Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model.

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.

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.

Predictors of Long-Term Survival in Pancreatic Ductal Adenocarcinoma after Pancreatectomy: TP53 and SMAD4 Mutation Scoring in Combination with CA19-9.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a fatal cancer for which even unfavorable clinicopathological factors occasionally fail to preclude long-term survival. We sought to establish a scoring system that utilizes measurable pre-intervention factors for predicting survival following surgical resection. METHODS: We retrospectively analyzed 34 patients who died from short-term recurrences and 32 long-term survivors among 310 consecutively resected patients with PDA. A logistic regression model was used to define factors related to clinical parameters, molecular profiles of 18 pancreatic cancer-associated genes, and aberrant expression of major tumor suppressors. RESULTS: Carbohydrate antigen 19-9 (CA19-9) had the best ability to classify patients with short-term recurrence and long-term survivors [odds ratio 21.04, 95% confidence interval (CI) 4.612-96.019], followed by SMAD4 and TP53 mutation scoring (odds ratio 41.322, 95% CI 3.156-541.035). Missense TP53 mutations were strongly associated with the nuclear expression of p53, whereas truncating mutations were associated with the absence of nuclear p53. The former subset was associated with a worse prognosis. The combination of aberrant SMAD4 and mutation types of TP53 exhibited a better resolution for distinguishing patients with short-term recurrences from long-term survivors (compared with the assessment of the number of mutated KRAS, CDKN2A, TP53, and SMAD4 genes). Calibration of mutation scores combined with CA19-9 in a logistic regression model setting demonstrated a practical effect in classifying long survivors and patients with early recurrence (c-statistic = 0.876). CONCLUSIONS: Genetic information, i.e., TP53 mutation types and SMAD4 abnormalities, combined with CA19-9, will be a valuable tool for improving surgical strategies for pancreatic cancer.

A rare case of localized IgG4-related sclerosing cholecystitis mimicking gallbladder cancer.

Objective: IgG4-related sclerosing cholecystitis is generally associated with IgG4-related sclerosing cholangitis and presents with diffuse, circumferential thickening of the gallbladder wall. We report a rare case of localized IgG4-related sclerosing cholecystitis without IgG4-related sclerosing cholangitis, which was difficult to differentiate from gallbladder cancer preoperatively. Patient: A 56-year-old man with suspected IgG4-related disease or gallbladder cancer was admitted to our ward. The serum IgG4 level was elevated at 721 mg/dL. Computed tomography (CT) demonstrated focal wall thickening of the gallbladder fundus. Drip infusion cholecystocholangiography with CT revealed no dilation, stenosis, or border irregularity of the bile duct. Results: For diagnostic and treatment purposes, cholecystectomy with wedge resection of the gallbladder bed was performed. The pathological diagnosis was IgG4-related sclerosing cholecystitis. Conclusion: It is difficult to differentiate IgG4-related sclerosing cholecystitis from gallbladder cancer in cases involving localized thickening of the gallbladder wall. In similar cases, surgical resection with cancer in mind might be performed based on present clinical knowledge.