Faculty Bibliography

OBJECTIVE:We evaluated survival outcomes in patients with distal pancreatic ductal adenocarcinoma (D-PDAC) after distal pancreatectomy (DP) and adjuvant chemotherapy or chemoradiation. METHODS:A retrospective analysis of patients who underwent DP for D-PDAC from 2000 to 2015 at the Johns Hopkins Hospital was performed. Demographics, baseline risk factors, and type of adjuvant treatment were assessed for associations with overall survival (OS) and disease-free survival (DFS). Comparisons were made with log-rank tests and Cox proportional hazards regression models. RESULTS:A total of 294 patients underwent DP for D-PDAC. Of these, 105 patients were followed at the Johns Hopkins Hospital. Forty-five patients received chemotherapy only and 60 patients received chemoradiation. The median OS with chemoradiation was 33.6 months and 27.9 months (P = 0.54) with chemotherapy only. The median DFS was 15.3 months with chemoradiation and 19.8 months with chemotherapy only (P = 0.89). Elevated carbohydrate antigen 19-9, stage II to III disease, splenic vein involvement, and vascular invasion were significant risk factors in multivariate analyses. CONCLUSIONS:In this retrospective analysis, there were no significant differences in OS or DFS with chemoradiation compared with chemotherapy alone after DP in patients with D-PDAC.

Purpose: To examine the prognostic impact of various exon, codon, and point mutations of the KRAS gene in patients with resected colorectal liver metastases.
Method(s): Patients who underwent resection for colorectal liver metastases with a known KRAS mutation were included from 9 centers from the International Genetic Consortium for Liver Metastases.
Result(s): 1567 patients met the inclusion criteria. KRAS mutations were found in 562 patients (36%). Out of these mutations, 415 (74%) were situated in codon 12, 111 (20%) in codon 13, and median overall survival (OS) was similar (p = 0.282). Less common mutations in Exon 3 (n = 14) and Exon 4 (n = 20) also had similar OS (p = 0.603). Median OS ranged from 16.8 to 80.3 months across specific point mutations. Median OS for 244 patients with high-risk mutations (G12A, G12V, G12R, G13R, and G13D) was 34.2 (28.7-39.8) months compared to 53.1 (41.8-64.3) months for 288 patients with low-risk mutations (G12C, G12D, G12S, G13C, Exon 3, and Exon 4) and 60.8 (55.1-66.6) months in the 996 patients with KRAS wild-type (Figure). On multivariable analysis, the KRAS risk groups were identified as independent prognostic factors.
Conclusion(s): Several KRAS point mutations are associated with inferior prognosis. Stratifying patients based on KRAS point mutations not only refines prognostication but may also help assess whether different treatments are more appropriate for specific subgroups. [Formula presented]
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Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVax^TM (termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.

BACKGROUND:In pancreatic cancer, extensive tumor involvement of the mesenteric venous system poses formidable challenges to operative resection. Such involvement can result from cavernous collateral veins leading to increased intraoperative blood loss or long-segment vascular defects of not only just the superior mesenteric vein but also even jejunal/ileal branches. Strategies to facilitate margin-free resection and safe vascular reconstruction in pancreatic surgery are important, particularly because systemic control of the tumor is improving with multi-agent chemotherapy regimens. METHODS:We describe a systematic, multidisciplinary assessment for patients with pancreatic cancer that involves the superior mesenteric vein, as well as the preoperative planning of those undergoing operative resection. In addition, detailed descriptions of operative approaches and technical strategies, which evolved with increasing experience at a high-volume center, are presented. RESULTS:For the preoperative evaluation of tumor-free, vascular locations for potential reconstruction and collateralization, computed tomographic imaging with high-resolution of vascular structures (used with 3-dimensional or cinematic rendering) allows a precise calibration of radiographic data with intraoperative findings. From an operative perspective, we identified 5 potential strategies to consider for resection: collateral preservation, mesoportal bypass (preresection), mesoportal interposition graft (postresection), mesocaval shunt, and various combinations of these strategies. Many of these techniques use interposition grafts, making it essential to assess autologous veins (preferred conduit for reconstruction) or to prepare cryopreserved vascular allografts (an alternative conduit, which must be thawed and should be matched for size and blood type). CONCLUSION/CONCLUSIONS:Herein we share operative strategies to overcome involvement of the superior mesenteric vein in pancreatic cancer. Improvements in preoperative planning and operative technique can address common barriers to resection with curative intent.

OBJECTIVE:The purpose of this study is to determine preoperative factors that are predictive of malignancy in patients undergoing pancreatic resection for intraductal papillary mucinous neoplasms (IPMN). SUMMARY BACKGROUND DATA:IPMN of the pancreas may be precursor lesions to pancreatic cancer (PC) and represent a target for early diagnosis or prevention. While there has been much effort to define preoperative risk factors for malignant pathology, guidelines are ever-changing and controversy remains surrounding which patients would benefit most from resection. METHODS:We performed a retrospective analysis of 901 consecutive patients obtained from two tertiary referral centers who underwent pancreatic resection for histologically proven IPMN between 2004 and 2017. Collected data included patient demographic characteristics, preoperative symptoms, radiological findings, and laboratory data. RESULTS:Main pancreatic duct (MPD) dilatation was the only variable that was significantly associated with increased probability of malignancy (defined high-dysplasia or invasion) on both univariate and multivariate analysis. Even middle-range MPD dilatation from 5 mm to 9.9 mm (n = 286) was associated with increased odds of HG-IPMN (OR = 2.74; 95% CI = 1.80-4.16) and invasion (OR = 4.42; 95% CI = 2.55-7.66). MPD dilatation >10 mm (n = 150) had even greater odds of HG-IPMN (OR = 6.57; 95% CI = 3.94-10.98) and invasion (OR = 15.07; 95% CI = 8.21-27.65). A cutoff of 5 to 7 mm MPD diameter was determined to be the best predictor to discriminate between malignant and benign lesions. CONCLUSIONS:In agreement with current IPMN management guidelines, we found MPD dilatation, even low levels from 5 mm to 9.9 mm, to be the single best predictor of HG-IPMN or invasion, highlighting the critical role that MPD plays in the selection of surgical candidates.

Importance/UNASSIGNED:In patients who undergo surgery for colorectal cancer liver metastases (CRLM), a number of somatic mutations have been associated with worse overall (OS) and recurrence-free survival (RFS). Although useful, an association with prognosis does not necessarily equate to an impact on surgical management. Objective/UNASSIGNED:The aim of this review was to investigate whether the best-studied somatic mutations impact surgical management of CRLM by informing: (I) post-hepatectomy surveillance; (II) selection of surgical technique; (III) selection of optimal margin width; and (IV) selection of patients for surgery. Lastly, we discuss the refinement of genetic data from overall mutation status to specific variants, as well as lesser studied somatic mutations. Evidence Review/UNASSIGNED:We conducted a computerized search using PubMed and Google Scholar for reports published so far, using mesh headings and keywords related to genetic data and CRLM. Findings/UNASSIGNED:Genetic data may impact surgical management of CRLM in three ways. Firstly, KRAS mutations can predict lung recurrences. Secondly, KRAS mutations may help tailor margin width. Thirdly, KRAS mutations may help tailor surgical technique. Conclusions/UNASSIGNED:Although genetic data may impact post-hepatectomy surveillance, selection of surgical technique and optimal margin width, their use to guide surgical selection remains elusive, as the data cannot support denying surgery to patients according to their somatic mutation profile.

BACKGROUND AND AIMS/OBJECTIVE:Single-cell next-generation sequencing (scNGS) technology has been widely used in genomic profiling, which relies on whole-genome amplification (WGA). However, WGA introduces errors and is especially less accurate when applied to single nucleotide variant (SNV) analysis. Targeted scNGS for SNV without WGA has not been described. We aimed to develop a method to detect circulating tumor cells (CTCs) with DNA SNVs. METHODS:We tested this targeted scNGS method with three driver mutant genes (KRAS/TP53/SMAD4) on one pancreatic cancer cell line AsPC-1 and then applied it to patients with metastatic PDAC for the validation. RESULTS:All single-cell of AsPC-1 and spiked-in AsPC-1 cells in healthy donor blood, which were isolated by the filtration with size or by flow cytometry, were detected by targeted scNGS method. All blood samples from six patients with metastatic PDAC, for the validation of target scNGS method, showed CTCs with SNVs of KRAS/TP53/SMAD4 and the positive confirmation of immunofluorescent stainings with Pan-CK/Vimentin/CD45. Four patients with early stage disease, one patient with benign pancreatic cyst and a healthy control sample all showed concordant results between targeted scNGS and CTC enumeration. CONCLUSIONS:The novel technique of targeted scNGS for SNV analysis, without pre-amplification, is a promising method for identifying and characterizing circulating tumor cells.

PURPOSE/OBJECTIVE:We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC). METHODS AND MATERIALS/METHODS:Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥2 mm change in the median and mean interbleb surface distance with a P value <.05 required to reject the null hypothesis and conclude equivalence. For patients undergoing pancreaticoduodenectomy, hydrogel sites were histologically examined for location and local inflammatory reactions. RESULTS:Hydrogel placement was successful in 6 of the 6 evaluable patients. The average changes in median and mean interbleb distances were -0.43 mm and -0.35 mm, respectively, with P < .05. The average change in volume from sim-CT to post-SBRT CT was -1.0%, with P < .05. One patient experienced grade 3 nausea after fiducial/hydrogel placement, with no other adverse events to date. CONCLUSIONS:These data demonstrate feasibility and safety of injecting a hydrogel marker in the pancreaticoduodenal groove in patients with BR/LAPC and set the stage for a follow-up clinical trial to place hydrogel as a spacer between the pancreatic tumor and dose-limiting, radiosensitive duodenum.