Faculty Bibliography

Pancreatic cancer, most commonly referring to pancreatic ductal adenocarcinoma (PDAC), remains one of the most deadly diseases, with very few effective therapies available. Emerging as a new modality of modern cancer treatments, immunotherapy has shown promises for various cancer types. Over the past decades, the potential of immunotherapy in eliciting clinical benefits in pancreatic cancer have also been extensively explored. It has been demonstrated in preclinical studies and early phase clinical trials that cancer vaccines were effective in eliciting anti-tumor immune response, but few have led to a significant improvement in survival. Despite the fact that immunotherapy with checkpoint blockade (e.g., anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] and anti-programmed cell death 1 [PD-1]/PD-L1 antibodies) has shown remarkable and durable responses in various cancer types, the application of checkpoint inhibitors in pancreatic cancer has been disappointing so far. It may, in part, due to the unique tumor microenvironment (TME) of pancreatic cancer, such as existence of excessive stromal matrix and hypovascularity, creating a TME of strong inhibitory signaling circuits and tremendous physical barriers for immune agent infiltration. This informs on the need for combination therapy approaches to engender a potent immune response that can translate to clinical benefits. On the other hand, lack of effective and validated biomarkers to stratify subgroup of patients who can benefit from immunotherapy poses further challenges for the realization of precision immune-oncology. Future studies addressing issues such as TME modulation, biomarker identification and therapeutic combination are warranted. In this review, advances in immunotherapy for pancreatic cancer were discussed and opportunities as well as challenges for personalized immune-oncology were addressed.

BACKGROUND:A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT). METHODS:The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed. RESULTS:The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity. CONCLUSIONS:Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.

OBJECTIVE:Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA:IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS:Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS:We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS:For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer.

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19-9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.