Faculty Bibliography

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.

BACKGROUND:Recently, a tumor-burden "metro ticket" score (TBS) based on final pathology was proposed to predict outcome following resection of colorectal liver metastasis (CRLM). We sought to validate the TBS prognostic tool using preoperative radiologic cross-sectional imaging. METHODS:Imaging TBS was defined on a Cartesian plane that incorporated both maximum tumor size (x-axis) and lesion number (y-axis) assessed by pre-operative imaging. The discriminatory power (area under the curve [AUC]) and goodness-of-fit (Harrel's C statistic and Somer's D statistics) of the imaging TBS model was assessed. RESULTS:Imaging and pathologic TBS correlated strongly (r = 0.76, P < 0.01). Among patients treated with neoadjuvant therapy, the correlation was strongest among patients with progressive disease/stable disease (PD/SD) (r = 0.81). Discriminatory power of the imaging-based versus pathology-based TBS models were comparable (AUC 0.64 vs. 0.67, respectively P > 0.05). An incremental worsening of long-term survival was noted as the imaging TBS increased (5-year OS: Zone1, Zone2, and Zone3-61.3%, 46.7%, and 38.5%, respectively; P = 0.03). The imaging-based TBS model outperformed the "classic" pathology-based Fong score (Harrel's C-index: imaging TBS-0.56 vs. Fong score-0.53; Somers'D-index: imaging TBS-012 vs. Fong score-0.06). CONCLUSIONS:Imaging-based TBS was superior to traditional tumor size and number and was comparable to pathology-based TBS. Imaging-based TBS may have the potential to facilitate improved preoperative risk stratification of patients with CRLM.

BACKGROUND:Although the prognostic role of surgical margin status after resection of colorectal liver metastasis (CRLM) has been previously examined, controversy still surrounds the importance of surgical margin status in patients with multiple tumors. METHODS:Patients who underwent curative-intent surgery for CRLM from 2000 to 2015 and who presented with multiple tumors were identified. Patients with R1 resection status determined by the closest resection margin of the non-largest tumor were classified as R1-Type 1; patients with R1 status determined by the resection margin of the largest tumor were defined as R1-Type 2. Data regarding surgical margin status, size of tumors, and overall survival (OS) were collected and assessed. RESULTS:A total of 251 patients met inclusion criteria; 156 patients (62.2%) had a negative margin (R0), 50 had an R1-type 1 (19.9%), and 45 had an R1-type 2 (17.9%) margin. Median and 5-year OS in the entire cohort was 56.4 months and 48.0%, respectively. When all R1 (Type 1 + Type 2) patients were compared with R0 patients, an R1 was not associated with worse prognosis (P = 0.05). In contrast, when R1-type 2 patients were compared with R0 patients, an R1 was strongly associated with worse OS (P = 0.009). On multivariate analysis, although the prognostic impact of all R1 was not associated with OS (hazard ratio [HR] 1.56; P = 0.08), R1-Type 2 margin status independently predicted a poor outcome (HR 1.93; P = 0.03). CONCLUSIONS:The impact of margin status varied according to the size of the tumor assessed. While R1 margin status defined according to the non-largest tumor was not associated with OS, R1 margin status relative to the largest index lesion was associated with prognosis.

BACKGROUND:Distal pancreatectomy (DP) is performed to treat tumors of the pancreatic body and tail. Traditionally, splenectomy is performed with a DP, however, laparoscopic spleen-preserving DP (SPDP) using Warshaw's (splenic vessels ligation) or Kimura's (splenic vessels preservation) techniques have been reported. The clinical benefits of using either technique remain unclear. In this study, we conducted a meta-analysis to compare the clinical outcomes of patients undergoing Warshaw's and Kimura SPDP. This is the first study to evaluate the geographical variation in outcomes of Warshaw's and Kimura SPDP. METHODS:Databases of PubMed, Embase, and Cochrane library were used to identify studies reporting Warshaw's and Kimura SPDP. Clinical outcomes were compared. Pooled odds risk and weighted mean difference with 95% confidence interval were calculated using random effect models. RESULTS:Fourteen non-randomized controlled studies involving 945 patients met our selection criteria. 301 (31.9%) patients underwent Warshaw's SPDP; 644 (68.1%) underwent Kimura SPDP. Compared to Warshaw's SPDP, patients undergoing Kimura SPDP had a lower incidence of post-operative complications including spleen infarction (OR = 9.64, 95% CI = 5.79 to 16.05, P < 0.001) and gastric varices (OR = 11.88, 95% CI = 5.11 to 27.66, P < 0.001). The length of surgery was significantly shorter for Warshaw's SPDP (WMD = -18.12, 95%CI = -26.52 to -9.72, p < 0.001). Decreased blood loss was reported for patients undergoing Warshaw's SPDP (WMD = -59.72, 95%CI = -102.01 to -17.43, p = 0.006). There were no differences between the two groups' rates of conversion to an open procedure (P = 0.35), postoperative pancreatic fistula (P = 0.71), need for reoperation (P = 0.25), and length of hospital stay (P = 0.38). CONCLUSION/CONCLUSIONS:Both Warshaw's and Kimura are safe SPDP techniques. These data suggest Kimura SPDP is the preferred technique due to less risk of splenic infarct and gastric varices. Despite evidence of regional variation in volume performed (between Kimura and Warshaw's), there are no statistically significant differences in outcomes between these techniques.

BACKGROUND:Rates of superficial surgical site infection (SSI) following pancreaticoduodenectomy remain high. Following resection for cancer, complications such as SSI impact adjuvant therapy delivery and portend worse survival. An incisional negative pressure dressing (iVAC) has been demonstrated to reduce SSI in other high-risk cohorts. METHODS:Following a comprehensive effort to identify patients at high risk for SSI, the practice patterns at a single academic center shifted and iVAC use increased. SSI rates were tracked in a prospectively maintained database and are reported. RESULTS:394 patients underwent pancreaticoduodenectomy over 21 months. 120 patients (30.5%) had an iVAC applied. The overall rate of SSI was 19.8%. On multivariate analysis, increased risk for SSI was associated with neoadjuvant therapy, preoperative biliary interventions and prior abdominal surgery. iVAC use decreased the rate of SSI (OR 0.45, p = 0.015). In the highest-risk patients, SSI rate declined from 50% in patients without an iVAC to 19.1% with iVAC use (p = 0.015). CONCLUSION:The use of an iVAC following pancreaticoduodenectomy is associated with decreased SSI rates. This is particularly true for patients at highest risk as defined by a previously established risk scoring system in patients undergoing open pancreaticoduodenectomy.

BACKGROUND:Although experimental data strongly support the pro-tumorigenic role of postoperative liver regeneration, this hypothesis has not been clinically investigated. We aimed to examine the impact of liver regeneration determined by volumetric imaging on recurrence following resection of colorectal liver metastasis (CRLM). METHODS:). Early and late kinetic growth rates (KGR) were defined as the postoperative increases in liver volume within 2-3 and 8-10 months from surgery, respectively, divided by the corresponding time interval. RESULTS:Median early and late KGR was 2.6%/month (IQR: -0.9 to 12.3) and 1.0%/month (IQR: -0.64 to 2.91), respectively. Late KGR predicted intrahepatic recurrence after 1 year from surgery (AUC 0.677, P = 0.011). Specifically, patients with a late KGR ≥1% had a higher cumulative risk of recurrence compared with patients with a KGR <1% (P = 0.038). In multivariate analysis, KGR ≥1% independently predicted recurrence (P = 0.027). DISCUSSION:A KGR ≥1% during the late regeneration phase was associated with increased risk of intrahepatic recurrence. These data may inform the timing of adjuvant therapy administration and focus surveillance strategies for high-risk patients.

CEL-HYB is a hybrid allele that arose from a crossover between the 3' end of the Carboxyl ester lipase (CEL) gene and the nearby CEL pseudogene (CELP) and was recently identified as a risk factor for chronic pancreatitis. Since chronic pancreatitis is a risk factor for the development of pancreatic cancer, we compared the prevalence of the CEL-HYB allele in patients with pancreatic ductal adenocarcinoma to spousal controls and disease controls. The CEL-HYB allele was detected using Sanger and next generation sequencing. There was no significant difference in the prevalence of the CEL-HYB allele between cases with pancreatic ductal adenocarcinoma compared to controls; 2.6% (22/850) vs. 1.8% (18/976) (p=0.35). CEL-HYB carriers were not more likely to report a history of pancreatitis. Patients with pancreatic cancer are not more likely than controls to be carriers of the CEL-HYB allele.

BACKGROUND:The current staging system for pancreatic ductal adenocarcinoma (PDAC) includes information about size and local extension of the primary tumor (T stage). The value of incorporating any local tumor extension into pancreatic staging systems has been questioned because it often is difficult to evaluate tumor extension to the peri-pancreatic soft tissues and because most carcinomas of the head of the pancreas infiltrate the intra-pancreatic common bile duct. This study sought to evaluate the prognostic implications of having PDAC with local tumor extension. METHODS:A single-institution, prospectively collected database of 1128 patients who underwent surgical resection for PDAC was queried to examine the prognostic significance of extra-pancreatic tumor involvement ("no involvement," "duodenal involvement," and "extensive involvement"; e.g., gastric, colon or major vein involvement). RESULTS:The median overall survival for the patients without extra-pancreatic involvement was 26 months versus 19 months for the patients with duodenal involvement and 16 months for the patients with extensive involvement (p < 0.001). In the multivariable analysis, duodenal and extensive involvement independently predicted increased risk of death compared with no involvement (hazard ratio [HR] 1.30; 95% confidence interval [CI] 1.08-1.57 and 1.78; 95% CI 1.25-2.55, respectively). A multivariable model combining duodenal and extensive extra-pancreatic involvement, tumor grade, lymph node ratio, and other prognostic features had the highest c-index (0.67). CONCLUSIONS:Inclusion of duodenal involvement in the staging of PDAC adds independent prognostic information.