Faculty Bibliography

Recognition and management of aberrant hepatic arterial anatomy for patients undergoing pancreaticoduodenectomy (PD) are critical to ensure safe completion of the operation. When the common hepatic artery (CHA) is noted to emanate from the superior mesenteric artery (Michels' type 9 variant), it is vulnerable to injury during the dissection required for PD. While this anatomy does not preclude an operation, care must be taken to avoid injury, often by identifying the CHA throughout its entire course before beginning the dissection of the portal venous structures. The oncologic principle that cautions against resection of a pancreatic cancer when it involves the CHA in its standard position may not universally apply to tumors that focally involve the CHA in the type 9 anatomic variant. In highly selected patients, surgical resection may be entertained as disease biology may be analogous to local involvement of the gastroduodenal artery in a patient with standard anatomy. Here, we review the indications, techniques, and outcomes associated with arterial resection and reconstruction during pancreatectomy among patients with a pancreatic tumor involving a common hepatic artery arising from the superior mesenteric artery.

OBJECTIVE:The aim of this study was to evaluate the feasibility and reproducibility of diffusion-weighted imaging in distinguishing between mucin-producing and serous pancreatic cysts. METHODS:Forty-four pancreatic cysts (43 patients, 27 women; mean age, 57 years; 26 mucin-producing cysts, 18 serous cysts) that underwent histological examination or cyst analysis after diffusion-weighted magnetic resonance imaging were retrospectively reviewed. Three blinded readers independently evaluated signal intensity and apparent diffusion coefficient (ADC). Intraobserver and interobserver agreements were calculated. Fisher exact test and Welch t test were used to compare signal intensity and ADC values, respectively, with pathological results. Receiver operating characteristic analysis was used to determine diagnostic accuracy of various thresholds for ADC. A P value less than 0.05 was considered statistically significant. RESULTS:Mean ADC values of the mucin-producing cysts were 3.26 × 10, 3.27 × 10, and 3.35 × 10 mm/s for the 3 readers, respectively. Mean ADC values of the serous cysts were 2.86 × 10, 2.85 × 10, and 2.85 × 10 mm/s for the 3 readers, respectively. Differences in ADC values between the 2 cyst groups were 12.4%, 12.9%, and 14.8% for the 3 readers, respectively (P < 0.001). Intraobserver and interobserver agreement was excellent. A threshold ADC of 3 × 10 mm/s resulted in correct identification of cysts in 77% to 81% of cases, with sensitivity and specificity ranging between 84% and 88% and 66% and 72%, respectively. CONCLUSIONS:Diffusion-weighted imaging may be a helpful tool in distinguishing between mucin-producing and serous pancreatic cysts.

Pancreatic neuroendocrine tumor (PanNET) is a neoplastic entity in which few prognostic factors are well-known. Here, we aimed to evaluate the prognostic significance of N-myc downstream-regulated gen-1 (NDRG-1), O6-methylguanine DNA methyltransferase (MGMT) and Pleckstrin homology-like domain family A member 3 (PHLDA-3) by immunohistochemistry (IHC) and methylation analysis in 92 patients with resected PanNET and follow-up longer than 24 months. In multivariate analyses, ki-67 and our immunohistochemistry prognostic score (IPS-based on MGMT, NDRG-1 and PHLDA-3 IHC expression) were independent prognostic factors for disease-free-survival (DFS), while age and IPS were independent prognostic factors for overall survival (OS). Our IPS could be a useful prognostic biomarker for recurrence and survival in patients following resection for PanNET.

Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. Surgical resection offers the best opportunity for prolonged survival but is limited to patients with locally resectable disease without distant metastases. Regrettably, most patients are diagnosed at a point in which curative surgery is no longer a treatment option. In these patients, management of symptoms becomes paramount to improve quality of life and potentially increase survival. This article reviews the palliative management of unresectable pancreatic cancer, including potential palliative resection, surgical and endoscopic biliary and gastric decompression, and pain control with celiac plexus block.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

PURPOSE/OBJECTIVE:Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS AND MATERIALS/METHODS:Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival. RESULTS:Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P<.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC <500 cells/mm(3) vs 13.8% of SBRT patients; P<.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002). CONCLUSIONS:SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

OBJECTIVE:Arterial resection (AR) during pancreatic tumor resection is controversial. We examined the safety and efficacy of AR during pancreatectomy. METHODS:We used a prospective institutional database that includes 6522 patients who underwent pancreatectomy from 1970 to 2014; 35 had AR. We performed a 2:1 propensity match for patients without and with AR on the basis of preoperative patient and tumor variables. We then compared operative and postoperative outcomes between matched groups. RESULTS:AR included 18 hepatic, 8 celiac, 3 splenic, 3 middle colic, 2 superior mesenteric, and 1 left renal artery. There were 20 primary, 4 vein, and 2 graft reconstructions; 11 were emergent and 24 elective. Before matching, patients with AR were younger (58 ± 2 vs 63 ± 0.2 years old; P = .05), more likely to be of black race (26% vs 9%; P = .003), to have received preoperative chemotherapy (17% vs 2%; P < .001), have a later stage and larger tumor (4 ± 0.8 vs 3 ± 0.04 cm; P = .05), more resections that included removal of all macroscopic disease, but microscopic residual tumor remained (31% vs 14%; P = .02), greater blood loss (1285 ± 276 vs 822 ± 16 mL; P = .02), and more frequent cardiac complications (11% vs 4%; P = .03) compared with patients without AR. After propensity matching, baseline patient characteristics were similar between groups. For perioperative outcomes, the groups did not differ in surgical time, blood loss, length of stay, or complications including anastomotic leaks, bleeding, cardiac, infectious complications, or liver infarct or failure (all; P = not significant). Patency was 97% at a mean follow-up of 510 ± 184 days with 1 hepatic artery AR thrombosis. Long-term outcomes were significantly different: patients with AR had a lower rate of local tumor recurrence (20% vs 47%; P = .007) but also lower 1-year (50% vs 87%; P = .002) and median survival (22 ± 18 vs 49 ± 7 months; P = .002). CONCLUSIONS:AR during pancreatectomy is safe and not associated with increased complications. Although it significantly reduces the risk of local tumor recurrence, AR is associated with worse survival compared with patients who do not undergo AR.

BACKGROUND:Non-invasive intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia and IPMN-associated invasive pancreatic ductal adenocarcinoma (PDAC) are frequently included under the term "malignancy". The goal of this study is to clarify the difference between these two entities. METHODS:From 1996 to 2013, data of 616 patients who underwent pancreatic resection for an IPMN were reviewed. RESULTS:The median overall survival for patients with IPMN with high-grade dysplasia (92 months) was similar to survival for patients with IPMN with low/intermediate-grade dysplasia (118 months, p = 0.081), and superior to that of patients with IPMN-associated PDAC (29 months, p < 0.001). IPMN-associated PDAC had lymph node metastasis in 53%, perineural invasion in 58%, and vascular invasion in 33%. In contrast, no lymph node metastasis, perineural or vascular invasion was observed with high-grade dysplasia. None of the patients with IPMN with high-grade dysplasia developed recurrence outside the remnant pancreas. In stark contrast 58% of patients with IPMN-associated PDAC recurred outside the remnant pancreas. The rate of progression within the remnant pancreas was significant in patients with IPMN with high-grade (24%) and with low/intermediate dysplasia (22%, p = 0.816). CONCLUSION/CONCLUSIONS:Non-invasive IPMN with high-grade dysplasia should not be considered a malignant entity. Compared to patients with IPMN with low/intermediate-grade dysplasia, those with high-grade dysplasia have an increased risk of subsequent development of PDAC in the remnant pancreas.

Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion.