Faculty Bibliography

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.

OBJECTIVES/OBJECTIVE:At diagnosis, 30% of patients with pancreatic cancer are unresectable stage 3 locally advanced. The standard treatment for locally advanced pancreatic cancer (LAPC) is not defined. The current study was conducted to assess the roles of chemotherapy and chemoradiation for LAPC treatment. MATERIALS AND METHODS/METHODS:Between June 2006 and March 2011, 100 patients with LAPC were treated at the Johns Hopkins Hospital. Retrospective analysis was performed to compare cumulative incidence of progression (CIP) and overall survival (OS) among different subgroups. RESULTS:For the 100 patients, the median OS was 15.8 months and the median CIP was 8.4 months. The combination of chemotherapy and chemoradiation before disease progression was significantly associated with improved CIP (P=0.001) and improved OS when compared with chemoradiation alone (median OS: 16.4 vs. 11.1 mo, P=0.03). Among patients receiving combination treatment, patients who received chemotherapy first followed by chemoradiation had a trend toward lower CIP (P=0.09) and improved OS (median OS: 18.1 vs. 11.0 mo, P=0.09). Patients who received >2 cycles of chemotherapy before chemoradiation had a significantly decreased CIP (P=0.008) and a trend toward better OS (median OS: 19.4 vs. 15.7 mo, P=0.10). On multivariate analysis, receiving >2 cycles of chemotherapy before chemoradiation was associated with improved CIP. CONCLUSIONS:Although combination chemotherapy and chemoradiation is favored in the treatment of LAPC, longer induction chemotherapy may play a more important role in sensitization of tumors to subsequent chemoradiation. Our results support treating patients with induction chemotherapy for at least 3 cycles followed by consolidative chemoradiation. These results merit further validation by a prospective study.

OBJECTIVES/OBJECTIVE:To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. BACKGROUND:The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. METHODS:IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. RESULTS:Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04-4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10-5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. CONCLUSIONS:Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.

INTRODUCTION/BACKGROUND:International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication. METHODS:Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis. RESULTS:Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (N = 88) of the overall series, with 35 % (N = 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 (IQR: 21-54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both P < 0.000001), respectively. CONCLUSION/CONCLUSIONS:This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.

BACKGROUND:Little is known regarding the effects of caseload volume of other relevant members of the "surgical team." The present study sought to report variations in health care utilization and outcomes relative to surgeon and anesthesiologist volume among patients undergoing pancreatic surgery. METHODS:A total of 969 patients undergoing pancreatic surgery from 2011-2013 were identified at a large, tertiary care center. Multivariable regression analyses explored the effects of provider volume on crystalloid administration, blood transfusions, mortality, length of stay, and hospital charges. RESULTS:A total of 11 surgeons were identified while 100 anesthesiologists were involved in providing care to all patients. Annual case volume for surgeons ranged from 5-101 pancreatic resections per year; each anesthesiologist was involved in a fewer number of cases per year with a maximum of 15 patients treated by the same anesthesiologist. Higher volume surgeons had higher transfusions (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.38-2.47; P < 0.001), greater crystalloid administration (OR, 1.62; 95% CI, 1.24-2.12; P < 0.001), and longer length of stay (OR, 1.74; 95% CI, 1.20-2.53; P = 0.003). In contrast, 30-d readmission was lower among higher volume surgeons (low volume versus high volume; 23.1% versus 11.6%; P < 0.001). Variations in patient-related outcomes were not associated with anesthesia provider volume (all P > 0.05). Similarly, total hospital charges and mortality were not associated with provider volumes (both P > 0.05). CONCLUSIONS:Although variability exists in health care practices among providers at the surgeon level, less is observed among anesthesiologists. Although a proportion of this variability can be explained by provider volumes, a significant proportion remains unexplained possibly due to nonmodifiable factors such as patient case mix.