Faculty Bibliography

Background/UNASSIGNED:Pancreatic ductal adenocarcinoma (PDAC) often presents with nonspecific symptoms and the workup is not standardized. To study the impact of delays in diagnosis and in the initiation of treatment, we investigated the relationship between length of diagnostic intervals and surgical resectability. Methods/UNASSIGNED:We performed a retrospective chart review of patients evaluated for PDAC at Johns Hopkins in 2014. Data were collected on the patient (date of first symptoms-first medical appointment), diagnostic (first medical appointment-diagnosis of PDAC), and treatment (diagnosis of PDAC-1st day of treatment) time intervals, and the upfront treatment received. Asymptomatic patients diagnosed incidentally, or for whom records were incomplete, were excluded from analysis. Results/UNASSIGNED:Of 453 charts reviewed, 116 patients met inclusion criteria. The median patient interval was 14 days [interquartile range (IQR): 6-30 days], the median diagnostic interval was 22 days (IQR: 8-46 days), and the median treatment interval was 26 days (IQR: 15-35 days). Thirty-eight patients (33%) received upfront surgery and 78 (67%) received nonsurgical treatment. After adjusting for multiple factors, the odds of receiving surgery significantly increased for individuals with a patient interval of 30 days or less [adjusted odds ratio (aOR): 3.41; 95% confidence interval (CI): 1.08-13.20; P=0.050] and with a diagnostic interval of 60 days or less (aOR: 15.68; 95% CI: 2.95-291.00, P=0.009). Conclusions/UNASSIGNED:A patient interval less than 1 month and a diagnostic interval less than 2 months for symptomatic PDAC are associated with increased odds of upfront surgical resection. These data provide initial evidence that reducing diagnostic delays may lead to improved outcomes in PDAC.

BACKGROUND AND OBJECTIVES/OBJECTIVE:While preoperative treatment is frequently administered to CRLM patients, the impact of chemotherapy, with or without bevacizumab, on liver regeneration remains controversial. METHODS:The early and late regeneration indexes were defined as the relative increase in liver volume (RLV) within 2 and 9 months from surgery. Regeneration rates of the preoperative treatment groups were compared. RESULTS:Preoperative chemotherapy details and volumetric data were available for 185 patients; 78 (42.2%) received preoperative chemotherapy with bevacizumab (Bev+), 46 (24.8%) received chemotherapy only (Bev-), and 61 (33%) received no chemotherapy. Patients in the Bev+ and Bev- groups received similar chemotherapy cycles (4 [3-6] vs 4 [4-6]; P = 0.499). Despite the comparable clinicopathological characteristics and Resected Volume/Total Liver Volume (TLV) at surgery (P = 0.944) of both groups, Bev+ group had higher early and late regeneration (17.2% vs 4.3%; P = 0.035 and 14.0% vs 9.4%; P = 0.091, respectively). Of note, early and late regeneration rates (3.7% and 10.9% vs 6.6% and 5.5%, respectively) were comparable between the no chemotherapy and Bev- groups (all P > 0.05). In multivariable analysis -adjusted for gender, age, portal vein embolization, preoperative chemotherapy, resected liver volume, tumor number, postoperative chemotherapy, fibrosis, steatosis- bevacizumab independently predicted early liver regeneration (P = 0.019). CONCLUSION/CONCLUSIONS:Our findings suggest that preoperative bevacizumab administered along with chemotherapy was associated with enhanced volumetric restoration. Interestingly, this effect was more pronounced among patients who received oxaliplatin-based regimens and bevacizumab compared to those treated with irinotecan-based regimens and bevacizumab.

Background and Objectives Despite routine inclusion of lymphovascular invasion (LVI) status in pathologic reports of resected pancreatic ductal adenocarcinomas (PDA), the clinical implications of LVI have not been well characterized. Methods This study is a retrospective review of 2640 patients who underwent a pancreatectomy for PDA at Thomas Jefferson University Hospital, Massachusetts General Hospital, or Johns Hopkins Hospital (2003-2014). Clinical and pathologic records were extracted from institutional databases. Results The median post-resection survival for the total cohort was 19.2 months with a 5-year survival rate of 15.2%. In a multivariate Cox proportional hazards model including conventional pathologic features, LVI was an independent predictor of survival (HR = 1.14, P = 0.017). In a stratified Kaplan-Meier survival analysis, patients with N0, LVI- PDA had a significantly improved overall survival compared to those with N0, LVI+ PDA (median 31 vs 24 mo, P = 0.020). Similarly, patients with N1, LVI- PDA had superior survival to patients with N1, LVI+ disease (18.6 vs 16.5 mo, P = 0.001). Conclusions As the first large scale study focused on the clinical impact of LVI status in PDA, these data indicate that this routinely reported pathologic feature is a bona fide and independent adverse prognostic factor.

BACKGROUND:Although laparoscopic distal pancreatectomy is considered a standard approach, 10% to 40% of these are converted. The preoperative risk factors for conversion are not well described. The aim of this study was to identify risk factors associated with conversion. METHODS:Clinicopathological variables of 211 consecutive patients who underwent laparoscopic distal pancreatectomy between January 2007 and December 2015 at Johns Hopkins were analyzed to identify factors associated with conversion. Furthermore, the learning curve for laparoscopic distal pancreatectomy was studied. RESULTS:On univariate analysis of diabetes mellitus, preoperative diagnosis of malignant disease, multiorgan resection, surgeons' years and case experience were significantly associated with conversion (all P < .05). Risk factors independently associated with conversion included diagnosis of malignant disease (odds ratio = 5.40; 95% confidence interval, 1.93-15.12, P = .001), multiorgan resection (odds ratio = 7.10; 95% confidence interval, 1.60-31.53, P = .01), and surgeons' case experience (odds ratio = 0.32; 95% confidence interval, 0.12-0.85, P = .023). Intraoperative reasons for conversion included presence of excessive intraabdominal and retroperitoneal fat (N = 10, 32.3%), adhesions (N = 10, 32.3%), extent of tumor invasion (N = 8, 25.8%), anatomy of vessels (N = 6, 19.4%), and intraoperative bleeding (N = 2, 6.5%). CONCLUSION:Patients undergoing laparoscopic distal pancreatectomy with a preoperative diagnosis of malignant disease or possible multiorgan resection are at a higher risk of conversion. Surgeon experience of performing >15 procedures significantly reduces the risk of conversion.

BACKGROUND:Sarcomatoid carcinoma of the pancreas (SCP) is a rare histologic subtype of undifferentiated pancreatic carcinoma. Historically, this has been associated with a worse overall prognosis than adenocarcinoma. However, the clinical course and surgical outcomes of SCP remain poorly characterized owing to its rarity. METHODS:A single-institution, prospectively maintained database was queried for patients who underwent pancreatic resection with a final diagnosis of SCP. We describe their histology, clinicopathologic features, and perioperative outcomes. Survival data are highlighted, and common traits of long-term survivors are examined. RESULTS:Over a 25-year period, 7009 patents underwent pancreatic resection at our institution. Eight (0.11%) were diagnosed with SCP on final histopathology. R0 resection was achieved in six patients (75%). Four patients had early recurrence leading to death (<3 months). Two (25%) experienced long-term survival (>5 years), with the longest surviving nearly 16 years despite the presence of lymph node metastasis. There were no deaths attributed to perioperative complications. Both long-term survivors had disease in the body/tail of the pancreas and received adjuvant radiotherapy. One also received adjuvant gemcitabine-based chemotherapy. CONCLUSIONS:SCP is a rarely appreciated subset of pancreatic malignancy that does not necessarily portend to a uniformly dismal prognosis. Although some have rapid recurrence and an early demise, long-term survival may be possible. Future studies are needed to better define the cohort with potential for long-term survival so that aggressive therapies may be tailored appropriately in this patient subset.

Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015. Results Thirty-three (3.9%; 95% CI, 3.0% to 5.8%) of 854 patients with pancreatic cancer had a deleterious germline mutation, 31 (3.5%) of which affected known familial pancreatic cancer susceptibility genes: BRCA2 (12 patients), ATM (10 patients), BRCA1 (3 patients), PALB2 (2 patients), MLH1 (2 patients), CDKN2A (1 patient), and TP53 (1 patient). Patients with these germline mutations were younger than those without (mean ± SD, 60.8 ± 10.6 v 65.1 ± 10.5 years; P = .03). Deleterious germline mutations were also found in BUB1B (1) and BUB3 (1). Only three of these 33 patients had reported a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Five (1.7%) of 288 patients with other periampullary neoplasms also had a deleterious germline mutation. Conclusion Germline mutations in pancreatic cancer susceptibility genes are commonly identified in patients with pancreatic cancer without a significant family history of cancer. These deleterious pancreatic cancer susceptibility gene mutations, some of which are therapeutically targetable, will be missed if current family history guidelines are the main criteria used to determine the appropriateness of gene testing.

OBJECTIVE:To investigate the potential clinical advantage of anatomical resection versus nonanatomical resection for colorectal liver metastases, according to KRAS mutational status. BACKGROUND:KRAS-mutated colorectal liver metastases (CRLM) are known to be more aggressive than KRAS wild-type tumors. Although nonanatomical liver resections have been demonstrated as a viable approach for CRLM patients with similar oncologic outcomes to anatomical resections, this may not be the case for the subset of KRAS-mutated CRLM. METHODS:389 patients who underwent hepatic resection of CRLM with known KRAS mutational status were identified. Survival estimates were calculated using the Kaplan-Meier method, and multivariable analysis was conducted using the Cox proportional hazards regression model. RESULTS:In this study, 165 patients (42.4%) underwent nonanatomical resections and 140 (36.0%) presented with KRAS-mutated CRLM. Median disease-free survival (DFS) in the entire cohort was 21.3 months, whereas 1-, 3-, and 5-year DFS was 67.3%, 34.9%, and 31.5% respectively. Although there was no difference in DFS between anatomical and nonanatomical resections in patients with KRAS wild-type tumors (P = 0.142), a significant difference in favor of anatomical resection was observed in patients with a KRAS mutation (10.5 vs. 33.8 months; P < 0.001). Five-year DFS was only 14.4% in the nonanatomically resected group, versus 46.4% in the anatomically resected group. This observation persisted in multivariable analysis (hazard ratio: 0.45; 95% confidence interval: 0.27-0.74; P = 0.002), when corrected for number of tumors, bilobar disease, and intraoperative ablations. CONCLUSIONS:Nonanatomical tissue-sparing hepatectomies are associated with worse DFS in patients with KRAS-mutated tumors. Because of the aggressive nature of KRAS-mutated CRLM, more extensive anatomical hepatectomies may be warranted.

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.