Faculty Bibliography

OBJECTIVE:The aim of this study was to examine if the prognostic significance of margin status in hepatectomy for colorectal cancer liver metastasis (CRLM) varies for different levels of tumor burden because hepatectomy indications for CRLM have been recently expanded to include patients with a higher tumor burden in whom achieving an R0 resection is difficult. METHODS:. The principal findings were validated using a cohort from the United States. RESULTS:R1 resection rates significantly increased as TBS increased: 4/86 (4.7%) in patients with TBS < 3, 29/171 (17.0%) in patients with TBS ≥ 3 and < 9, and 9/33 (27.3%) in patients with TBS ≥ 9 (p < 0.001). R0 resection was significantly superior to R1 resection in patients with TBS ≥ 5; however, this was not the case for TBS ≥ 6, as confirmed by both univariate and multivariate analyses. Furthermore, prehepatectomy chemotherapy was associated with significantly improved survival for patients with TBS ≥ 8. Analysis of the validation cohort yielded similar results. CONCLUSIONS:R0 resection appeared to have a positive impact on prognosis among patients with low tumor burden; however, this was not the case for patients with high tumor burden. As such, systemic treatment, in addition to surgery, may be central to achieving satisfactory outcomes in the latter patient population.

Liver cancer is the fourth leading cause of cancer-related mortality and is distinguished by a relative paucity of chemotherapy options. It has been hypothesized that intratumor genetic heterogeneity may contribute to the high failure rate of chemotherapy. Here, we evaluated functional heterogeneity in a cohort of primary human liver cancer organoid lines. Each primary human liver cancer surgical specimen was used to generate multiple cancer organoid lines, obtained from distinct regions of the tumor. A total of 27 liver cancer lines were established and tested with 129 cancer drugs, generating 3,483 cell survival data points. We found a rich intratumor, functional (drug response) heterogeneity in our liver cancer patients. Furthermore, we established that the majority of drugs were either ineffective, or effective only in select organoid lines. In contrast, we found that a subset of drugs appeared pan-effective, displaying at least moderate activity in the majority of these cancer organoid lines. These drugs, which are FDA approved for indications other than liver cancers, deserve further consideration as either systemic or local therapeutics. Of note, molecular profiles, obtained for a reduced sample set, did not correlate with the drug response heterogeneity of liver cancer organoid lines. Taken together, these findings lay the foundation for in-depth studies of pan-effective drugs, as well as for functional personalized oncology approaches. Lastly, these functional studies demonstrate the utility of cancer organoid drug testing as part of a drug discovery pipeline.

OBJECTIVE:To identify a clinical fistula risk score following distal pancreatectomy. BACKGROUND:Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive. METHODS:This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001-2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c-statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution. RESULTS:CR-POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF included: age (<60 yrs: OR 1.42, 95% CI 1.05-1.82), obesity (OR 1.54, 95% CI 1.19-2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06-2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17-2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18-2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25-3.17), and vascular resection (OR 2.29, 95% CI 1.25-3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPF: method of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51-3.78) but reduced fistula severity (P < 0.001). CONCLUSIONS:From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.

INTRODUCTION:Approximately, 20% of patients with pancreatic ductal adenocarcinoma have resectable disease at diagnosis. Given improvements in locoregional and systemic therapies, some patients with borderline resectable pancreatic cancer (BRPC) can now undergo successful resection. The outcomes of patients with BRPC after neoadjuvant therapy remain unclear. METHODS:A prospectively maintained single-institution database was utilized to identify patients with BRPC who were managed at the Johns Hopkins Pancreas Multidisciplinary Clinic (PMDC) between 2013 and 2016. BRPC was defined as any tumor that presented with radiographic evidence of the involvement of the portal vein (PV) or superior mesenteric vein (SMV) that was deemed to be technically resectable (with or without the need for reconstruction), or the abutment (< 180° involvement) of the common hepatic artery (CHA) or superior mesenteric artery (SMA), in the absence of involvement of the celiac axis (CA). We collected data on treatment, the course of the disease, resection rate, and survival. RESULTS:Of the 866 patients evaluated at the PMDC during the study period, 151 (17.5%) were staged as BRPC. Ninety-six patients (63.6%) underwent resection. Neoadjuvant chemotherapy was administered to 142 patients (94.0%), while 78 patients (51.7%) received radiation therapy in the neoadjuvant setting. The median overall survival from the date of diagnosis, of resected BRPC patients, was 28.8 months compared to 14.5 months in those who did not (p < 0.001). Factors associated with increased chance of surgical resection included lower ECOG performance status (p = 0.011) and neck location of the tumor (p = 0.001). Forty-seven patients with BRPC (31.1%) demonstrated progression of disease; surgical resection was attempted and aborted in 12 patients (7.9%). Eight patients (5.3%) were unable to tolerate chemotherapy; six had disease progression and two did not want to pursue surgery. Lastly, four patients (3.3%) were conditionally unresectable due to medical comorbidities at the time of diagnosis due to comorbidities and failed to improve their status and subsequently had progression of the disease. CONCLUSION:After initial management, 31.1% of patients with BRPC have progression of disease, while 63.6% of all patients successfully undergo resection, which was associated with improved survival. Factors associated with increased likelihood of surgical resection include lower ECOG performance status and tumor location in the neck.