Reconsidering resectable oncological conditions in pancreatic tail cancer: A multicenter retrospective study on prognostic factors in pancreatic tail cancer after resection (HOPS Pt-01).

BACKGROUND: Pancreatic tail cancer (Pt-PC) is generally considered resectable when metastasis is absent, but doubts persist in clinical practice due to the variability in local tumor extent. We conducted a multicenter retrospective study to comprehensively identify prognostic factors associated with Pt-PC after resection. METHODS: We enrolled 100 patients that underwent distal pancreatectomy. The optimal combination of factors influencing relapse-free survival (RFS) was determined using the maximum likelihood method (MLM) and corrected Akaike and Bayesian information criteria (AICc and BIC). Prognostic elements were then validated to predict oncological outcomes. RESULTS: Therapeutic interventions included neoadjuvant treatment in 16 patients and concomitant visceral resection (CVR) in 37 patients; 89 patients achieved R0. Median RFS and OS after surgery were 23.1 and 37.1 months, respectively. AICc/BIC were minimized in the model with ASA-PS (≥2), CA19-9 (≥112 U/mL at baseline, non-normalized postoperatively), need for CVR, 6 pathological items (tumor diameter ≥19.5 mm, histology G1, invasion of the anterior pancreatic border, splenic vein invasion, splenic artery invasion, lymph node metastasis), and completed adjuvant treatment (cAT) for RFS. Regarding the predictive value of these 11 factors, area under the curve was 0.842 for 5-year RFS. Multivariate analysis of these 11 factors showed that predictors of RFS include CVR (hazard ratio, 2.13; 95 % confidence interval, 1.08-4.19; p = 0.028) and cAT (0.38, 0.19-0.76; p = 0.006). CONCLUSIONS: The MLM identified certain Pt-PC cases warranting consideration beyond resectable during clinical management. Particular attention should be paid to conditions requiring CVR, even though immortal time bias remains unresolved with adjuvant treatment.

Tumor-Informed Approach Improved ctDNA Detection Rate in Resected Pancreatic Cancer.

Pancreatic cancer is one of the cancers with very poor prognosis; there is an urgent need to identify novel biomarkers to improve its clinical outcomes. Circulating tumor DNA (ctDNA) from liquid biopsy has arisen as a promising biomarker for cancer detection and surveillance. However, it is known that the ctDNA detection rate in resected pancreatic cancer is low compared with other types of cancer. In this study, we collected paired tumor and plasma samples from 145 pancreatic cancer patients. Plasma samples were collected from 71 patients of treatment-naïve status and from 74 patients after neoadjuvant therapy (NAT). Genomic profiling of tumor DNA and plasma samples was conducted using targeted next-generation sequencing (NGS). Somatic mutations were detected in 85% (123/145) of tumors. ctDNA was detected in 39% (28/71) and 31% (23/74) of treatment-naïve and after-NAT groups, respectively, without referring to the information of tumor profiles. With a tumor-informed approach (TIA), ctDNA detection rate improved to 56% (40/71) and 36% (27/74) in treatment-naïve and after-NAT groups, respectively, with the detection rate significantly improved (p = 0.0165) among the treatment-naïve group compared to the after-NAT group. Cases who had detectable plasma ctDNA concordant to the corresponding tumor showed significantly shorter recurrence-free survival (RFS) (p = 0.0010). We demonstrated that TIA improves ctDNA detection rate in pancreatic cancer, and that ctDNA could be a potential prognostic biomarker for recurrence risk prediction.

A drainage strategy for postoperative pancreatic fistula after left-sided pancreatectomy based on the wall status of collected fluid.

PURPOSE: Postoperative pancreatic fistula (POPF) after pancreatectomy is one of the severe postoperative adverse events. We aimed to clarify the outcomes of a strategy for POPF after left-sided pancreatectomy with one-step endoscopic ultrasonography-guided drainage (EUSD) and percutaneous drainage (PCD) based on the wall status of collected fluid. METHODS: From January 2012 to September 2017, 90 of 336 patients developed grade B/C POPF and were retrospectively analyzed. Primary outcome measures were the technical and clinical success and resolution rates. Secondary outcome measures were time from surgery to intervention, and time from intervention to discharge/resolution or stent/tube removal and adverse events. RESULTS: Seventeen patients underwent EUSD and 73 patients underwent PCD for POPF. The technical success rates were 100% in both the EUSD and PCD groups. The clinical success and resolution rates in the EUSD group were 100%, while those in the PCD group were 98.6%. The time from surgery to intervention was significantly longer in the EUSD group than in the PCD group (20 vs. 11 days, p < 0.001). The time from intervention to discharge/resolution was significantly shorter in the EUSD group than in the PCD group (11 vs. 22 days, p < 0.001/10 vs. 20 days, p < 0.001). The time from intervention to stent/tube removal was significantly shorter in the PCD group than in the EUSD group (20.5 vs. 873 days, p < 0.001). Adverse event rates were similar in the two groups (11.8% vs. 5.5%). CONCLUSION: A drainage strategy for POPF based on the wall status of collected fluid is appropriate.

[A case of mediastinal pancreatic pseudocyst diagnosed and treated successfully by endoscopic procedure].

A 60-year-old man was admitted for investigation of a mediastinal cystic lesion. During endoscopic retrograde pancreatography, the contrast medium leaked from the head of the main pancreatic duct, and the cystic fluid collected with endoscopic ultrasonography (EUS) -guided aspiration showed high levels of pancreatic enzymes. Therefore, we diagnosed mediastinal pancreatic pseudocyst. The pseudocyst shrank as a result of EUS-guided drainage, and an endoscopic nasopancreatic drainage tube was then placed to close the fistula of the pancreatic duct. This case suggests that endoscopic procedures could be useful for the diagnosis and treatment of mediastinal pancreatic pseudocyst. We review 48 case reports of mediastinal pancreatic pseudocyst and discuss the usefulness of endoscopic procedures for diagnosis and treatment.

Efficacy and limitations of the histological diagnosis of type 1 autoimmune pancreatitis with endoscopic ultrasound-guided fine needle biopsy with large tissue amounts.

OBJECTIVES: We examined the efficacy and limitations of acquiring large specimens by endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for diagnosing type 1 autoimmune pancreatitis (AIP). METHODS: Patients from 12 institutions with non-neoplastic diseases or pancreatic ductal adenocarcinoma (PDAC) with large EUS-FNB specimens were investigated. Slides stained with hematoxylin-eosin, elastic, IgG4, and IgG stains were evaluated. The IgG4- and IgG-positive cell numbers were counted in three foci. The diagnoses were based on the Japan Pancreas Society 2011 (JPS 2011) criteria and the International Consensus Diagnostic Criteria (ICDC). RESULTS: We analyzed 85 non-neoplastic (definite type 1 AIP in 73/85 based on the ICDC) cases and 64 PDAC cases. IgG4-positive cells were numerous (>10 in 85.9%), and the IgG4/IgG ratios were high (>40% in 81.2%). Plasma cell crushing by an artifact caused unsuccessful immunostaining, notably in smaller samples. Tissue lengths were an important factor for the presence of storiform fibrosis and obliterative phlebitis, but storiform fibrosis was equivocal even in large tissues. A definite or possible histological diagnosis was achieved in 45.9% (39/85) and 41.2% (35/85), respectively, and contributed to the definite final diagnosis of type 1 AIP in 33.3% (ICDC) and 55.6% (JPS 2011) in cases with segmental/focal lesions. In the PDAC group, >10 IgG4-positive cells was rare (2/58), but elastic stains revealed fibrous venous occlusions in 10.3% (6/58). CONCLUSIONS: EUS-FNB with large tissue amounts was useful for diagnosing type 1 AIP, notably by facilitating successful IgG4 immunostaining, but definite diagnosis may not be achieved even in cases with large specimens.

Phase II clinical trial of gemcitabine plus oxaliplatin in patients with metastatic pancreatic adenocarcinoma with a family history of pancreatic/breast/ovarian/prostate cancer or personal history of breast/ovarian/prostate cancer (FABRIC study).

BACKGROUND: A family/personal history of breast, ovarian, or pancreatic cancer is a useful predictive marker for response to platinum-based chemotherapy in treating patients with pancreatic cancer. These cancers, and prostate cancer, are known as BRCA-related malignancies. We evaluated the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with metastatic pancreatic cancer with a family/personal history of these cancers. METHODS: Chemotherapy-naïve patients with metastatic pancreatic cancer with a family history of pancreatic/breast/ovarian/prostate cancer or a personal history of breast/ovarian/prostate cancer were included. Patients received fixed dose-rate gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) every 2 weeks. The primary endpoint was 1-year survival, and the threshold and expected values were set at 30 and 50%, respectively. The target sample size was determined to be 43, with a one-sided alpha value of 5% and power of 80%. A total of 45 patients were enrolled. RESULTS: Among the first 43 enrolled patients, the 1-year survival rate was 27.9% [90% confidence interval (CI) 17.0-41.3], which did not meet the primary endpoint. Median overall survival, progression-free survival, and response rates were 7.6 months (95% CI 6.0-10.7), 4.0 months (95% CI 2.0-4.6), and 26.7% (95% CI 14.6-41.9), respectively, in all registered patients. The GEMOX regimen was generally tolerated; the most common grade three or higher adverse events were hematological toxicities. CONCLUSION: GEMOX did not show the expected efficacy in patients with metastatic pancreatic cancer with a family or personal history of pancreatic/breast/ovarian/prostate cancer. Selection of GEMOX based on family/personal history is not recommended. TRIAL REGISTRATION NUMBER: UMIN000017894.

MicroRNA-31 reflects IL-6 expression in cancer tissue and is related with poor prognosis in bile duct cancer.

Bile duct cancer is a highly aggressive malignancy wherein early diagnosis is difficult and few treatment options are available. MicroRNA-31 (miR-31) is reported to be related with survival in patients with gastrointestinal cancers; however, the regulatory mechanism of miR-31 and association between miR-31 expression and survival in patients with bile duct cancer cases have not been established. Thus, we evaluated miR-31 expression in bile duct cancer tissues and assessed its relationship with prognosis. Additionally, we examined the effects of several cytokines on miR-31 expression. The study included 81 samples of bile duct cancer tissues. MiR-31 expression in bile duct cancer cells was significantly higher than that in normal bile duct epithelial cells (P = 0.038). There were no significant associations between miR-31 expression and clinical or pathological characteristics, except for tumour size (P = 0.012). In Kaplan-Meier analysis, high miR-31 expression was significantly associated with shorter survival (log-rank test, P = 0.0082). In multivariate Cox regression analysis, high miR-31 expression was significantly associated with prognosis (P = 0.043), independent of clinical or pathological features. Interleukin-6 (IL-6) significantly promoted miR-31 expression and cell proliferation in a dose-dependent manner, and the inhibition of STAT-3 signalling significantly suppressed miR-31 expression and cell proliferation. In conclusion, high expression was significantly associated with poor prognosis in bile duct cancer patients. The IL-6-STAT-3 signalling regulated bile duct cancer cell proliferation and miR-31 expression. Our findings suggest that miR-31 may be a promising biomarker that reflects IL-6 expression in bile duct cancer tissues and predicts poor prognosis.

MicroRNA-196b is an independent prognostic biomarker in patients with pancreatic cancer.

Pancreatic cancer is a highly aggressive malignancy, with <50% patients surviving beyond 6 months after the diagnosis, and thus, there is an urgent need to explore new diagnostic and therapeutic approaches for this disease. Therefore, we conducted microRNA (miRNA) array analysis to detect miRNA molecules potentially associated with pancreatic cancer malignancy. To assess the identified miRNAs, we performed quantitative reverse transcription-PCR on 248 pancreatic ductal adenocarcinomas (UICC stage II). We also examined miRNA expression [microRNA-21 (miR-21) and microRNA-31 (miR-31)] and epigenetic alterations, including CpG island methylator phenotype (CIMP), potentially associated with the identified miRNAs. For functional analysis, we conducted proliferation and invasion assays using a pancreatic cancer cell line. miRNA array analysis revealed that microRNA-196b (miR-196b) was the most up-regulated miRNA in pancreatic cancer tissues compared with normal pancreatic duct cells. High miR-196b expression was associated with miR-21 (P = 0.0025) and miR-31 (P = 0.0001) expression. It was also related to poor prognosis in the multivariate analysis using overall survival (hazard ratio: 1.66; 95% confidence interval: 1.09-2.54; P = 0.019). Functional analysis demonstrated that miR-196b inhibitor decreased cell proliferation and that miR-196b mimic promoted cancer cell invasion. In conclusion, a significant association of high miR-196b expression with poor prognosis was observed in pancreatic cancer. Our data also revealed that miR-196b played an oncogenic role and that the transfection of the miR-196b inhibitor had an anti-tumour effect in the pancreatic cancer cell line. These results suggest that miR-196b is a promising diagnostic biomarker and therapeutic target in pancreatic cancer.

The effect of forced expression of mutated K-RAS gene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy.

Mutation in K-RAS (K-RAS-MT) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin-like growth factor-1 receptor (IGF-1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody. In this study, we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants. We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC-3. We assessed the effect of forced expression of K-RAS-MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti-tumor effects of dominant negative IGF-1R (IGF-1R/dn) and an IGF-1R inhibitor, picropodophyllin, on the K-RAS-MT transfectants. Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF-1R blockade suppressed cell growth, colony formation, migration, and invasion, and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells, even when K-RAS-MT was over-expressed. IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase (ERK) pathway in the K-RAS-MT transfectants. IGF-1R/dn, moreover, inhibited the growth of murine xenografts expressing K-RAS-MT. Thus, K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated. © 2016 Wiley Periodicals, Inc.

Development of hypertension within 2 weeks of initiation of sorafenib for advanced hepatocellular carcinoma is a predictor of efficacy.

BACKGROUND: Sorafenib is an agent that inhibits vascular endothelial growth factor and is associated with onset or worsening of hypertension in some patients. We conducted a retrospective analysis of whether the development of hypertension during sorafenib treatment of advanced hepatocellular carcinoma could be a predictor of anti-cancer efficacy. METHODS: The study included 38 patients with advanced hepatocellular carcinoma who had received sorafenib for at least 1 month between January 2010 and December 2012. A retrospective analysis of the efficacy of sorafenib was conducted by dividing the patients into two groups-a hypertension group, presenting with grade 2 or higher hypertension according to the Common Terminology Criteria for Adverse Events (CTCTE) version 4.0; and a non-hypertension group, which included all other patients. This study evaluated the occurrence of hypertension within 2 weeks of initiation of therapy in order to avoid any treatment duration bias. Images were evaluated using the modified Response Evaluation Criteria in Solid Tumors. The response rate, time to progression, and overall survival were assessed. RESULTS: Twenty-two patients (58 %) developed grade 2 or higher hypertension within 2 weeks of initiation of therapy. The response rate was significantly higher in the hypertension group. Median time to progression was 153 days in the hypertension group versus 50.5 days in the non-hypertension group, which was significantly longer in the hypertension group. Moreover, median overall survival was 1,329 days in the hypertension group versus 302 days in the non-hypertension group, which was significantly longer in the hypertension group. CONCLUSIONS: Hypertension within 2 weeks of initiation of therapy may be a predictor of the anti-cancer efficacy of sorafenib when used for the treatment of advanced hepatocellular carcinoma.