Faculty Bibliography

BACKGROUND & AIMS:Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS:We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS:We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS:In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.

Background: Intraductal papillary mucinous neoplasm (IPMN) is premalig-nant pancreatic lesion. International guidelines suggest several treatments and malignancy predictors but offer limited predictors of individual risk. A nomo-gram to predict individual IPMN malignancy risk was released with good diagnostic performance, basedona cohort of2258 Korean or Japanese patients with IPMN. This study validated a nomogram to predict malignancy risk and inva-siveness of IPMN, using Eastern and Western cohorts.
Method(s): We collected clinicopathological and radiological data of patients who underwent pancreas resection for IPMN at 4 centers each in Eastern and Western countries. After excluding patients with >=1 missing malignancy predictor in the nomogram (main pancreatic duct diameter, cyst size, presence of mural nodule, serum CEA and CA 19-9 levels, and age), we analyzed data of the remaining 393 patients (Eastern: n = 265; Western: n = 128).
Result(s): Although mean age, sex, log value of serum CA 19-9, tumor location, main duct diameter, cyst size and presence of mural nodule differed between the Korea/Japan, Eastern and Western cohorts, rates of malignancy and invasive cancer did not significantly differ. Areas under the receiver operating characteristics curve (AUC) values using the nomogram to predict malignancy were Eastern: 0.745, Western: 0.856, and combined cohorts: 0.776; and to predict in-vasiveness were Eastern: 0.736, Western: 0.891, and combined cohorts: 0.788.
Conclusion(s): External validation of the nomogram showed good performance in predicting malignancy and invasive cancer in both Eastern and Western IPMN patients. The nomogram could be globally applicable to decide customized treatment options for patients with IPMN

Background and Objectives: We previously proposed a nomogram predicting individual risks of malignancy and invasiveness of intraductal papillary mucinous neoplasms and validated it in an external cohort. However, it is difficult to apply if data on tumor marker are lacking. The aim of the current study was to develop a new nomogram based on radiologic findings using previous nomogram development and an external validation cohort.
Material(s) and Method(s): A total of 3049 patients who underwent surgical resection at 30 tertiary institutes in 7 countries were enrolled and clinicopathologic data were retrospectively analyzed. Based on fitted model, area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search.
Result(s): The study consisted of 1914 (62.8%) patients for previous nomogram development and 1135 patients (37.2%) in the external validation cohort. Among patients, 1898 (62.3%) had low, 577 (18.9%) had high grade dysplasia, and 574 (18.8%) had invasive carcinoma. Patients were allocated randomly into model development and test sets to construct the nomogram, with fixed ratios according to malignancy and invasiveness. Exhaustive search resulted in three variables (cyst size, duct dilatation, and mural nodule) for malignancy and four variables (cyst size, duct dilatation, mural nodule, and location) for invasiveness being selected to construct the nomogram, and AUC was 0.742 and 0.741, respectively. AUC for test set was 0.727 and 0.704, respectively, and Hosmer-Lemeshow goodness of fit test showed good discrimination power (p = 0.066 and 0.067, respectively).
Conclusion(s): The new nomogram based on radiologic findings is accurate and helpful in identifying patients at risk of malignancy and invasiveness and selecting treatment options in clinical settings.
Copyright

OBJECTIVE:To examine the impact of surgical margin width on survival following R0 hepatic resection for colorectal metastases (CRLM). SUMMARY OF BACKGROUND DATA:Although negative resection margin is considered of paramount importance for the prognosis of patients with colorectal liver metastases, optimal resection margin width remains controversial. METHODS:Eligible studies examining the association between margin status after R0 hepatic resection for CRLM and survival, including overall survival (OS) and disease-free survival (DFS) were sought using the Medline, Cochrane, and EMBASE databases. Random-effects models were used for the calculation of pooled relative risks (RRs) with their 95% confidence intervals (95% CIs). RESULTS:Thirty-four studies were deemed eligible for inclusion representing a cohort of 11,147 hepatic resections. Wider resection margin (>1 vs <1 cm) was significantly associated with improved OS at 3 years (pooled RR = 0.86, 95% CI: 0.79-0.95), 5 years (pooled RR = 0.91, 95% CI: 0.85-0.97), and 10 years (pooled RR = 0.94, 95% CI: 0.88-1.00). Similarly, DFS was positively associated with >1 cm resection margin at 3, 5, and 10 years. Interestingly, >1 mm (vs <1 mm) resection margin was significantly associated with improved OS at all-time points. Meta-regression analyses did not reveal any significant modifying role of the study features under investigation, such as the administration of neoadjuvant/adjuvant therapy. CONCLUSIONS:Importantly, our findings suggest that while a >1 mm margin is associated with better prognosis than a submillimeter margin, achieving a margin >1 cm may result in even better oncologic outcomes and should be considered if possible.

PURPOSE:Introduction of effective neoadjuvant therapy for pancreas cancer has resulted in complex and aggressive operations involving vasculature resection. This results in complicated postoperative CT appearance of vasculature, which in addition to high rate of recurrence makes interpretation of imaging difficult. The aim of this study was to identify patterns of postoperative appearance of portal vein-superior mesenteric vein complex (PV-SMV). METHODS:A retrospective study was conducted on patients undergoing pancreaticoduodenectomy with PV-SMV resection and reconstruction (PVR) between 2004 and 2014. Clinicopathological data were collected from a prospectively maintained database. Postoperative CT scans were reviewed to identify patterns of venous and perivenous features. RESULTS:The mean age, of 70 patients included in the study, was 63.0 ± 12.2 years and 37 (52.9%) were males. The median time between surgery and postoperative scan was 10 days (IQR 7-25). Tangential resection with PVR via primary closure or use of a patch was performed in 37 (52.9%) patients while the rest underwent segmental resection with PVR via end-to-end anastomosis or use of a graft. Postoperative patterns of PV-SMV included concentric narrowing (N = 40, 57.1%), eccentric narrowing (N = 19, 27.1%) or partial venous thrombosis (N = 7, 10.0%). Perivenous features included perivenous fluid collection and induration (N = 57, 81.4%) and mass-like soft tissue thickening (N = 13, 18.6%). Long-term follow-up was available on 44 (62.9%) patients of which 28 (63.6%) demonstrated no recurrence of disease. CONCLUSION:This is a novel study that identifies and categorizes postoperative features of PV-SMV after PVR. These features overlap with those of disease recurrence and their better understanding can results in an accurate interpretation of postoperative imaging.