–IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m2 twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov ( NCT00411229 ). Findings 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4–41·7) in the chemotherapy and surgery group and 34·3 months (25·6–41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44–0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). Interpretation Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. Funding F Hoffmann-La Roche and Sanofi-Aventis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Aims
In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations.
Methods and results
We screened SMARCA4 alterations using ...immunohistochemistry on 1199 surgically resected GCs with information on Epstein–Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty‐seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4‐retained GCs, SMARCA4‐lost GCs were observed more frequently in the non‐EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV‐ or MSI‐associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4‐altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De‐differentiation‐like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV‐associated GC and non‐EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4‐lost or reduced GC, respectively.
Conclusions
SMARCA4‐altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4‐lost GC may represent a genuine SMARCA4‐deficient neoplasm, but most SMARCA4‐reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background
Laparoscopic cholecystectomy (LC) with associated procedures and endoscopic retrograde cholangiopancreatography (ERCP) have been the standard treatments for both common and rare biliary ...diseases. Mirizzi syndrome (MS) is a rare and complex biliary condition. We report our experience with MS treatment and investigate the value of laparoscopic procedures and ERCP in patient management.
Methods
From 2004 to 2017, 100 consecutive patients with MS were diagnosed by ERCP and underwent surgery in a referral center. Sixty patients were treated with intended LC, and 40 patients were treated with open cholecystectomy (OC). The clinical manifestations, ERCP and associated procedures, surgical procedures, and postoperative outcomes were investigated.
Results
The surgical mortality rate was 1%, while the surgical morbidity rate was 15%. The patients treated with intended LC suffered from less morbidity (5%). The percentage of postoperative residual biliary stones was 32% (n = 32), and only three patients underwent re‐operation (laparotomy) for stone removal. The laparotomy conversion rate in the intended LC group was 16.7% (10/60). The length of hospitalization for the patients with successful LC was significantly shorter than that for the patients with conversion and intended OC. Csendes classification was a risk factor for conversion from LC to OC (type I vs types II to V, P < .0001).
Conclusions
A combination of a laparoscopic procedure and ERCP may provide therapeutic benefits for patients with MS.
Highlight
Yeh and colleagues report that a combination of perioperative endoscopic retrograde cholangiopancreatography and laparoscopic surgery can provide clinical benefits for patients with Mirizzi syndrome with significantly less surgical morbidity and shorter hospital stay. Both preoperative diagnosis and postoperative residual biliary stones can be managed by endoscopic retrograde cholangiopancreatography with satisfactory outcomes.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The incidence of biliary events (BE) following percutaneous cholecystostomy (PC) in acute cholecystitis (AC) patients is high. Therefore, definitive laparoscopic cholecystectomy (LC) is ...recommended. We aimed to investigate the optimal timing of LC following PC with regard to the clinical course and pathological findings.
Methods
All 744 AC patients with PC were included. The incidence and median number of BE were investigated with the concept of competing risks. The 344 patients with interval LC were divided into two groups based on the pathological findings of resected gallbladders: the acute/acute‐and‐chronic group (AANC group) (n = 221) and the chronic group (n = 123). A comparative analysis of the demographic data and perioperative outcomes was performed.
Results
Among the 744 AC patients with PC, 142 patients experienced recurrent BE. The cumulative incidence of BE was 26.6%, and the median time to recurrence was 67.5 days. The PC‐to‐LC days of the chronic group were longer than those of the AANC group (73.51 vs 63.00, P < .001). The multivariate analysis indicated that the operation time was longer in the AANC group than in the chronic group (P = .040).
Conclusion
In terms of the clinical course and sequential pathological changes in the gallbladder, a 9‐ to 10‐week interval after PC is the optimal timing for LC.
Highlight
Hung and colleagues performed a retrospective study to determine the optimal timing of laparoscopic cholecystectomy following percutaneous cholecystostomy placement for acute cholecystitis. Based on the sequential pathological changes to the gallbladder and the risk of recurrent biliary events, 9‐10 weeks after percutaneous cholecystostomy was considered the optimal timing.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Minimally invasive pancreaticoduodenectomy (MIPD), which includes laparoscopic pancreaticoduodenectomy (LPD) and robotic pancreaticoduodenectomy (RPD), is a complex procedure that needs to ...be performed by experienced surgeons. However, the safety and oncologic performance have not yet been conclusively determined.
Methods
A systematic literature search was performed using the Embase, Medline, and PubMed databases to identify all studies published up to March 2015. Articles written in English containing the keywords: “pancreaticoduodenectomy” or “Whipple operation” combined with “laparoscopy,” “laparoscopic,” “robotic,” “da vinci,” or “minimally invasive surgery” were selected. Furthermore, to increase the power of evidence, articles describing more than ten MIPDs were selected for this review.
Results
Twenty-six articles matched the review criteria. A total of 780 LPDs and 248 RPDs were included in the current review. The overall conversion rate to open surgery was 9.1 %. The weighted average operative time was 422.6 min, and the weighted average blood loss was 321.1 mL. The weighted average number of harvested lymph nodes was 17.1, and the rate of microscopically positive tumor margins was 8.4 %. The cumulative morbidity was 35.9 %, and a pancreatic fistula was reported in 17.0 % of cases. The average length of hospital stay was 12.4 days, and the mortality rate was 2.2 %.
Conclusions
In conclusion, after reviewing one-thousand cases in the current literature, we conclude that MIPD offers a good perioperative, postoperative, and oncologic outcome. MIPD is feasible and safe in well-selected patients.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Near-infrared (NIR) fluorescence cholangiography by systemic administration of indocyanine green (ICG) enhances the visualization of the biliary tree anatomy. However, the simultaneous ...enhancement of liver parenchyma can disturb the visualization of critical details. We herein proposed a new technique of NIR cholecystocholangiography by intragallbladder ICG injection to increase the safety during laparoscopic cholecystectomy.
Methods
A total of 46 patients scheduled for laparoscopic cholecystectomy for symptomatic lithiasis (
n
= 21) or cholecystitis (
n
= 25) were enrolled. A fluorescence cholangiography by direct gallbladder injection of ICG was performed in all cases. Of them, the ICG was injected through a previously placed percutaneous transhepatic gallbladder drainage catheter (
n
= 18) or by intraoperative, percutaneous needle puncture of the gallbladder (
n
= 28). Visualization of biliary structures, including the cystic duct (CD), the common bile and hepatic ducts (CBD and CHD), the gallbladder neck, and the Hartmann’s pouch (HP), was performed using White Light (served as control modality) and by NIR enhancement.
Results
Cholecystocholangiography provided a significantly higher rate of visualization of the CD in case of cholecystitis with mild adhesions, and an improved visualization of the HP, CBD, and CHD in case of severe inflammation, when compared to White Light observation. There were no benefits of NIR in case of non-inflamed lithiasis.
Conclusions
Clinical translation of NIR cholecystocholangiography has been successful with a noise-free visualization of biliary anatomy. It can be considered in difficult cases to increase the safety of laparoscopic cholecystectomy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Epstein-Barr virus (EBV) is suggested to actively utilize its ebv-microRNAs (miRNAs) to manipulate viral and cellular functions during neoplasia transformation. A systemic profiling of ebv-miRNAs ...expressed in EBV-associated gastric carcinoma (EBVa GC) helps understand its epigenetic regulation of carcinogenesis.
A total of 1039 patients with gastric cancer were screened for EBVa GC using EBV-encoded RNAs in situ hybridization. A comprehensive profiling of ebv-miRNAs expressed in EBVa GC was constructed using stem-loop quantitative polymerase chain reaction. Functional assay of specific ebv-miRNA was conducted. Expression of epithelial-to-mesenchymal transition (EMT) markers among EBVa GC and non-EBVa GC was compared.
The prevalence of EBVa GC was 5.0% (52 out of 1039) in our series. The most abundant ebv-miRNAs of EBVa GC were Bart4, followed by Bart11, Bart2, Bart6, Bart9, and Bart18, in the decreasing order. Of them, Bart9 exhibited the same seed sequence as to hsa miR-200a and miR-141. Expression of E-cadherin of EBV-positive SNU-719 was increased after BART9 knockdown. Depleting endogenous Bart9 of SNU-719 induced a surged expression of miR-200a and miR-141, accompanied by decreased proliferative and invasive ability. Expression of mesenchymal markers in EBVa GC was increased compared with those of non-EBVa GC, albeit the two cohorts exhibited a comparable long-term survival.
We constructed a comprehensive profiling of ebv-miRNAs in EBVa GC. BART9 plays an important role during carcinogenesis through EMT. Inherent mesenchymal phenotype of EBVa GC represents a unique virus-induced morphology and microenvironment rather than being able to predict the prognosis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background & Aims Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We ...elucidated the biological and clinical significance of miR-214 downregulation in HCC. Methods MicroRNAs deregulated in HCC were identified using array-based microRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and the hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis. Results miR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumors and their surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, suppression of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media, lost by ectopic expression of miR-214 in the donor cells, was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions A novel role of microRNA in tumorigenesis is identified. Downregulation of miR-214 contributes to the unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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