Publications by authors named "Jeffrey Drebin"

114 Publications

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

Hepatology 2021 Mar 25. Epub 2021 Mar 25.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background/aims: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well-characterized, but their impact on outcome and prognosis remain unknown.

Approach/results: This bi-institutional study of patients with confirmed iCCA (n=412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were IDH1 (20%), ARID1A (20%), TP53 (17%), CDKN2A (15%), BAP1 (15%), FGFR2 (15%), PBRM1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions (fus), but neither was associated with outcome. For all patients, TP53 (p<0.0001), KRAS (p=0.0001), and CDKN2A (p<0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n=209), TP53mut (HR=1.82, 95%CI=1.08-3.06, p=0.03) and CDKN2A deletions (del) (HR=3.40, 95%CI=1.95-5.94, p<0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [p<0.001]; regional lymph node metastases [p<0.001]), whereas KRASmut (HR=1.69, 95%CI=0.97-2.93, p=0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS=18.3 vs. 74.2 months, p<0.001), with high-risk genetic alterations alone (median OS=38.6 months, 95%CI=28.8-73.5) or high-risk clinical variables alone (median OS=37.0 months, 95%CI=27.6-NA) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy.

Conclusions: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Since genetic profiling can be integrated into pre-treatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
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http://dx.doi.org/10.1002/hep.31829DOI Listing
March 2021

Contemporary Reappraisal of Intraoperative Neck Margin Assessment During Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma: A Review.

JAMA Surg 2021 Feb 3. Epub 2021 Feb 3.

Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.

Importance: Although margin-negative (R0) resection is the gold standard for surgical management of localized pancreatic ductal adenocarcinoma (PDAC), the question of how to manage the patient with a microscopically positive intraoperative neck margin (IONM) during pancreaticoduodenectomy remains controversial.

Observations: In the absence of randomized clinical trials, we critically evaluated high-quality retrospective studies examining the oncologic utility of re-resecting positive IONMs during pancreaticoduodenectomy for PDAC (2000-2019). Several studies have concluded that additional pancreatic resection to achieve an R0 margin in IONM-positive cases does not influence survival. The largest is a multi-institutional study of 1399 patients undergoing pancreaticoduodenectomy, which demonstrated that in comparison with patients undergoing R0 resection (n = 1196; median survival, 21 months), those with either final R1 resections (n = 131) or undergoing margin conversion from IONM-positive to R0 resection on permanent section (n = 72) demonstrated similar median survival times (13.7 and 11.9 months, respectively). Conversely, recent reports suggest that the conversion of IONM to R0 resection with additional resection or even total pancreatectomy may be associated with improved survival. The discordance between these conflicting studies could be explained in part by the influence of biologic and physiologic selection on the association of IONM re-resection and survival. Since most studies did not include patients receiving modern combination chemotherapy regimens, the intersection between margin status, tumor biology, and chemoresponsiveness remains unclear. Furthermore, there are no dedicated data to guide surgical management in IONM-positive pancreaticoduodenectomy for patients receiving neoadjuvant chemotherapy.

Conclusions And Relevance: Although data regarding the oncologic utility of additional resection to achieve a tumor-free margin following initial IONM positivity during pancreaticoduodenectomy for PDAC are conflicting, they suggest that IONM positivity may be a surrogate for biologic aggressiveness that is unlikely to be mitigated by the extent of surgical resection. The complex relationship between margin status and chemoresponsiveness warrants exploration in studies including patients receiving increasingly effective neoadjuvant chemotherapy.
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http://dx.doi.org/10.1001/jamasurg.2020.5676DOI Listing
February 2021

Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Treatment Does Not Predict Pathological Response and Survival in Resectable Pancreatic Ductal Adenocarcinoma.

Am Surg 2021 Jan 31:3134821989050. Epub 2021 Jan 31.

Department of Surgery, 5803Memorial Sloan Kettering Cancer Center, NY, USA.

Background: Neutrophil-to-lymphocyte ratio (NLR) has been reported as prognostic in pancreatic ductal adenocarcinoma (PDAC). Data about NLR changes during neoadjuvant therapy (NAT) and its relationship with pathological tumor response and survival are lacking.

Methods: Pancreatic ductal adenocarcinoma patients with NAT followed by resection between 2009 and 2015 were identified from a prospective database. Neutrophil-to-lymphocyte ratio was collected prior to NAT (baseline), on chemotherapy (prior to cycle 3), and prior to surgery. Baseline NLR, and changes in NLR between baseline and on chemotherapy (delta 1) and between baseline and surgery (delta 2) were compared with pathologic response (<90% and ≥90% defined as poor and good), overall (OS), and disease-free survival (DFS) using Wilcoxon rank-sum and Cox proportional hazard models.

Results: Of 93 patients, 17% had good pathological response. Median (interquartile range) NLR at baseline, third cycle, and surgery were 2.7 (2.0-3.7), 2.5 (1.9-4.1), and 3.1 (2.1-5.3), respectively. Median change in NLR from baseline to third cycle was .06 ( = .72), and .6 from baseline to surgery ( < .01). Baseline NLR, delta 1, and delta 2 were not associated with pathological response, OS, or DFS.

Discussion: Neutrophil-to-lymphocyte ratio increased after NAT, but a significant association between NLR and pathological response, OS, and DFS in resected PDAC patients was not observed.
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http://dx.doi.org/10.1177/0003134821989050DOI Listing
January 2021

Is minimally invasive surgery of lesions in the right superior segments of the liver justified? A multi-institutional study of 245 patients.

J Surg Oncol 2020 Dec 16;122(7):1428-1434. Epub 2020 Aug 16.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Controversy exists regarding the safety and feasibility of minimally invasive resection for lesions in segments 7 or 8. We compare outcomes of minimally invasive surgery (MIS) and Open parenchymal sparing liver resections at two high-volume centers.

Methods: From 2003 to 2016 we identified patients who underwent MIS or Open resections for lesions in segments 7 or 8 at two institutions (MSKCC and SGH). Outcomes were compared using univariate and multivariate analyses.

Results: Two-hundred and forty-five patients underwent resection of lesions in segments 7 or 8 (MIS 30% and Open 70%). Compared to the Open group, the MIS group had longer operative time (223 ± 88 vs 188 ± 72 minutes, P = .003), lower blood loss (297 ± 287 vs 448 ± 670 mL, P = .03), and shorter mean length of stay (5.2 ± 7.4 vs 8.3 ± 11.7 days, P < .001), which remained significant on multivariate analysis. No differences in Pringle time, rate of postoperative complications, or R0 resections were detected.

Conclusions: With appropriately selected patients treated by experienced MIS hepatopancreatobiliary surgeons, MIS resection of segments 7 or 8 is safe with similar rates of complications and R0 resections, with significantly less blood loss and shorter length of stay.
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http://dx.doi.org/10.1002/jso.26154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978501PMC
December 2020

Impact of Primary Tumor Laterality on Adjuvant Hepatic Artery Infusion Pump Chemotherapy in Resected Colon Cancer Liver Metastases: Analysis of 487 Patients.

Ann Surg Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Hepatic artery infusion (HAI) chemotherapy is associated with overall survival (OS) in patients with resected colon cancer liver metastases (CLM). The prognostic impact of primary tumor location in CLM following hepatic resection in patients receiving regional HAI is unknown. This study seeks to investigate the prognostic impact of HAI in relation to laterality in this patient population.

Methods: Consecutive patients with resected CLM, with known primary tumor site treated with and without HAI, were reviewed from a prospective institutional database. Correlations between HAI, laterality, other clinicopathological factors, and survival were analyzed, and Cox proportional hazard regression was used to determine whether laterality was an independent prognostic factor.

Results: From 1993 to 2012, 487 patients [182 with right colon cancer (RCC), 305 with left colon cancer (LCC)] were evaluated with a median follow-up of 6.5 years. Fifty-seven percent (n = 275) received adjuvant HAI. Patients with RCC had inferior 5-year OS compared with LCC (56% vs. 67%, P = 0.01). HAI was associated with improved 5-year OS in both RCC (68% vs. 45%; P < 0.01) and LCC (73% vs. 55%; P < 0.01). On multivariable analysis, HAI remained associated with improved OS (HR 0.52; 95% CI 0.39-0.70; P < 0.01) but primary tumor site did not (HR 0.83; 95% CI 0.63-1.11; P = 0.21). Additional significant prognostic factors on multivariable analysis included age, number of tumors, node-positive primary, positive margins, RAS mutation, two-stage hepatectomy, and extrahepatic disease. Cox proportional hazard regression determined no significant interaction between HAI and laterality on OS [parameter estimate (SEM), 0.12 (0.28); P = 0.67].

Conclusions: Our data show an association of adjuvant HAI and increased OS in patients who underwent curative hepatectomy, irrespective of primary tumor location. Laterality should therefore not impact decision-making when offering adjuvant HAI.
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http://dx.doi.org/10.1245/s10434-020-09369-7DOI Listing
November 2020

Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: To examine genomic correlates of CTR and overall survival (OS) in patients with IU-CRLM treated with combination systemic and hepatic artery infusion (HAI) chemotherapy.

Background: In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored.

Methods: Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation.

Results: Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23, 95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations were associated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease.

Conclusions: Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF, and co-altered RAS/RAF-TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.
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http://dx.doi.org/10.1097/SLA.0000000000004613DOI Listing
November 2020

Preoperative CT predictors of survival in patients with pancreatic ductal adenocarcinoma undergoing curative intent surgery.

Abdom Radiol (NY) 2020 Sep 28. Epub 2020 Sep 28.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected pancreatic ductal adenocarcinoma (PDAC).

Methods: This retrospective analysis included consecutive patients with PDAC who consented to genomic tumor testing and underwent preoperative imaging and curative intent surgical resection from December 2006 to July 2017. Two radiologists assessed preoperative CT imaging using the APA/SAR PDAC-reporting template. Univariable associations between overall survival and imaging variables were evaluated using Cox proportional hazards regression.

Results: The study included 168 patients (66 years ± 11; 91 women). 126/168 patients (75%) received upfront surgical resection whereas 42/168 (25%) received neoadjuvant therapy prior to surgical resection. In the entire cohort, features associated with decreased overall survival were tumor arterial contact of any kind (hazard ratio (HR) 1.89, 95% CI 1.13-3.14, p = 0.020), tumor contact with the common hepatic artery (HR 2.33, 95% CI 1.35-4.04, p = 0.009), and portal vein deformity (HR 3.22, 95% CI 1.63-6.37, p = 0.003). In the upfront surgical group, larger tumor size was associated with decreased overall survival (HR 2.30, 95% CI 1.19-4.42, p = 0.013). In the neoadjuvant therapy group, the presence of venous collaterals was the only feature associated with decreased overall survival (HR 2.28, 95% CI 1.04-4.99, p = 0.042).

Conclusion: The application of the APA/SAR pancreatic adenocarcinoma reporting template may identify predictors of survival that can aid in preoperative stratification of patients.
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http://dx.doi.org/10.1007/s00261-020-02726-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004545PMC
September 2020

Extrahepatic recurrence rates in patients receiving adjuvant hepatic artery infusion and systemic chemotherapy after complete resection of colorectal liver metastases.

J Surg Oncol 2020 Dec 25;122(8):1536-1542. Epub 2020 Sep 25.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection.

Methods: Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time-to-organ recurrence.

Results: Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow-up for survivors was 100 (range = 12-185) and 156 months (range = 18-217) for SYS and HAI + SYS, respectively. The 5-year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5-year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS.

Conclusion: Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.
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http://dx.doi.org/10.1002/jso.26221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938716PMC
December 2020

Differences in Liver Parenchyma are Measurable with CT Radiomics at Initial Colon Resection in Patients that Develop Hepatic Metastases from Stage II/III Colon Cancer.

Ann Surg Oncol 2021 Apr 20;28(4):1982-1989. Epub 2020 Sep 20.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Currently, there are no methods to identify patients with an increased risk of liver metastases to guide patient selection for liver-directed therapies. We tried to determine whether quantitative image features (radiomics) of the liver obtained from preoperative staging CT scans at the time of initial colon resection differ in patients that subsequently develop liver metastases, extrahepatic metastases, or demonstrate prolonged disease-free survival.

Methods: Patients who underwent resection of stage II/III colon cancer from 2004 to 2012 with available preoperative CT scans were included in this single-institution, retrospective case-control study. Patients were grouped by initial recurrence patterns: liver recurrence, extrahepatic recurrence, or no evidence of disease at 5 years. Radiomic features of the liver parenchyma extracted from CT images were compared across groups.

Results: The cohort consisted of 120 patients divided evenly between three recurrence groups, with an equal number of stage II and III patients in each group. After adjusting for multiple comparisons, 44 of 254 (17%) imaging features displayed different distributions across the three patient groups (p < 0.05), with the clearest distinction between those with liver recurrence and no evidence of disease. Increased heterogeneity in the liver parenchyma by radiomic analysis was protective of liver metastases.

Conclusions: CT radiomics is a promising tool to identify patients at high risk of developing liver metastases and is worthy of further investigation and validation.
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http://dx.doi.org/10.1245/s10434-020-09134-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940539PMC
April 2021

Early liver metastases after "failure" of adjuvant chemotherapy for stage III colorectal cancer: is there a role for additional adjuvant therapy?

HPB (Oxford) 2021 Apr 14;23(4):601-608. Epub 2020 Sep 14.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The utility of adjuvant chemotherapy after resection of colorectal liver metastasis (CLM) in patients with rapid recurrence after adjuvant chemotherapy for their primary tumor is unclear. The aim of this study was to evaluate the oncologic benefit of adjuvant hepatic arterial plus systemic chemotherapy (HAIC + Sys) in patients with early CLM.

Methods: A retrospective analysis of patients with early CLM (≤12 months of adjuvant chemotherapy for primary tumor) who received either HAIC + Sys, adjuvant systemic chemotherapy alone (Sys), or active surveillance (Surgery alone) following resection of CLM was performed. Recurrence and survival were compared between treatment groups using Kaplan-Meier methods and Cox proportional hazards models.

Results: Of 239 patients undergoing resection of early CLM, 79 (33.1%) received HAIC + Sys, 77 (32.2%) received Sys, and 83 (34.7%) had Surgery alone. HAIC + Sys was independently associated with reduced risk of RFS events (adjusted hazard ratio [HRadj]: 0.64, 95%CI:0.44-0.94, p = 0.022) and all-cause mortality (HRadj: 0.54, 95%CI:0.36-0.81, p = 0.003) compared to Surgery alone patients. Largest tumor >5 cm (HRadj: 2.03, 95%CI: 1.41-2.93, p < 0.001) and right-sided colon tumors (HRadj: 1.93, 95%CI: 1.29-2.89, p = 0.002) were independently associated with worse OS.

Conclusion: Adjuvant HAIC + Sys after resection of early CLM that occur after chemotherapy for node-positive primary is associated with improved outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.08.018DOI Listing
April 2021

Defining postoperative weight change after pancreatectomy: Factors associated with distinct and dynamic weight trajectories.

Surgery 2020 Dec 14;168(6):1041-1047. Epub 2020 Sep 14.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: Weight change offers the simplest indication of a patient's recovery after an operation. There have been no studies that have thoroughly investigated postoperative weight dynamics after pancreatectomy. The aim of this study was to define postoperative weight change after a pancreatectomy and determine factors associated with optimal and poor weight trajectories.

Methods: From 2004 to 2019, 1,090 proximal (65%) and distal (35%) pancreatectomies were performed in patients with adequate data in the medical records. Patient weights were acquired preoperatively and at postoperative months 1, 3, and 12. Optimal (top quartile, weight restoration) and poor (bottom quartile, persistent weight loss) postoperative weight cohorts were identified at 1 year postoperatively.

Results: The median percentage weight change 1 year postpancreatectomy was -6.6% (interquartile range: -1.4% to -12.5%), -7.8% for proximal pancreatectomy, and -4.2% for distal pancreatectomy. For most patients (interquartile range cohort), the median percentage weight change at 1, 3, and 12 months was -6.2%, -7.2%, and -6.6%. The independent factors associated with weight restoration were age <65, nonobesity (body mass index <30kg/m), receiving total parenteral nutrition/total enteral nutrition preoperatively, experiencing preoperative weight loss >10%, distal pancreatectomy, not undergoing vascular resection, and no readmission within 30 days. Conversely, persistent weight loss was associated with American Society of Anesthesiologists classes III to IV, obesity, malignancy, proximal pancreatectomy, blood loss ≥350mL, and experiencing readmission within 30 days. Focusing on pancreatic ductal adenocarcinoma (n = 372) patients, the factors associated with persistent weight loss were obesity, proximal pancreatectomy, and experiencing recurrence within 1 year; however, weight cohorts were not associated with overall survival for pancreatic ductal adenocarcinoma patients.

Conclusion: These data define weight kinetics after pancreatectomy. Ultimately, postoperative weight trajectories appear to be largely predetermined but may be mitigated by limiting readmissions and complications. Clinicians should use these data to identify patients who continue to lose weight between the first and third month postoperatively with a high suspicion for the requirement of nutritional monitoring or other interventions.
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http://dx.doi.org/10.1016/j.surg.2020.07.056DOI Listing
December 2020

A contemporary analysis of palliative procedures in aborted pancreatoduodenectomy: Morbidity, mortality, and impact on future therapy.

Surgery 2020 Dec 1;168(6):1026-1031. Epub 2020 Sep 1.

Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.

Background: Periampullary malignancies are often unresectable tumors that frequently cause biliary or duodenal obstruction. Advances in endoscopic and percutaneous options have lessened the need for operative palliation. Nevertheless, many patients are still found to be unresectable at the time of exploration, making palliative bypass a consideration. Several prior studies have examined the morbidity of operative palliation, but many were conducted over lengthy time periods, and few have examined the impact of these procedures on future therapy. This study is a contemporary analysis of the short- and long-term outcomes of palliative bypass procedures for unresectable periampullary malignancies at a single high-volume institution.

Methods: We identified a contemporary cohort of patients in whom a pancreatoduodenectomy was planned for periampullary malignancy but instead underwent an aborted procedure. Patients were divided into 5 procedure groups: laparoscopy only, laparotomy with or without cholecystectomy, gastrointestinal bypass, biliary bypass, and double bypass (gastrointestinal and biliary). Data regarding the patient cohort, procedures, morbidity/mortality, and the interval to initiation of systemic therapy were collected prospectively and reviewed retrospectively.

Results: Between July 2011 and November 2018, 128 out of 615 (17%) patients had an aborted pancreatoduodenectomy; 113 out of 128 patients had pancreatic adenocarcinoma, and 86 (67.1%) had duodenal or biliary obstruction at the time of operation. Patients who underwent laparoscopy only (n = 34) had no operative complications and a 90-day mortality of 6%; 88% of these patients went on to receive systemic therapy (median 21 days postprocedure). Double bypass was associated with a far lesser complication rate than in prior studies; 17% of patients had some complication(s), but only 9% had a severe complication. The 90-day all-cause mortality was 13%, and only 71% of these patients went on to receive systemic therapy (median 47 days postprocedure). Notably, 27 out of 34 (79%) of patients who underwent laparoscopy alone needed additional procedures for local obstruction, whereas only 5 out of 42 (12%) double bypass patients needed additional interventions. Median survival for the entire cohort was 10.3 months.

Conclusion: Palliative procedures in this cohort had a far lesser complication rate than that of historical series. Palliative procedures, however, delayed systemic therapy, and a fair number of patients never received additional treatments. Palliative procedures markedly decreased the need for future interventions. Intraoperative decisions regarding palliative procedures must incorporate the functional status and motivations of the patient; these procedures are increasingly safe but may still affect survival.
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http://dx.doi.org/10.1016/j.surg.2020.06.041DOI Listing
December 2020

Adjuvant Hepatic Artery Infusion Chemotherapy is Associated With Improved Survival Regardless of KRAS Mutation Status in Patients With Resected Colorectal Liver Metastases: A Retrospective Analysis of 674 Patients.

Ann Surg 2020 08;272(2):352-356

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: To investigate the impact of adjuvant hepatic artery infusion (HAI) in relation to KRAS mutational status in patients with resected colorectal cancer liver metastases (CRLM).

Background: Patients with KRAS-mutated CRLM have worse outcomes after resection. Adjuvant HAI chemotherapy improves overall survival after liver resection.

Methods: Patients with resected CRLM treated at MSKCC with and without adjuvant HAI who had available KRAS status (wild-type, WT; mutated, MUT) were reviewed from a prospectively maintained institutional database. Correlations between KRAS status, adjuvant HAI, clinical factors, and outcomes were analyzed. Cox proportional hazard model was used to adjust for confounders.

Results: Between 1993 and 2012, 674 patients (418 KRAS-WT, 256 MUT) with a median follow up of 6.5 years after resection were evaluated. Fifty-four percent received adjuvant HAI. Tumor characteristics (synchronous disease, number of lesions, clinical-risk score, 2-stage hepatectomy) were significantly worse in the HAI group; however, there were more patients with resected extrahepatic metastases in the no-HAI group. In KRAS-WT tumors, 5-year survival was 78% for patients treated with HAI versus 57% for patients without HAI [hazard ratio (HR) 0.51, P < 0.001]. In KRAS-MUT tumors, 5-year survival was 59% for patients treated with HAI versus 40% for patients without HAI (HR 0.56, P < 0.001). On multivariate analysis, HAI remained associated with improved OS (HR 0.53, P < 0.002) independent of KRAS status and other clinicopathologic factors.

Conclusion: Adjuvant HAI after resection of CRLM is independently associated with improved outcomes regardless of KRAS mutational status. Adjuvant HAI may mitigate the worse outcomes seen in patients with resectable KRAS-MUT CRLM.
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http://dx.doi.org/10.1097/SLA.0000000000003248DOI Listing
August 2020

Recurrence After Liver Resection of Colorectal Liver Metastases: Repeat Resection or Ablation Followed by Hepatic Arterial Infusion Pump Chemotherapy.

Ann Surg Oncol 2021 Feb 9;28(2):808-816. Epub 2020 Jul 9.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.

Background: The aim of this study was to investigate the effectiveness of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after complete resection or ablation of recurrent colorectal liver metastases (CRLM).

Methods: A retrospective cohort study was conducted of patients from two centers who were treated with resection and/or ablation of recurrent CRLM only between 1992 and 2018. Overall survival (OS) and hepatic disease-free survival (hDFS) were estimated using the Kaplan-Meier method. The Cox regression method was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CI).

Results: Of 374 eligible patients, 81 (22%) were treated with adjuvant HAIP chemotherapy. The median follow-up for survivors was 65 months (IQR 32-118 months). Patients receiving adjuvant HAIP were more likely to have multifocal disease and receive perioperative systemic chemotherapy at time of resection for recurrence. A median hDFS of 46 months (95% CI 29-81 months) was found in patients treated with adjuvant HAIP compared with 18 months (95% CI 15-26 months) in patients treated with resection and/or ablation alone (p = 0.001). The median OS and 5-year OS were 89 months (95% CI 52-126 months) and 66%, respectively, in patients treated with adjuvant HAIP compared with 57 months (95% CI 47-67 months) and 47%, respectively, in patients treated with resection and/or ablation only (p = 0.002). Adjuvant HAIP was associated with superior hDFS (adjusted HR 0.599, 95% CI 0.38-0.93, p = 0.02) and OS (adjusted HR 0.59, 95% CI 0.38-0.92, p = 0.02) in multivariable analysis.

Conclusion: Adjuvant HAIP chemotherapy after resection and/or ablation of recurrent CRLM is associated with superior hDFS and OS.
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http://dx.doi.org/10.1245/s10434-020-08776-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801355PMC
February 2021

Multimodal radiomics and cyst fluid inflammatory markers model to predict preoperative risk in intraductal papillary mucinous neoplasms.

J Med Imaging (Bellingham) 2020 May 25;7(3):031507. Epub 2020 Jun 25.

Queen's University, School of Computing, Kingston, Ontario, Canada.

Our paper contributes to the burgeoning field of surgical data science. Specifically, multimodal integration of relevant patient data is used to determine who should undergo a complex pancreatic resection. Intraductal papillary mucinous neoplasms (IPMNs) represent cystic precursor lesions of pancreatic cancer with varying risk for malignancy. We combine previously defined individual models of radiomic analysis of diagnostic computed tomography (CT) with protein markers extracted from the cyst fluid to create a unified prediction model to identify high-risk IPMNs. Patients with high-risk IPMN would be sent for resection, whereas patients with low-risk cystic lesions would be spared an invasive procedure. Retrospective analysis of prospectively acquired cyst fluid and CT scans was undertaken for this study. A predictive model combining clinical features with a cyst fluid inflammatory marker (CFIM) was applied to patient data. Quantitative imaging (QI) features describing radiomic patterns predictive of risk were extracted from scans. The CFIM model and QI model were combined into a single predictive model. An additional model was created with tumor-associated neutrophils (TANs) assessed by a pathologist at the time of resection. Thirty-three patients were analyzed (7 high risk and 26 low risk). The CFIM model yielded an area under the curve (AUC) of 0.74. Adding the QI model improved performance with an AUC of 0.88. Combining the CFIM, QI, and TAN models further increased performance to an AUC of 0.98. Quantitative analysis of routinely acquired CT scans combined with CFIMs provides accurate prediction of risk of pancreatic cancer progression. Although a larger cohort is needed for validation, this model represents a promising tool for preoperative assessment of IPMN.
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http://dx.doi.org/10.1117/1.JMI.7.3.031507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315109PMC
May 2020

Hepatocellular carcinoma in patients with no identifiable risk factors.

HPB (Oxford) 2021 Jan 24;23(1):118-126. Epub 2020 Jun 24.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: A subset of patients have no risk factors for the development of hepatocellular carcinoma (HCC). We evaluated differences in clinical variables between patients with and without risk factors who underwent surgical resection.

Methods: A prospectively maintained database was queried for patients who underwent R0/R1 resection of HCC between 1992 and 2016. Risk factors included HCV, HBV, hemochromatosis, alcoholic liver disease, or cirrhosis, stage 2 or 3 fibrosis or severe (>66%) steatosis of the non-neoplastic liver. Variables were compared between patients with and without risk factors.

Results: There were 416 patients who underwent resection; 276 (66%) had known risk factors while 140 (34%) did not. Patients without risk factors were more likely to be older, female and have hyperlipidemia or coronary artery disease (p < 0.004). These patients had larger tumors and were more likely to undergo major hepatectomy (p < 0.001). There was no difference in OS (5-year, 56% vs 47%, p = 0.335), RFS (27% vs 24%, p = 0.398), or the rates of intrahepatic (HR:1.16 [95%CI:0.95-1.57], p = 0.344) and extrahepatic recurrences (HR:0.72 [95%CI:0.4-1.3], p = 0.261) between groups.

Conclusion: Patients without risk factors for HCC presented with larger tumors yet had similar outcomes, suggesting these tumors may represent a different disease process, and underlying liver dysfunction can influence overall outcome.
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http://dx.doi.org/10.1016/j.hpb.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022289PMC
January 2021

Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma.

Cancer 2020 Sep 23;126(17):3939-3949. Epub 2020 Jun 23.

Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection.

Methods: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed.

Results: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035).

Conclusions: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.
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http://dx.doi.org/10.1002/cncr.33038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424538PMC
September 2020

Detailed Analysis of Margin Positivity and the Site of Local Recurrence After Pancreaticoduodenectomy.

Ann Surg Oncol 2021 Jan 25;28(1):539-549. Epub 2020 May 25.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering, New York, NY, USA.

Background: The association between a positive surgical margin and local recurrence after resection of pancreatic adenocarcinoma (PDAC) has been reported. Assessment of the location of the a positive margin and the specific site of local recurrence has not been well described.

Methods: A prospectively maintained database was queried for patients who underwent R0/R1 pancreaticoduodenectomy for PDAC between 2000 and 2015. The pancreatic, posterior, gastric/duodenal, anterior peritoneal, and bile duct margins were routinely assessed. Postoperative imaging was reviewed for the site of first recurrence, and local recurrence was defined as recurrence located in the remnant pancreas, surgical bed, or retroperitoneal site outside the surgical bed.

Results: During the study period, 891 patients underwent pancreaticoduodenectomy, and 390 patients had an initial local recurrence with or without distant metastases. The 5-year cumulative incidence of local recurrence by site included the remnant pancreas (4%; 95% confidence interval [CI], 3-5%), the surgical bed (35%; 95% CI, 32-39%), and other regional retroperitoneal site (4%; 95% CI, 3-6%). In the univariate analysis, positive posterior margin (hazard ratio [HR], 1.50; 95% CI, 1.17-1.91; p = 0.001) and positive lymph nodes (HR, 1.36; 95% CI, 1.06-1.75; p = 0.017) were associated with surgical bed recurrence, and in the multivariate analysis, positive posterior margin remained significant (HR, 1.40; 95% CI, 1.09-1.81; p = 0.009). An isolated local recurrence was found in 197 patients, and a positive posterior margin was associated with surgical bed recurrence in this subgroup (HR, 1.51; 95% CI, 1.08-2.10; p = 0.016).

Conclusion: In this study, the primary association between site of margin positivity and site of local recurrence was between the posterior margin and surgical bed recurrence. Given this association and the limited ability to modify this margin intraoperatively, preoperative assessment should be emphasized.
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http://dx.doi.org/10.1245/s10434-020-08600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918294PMC
January 2021

Invasive central venous monitoring during hepatic resection: unnecessary for most patients.

HPB (Oxford) 2020 Dec 23;22(12):1732-1737. Epub 2020 Apr 23.

Memorial Sloan Kettering Cancer Center, 1275 York Avenue, 10065, New York, NY, USA.

Background: Low central venous pressure (LCVP) anesthesia reduces blood loss during hepatic resection and historically has required a central venous catheter (CVC) for intra-operative monitoring. The aim of this study was to assess the effect of an evolution of practice to CVP monitoring without CVC on the perioperative outcomes after liver resection.

Methods: A retrospective study of partial hepatectomy patients from 2007 to 2016 who were over 18 years of age was performed.

Results: Of 3903 patients having partial hepatectomy, 2445 (62%) met inclusion criteria, and 404 (16%) had a CVC. Overall morbidity (33% non-CVC vs 38% CVC P = 0.076), major morbidity (16% vs 20% P = 0.067), and infective complications (superficial wound infection) 3% vs 4% P = 0.429; deep wound infection (5% vs 6% P = 0.720) did not differ between the two groups. In multivariate analysis, superficial wound infection, deep wound infection, and major complications were not associated with the presence of a CVC. All-cause mortality at 90 days was associated with CVC presence (OR 3.45, CI 1.74-6.85, P = 0.001) and age (OR 1.05, CI 1.02-1.08, P < 0.001).

Conclusion: Since the adoption of non-invasive CVP monitoring, there has been no increase in adverse peri-operative outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581625PMC
December 2020

Addition of adjuvant hepatic artery infusion to systemic chemotherapy following resection of colorectal liver metastases is associated with reduced liver-related mortality.

J Surg Oncol 2020 Jun 31;121(8):1314-1319. Epub 2020 Mar 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, New York.

Background: After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS).

Objective: This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared to adjuvant SYS alone.

Methods: Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI + SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risk methods.

Results: Of 361 eligible patients, 208 (57.6%) received HAI + SYS and 153 (42.4%) received SYS. The median follow up among survivors was 142 months (range = 12-217 months). Ten-year overall survival was 50.6% in the HAI + SYS group compared to 30.9% in those receiving SYS (P = .004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI + SYS group compared to 14.3% in the SYS group (P = .007).

Conclusion: The addition of HAI to SYS after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.
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http://dx.doi.org/10.1002/jso.25916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927157PMC
June 2020

Extended Experience with a Dynamic, Data-Driven Selective Drain Management Protocol in Pancreaticoduodenectomy: Progressive Risk Stratification for Better Practice.

J Am Coll Surg 2020 05 17;230(5):809-818.e1. Epub 2020 Feb 17.

Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA. Electronic address:

Background: Intraoperative drain use for pancreaticoduodenectomy has been practiced in an unconditional, binary manner (placement/no placement). Alternatively, dynamic drain management has been introduced, incorporating the Fistula Risk Score (FRS) and drain fluid amylase (DFA) analysis, to mitigate clinically relevant postoperative pancreatic fistula (CR-POPF).

Study Design: An extended experience with dynamic drain management was used at a single institution for 400 consecutive pancreaticoduodenectomies (2014 to 2019). This protocol consists of the following: drains omitted for negligible/low-risk FRS (0 to 2) and drains placed for moderate/high-risk FRS (3 to 10) with early (postoperative day [POD] 3) removal if POD1 DFA ≤5,000 U/L. Adherence to this protocol was prospectively annotated and outcomes were retrospectively analyzed.

Results: The overall CR-POPF rate was 8.7%, with none occurring in the negligible/low-risk cases. Moderate/high-risk patients manifested an 11.9% CR-POPF rate (n = 35 of 293), which was lower on-protocol (9.5% vs 21%; p = 0.014). After drain placement, POD1 DFA ≥5,000 U/L was a better predictor of CR-POPF than FRS (odds ratio 14.7; 95% CI, 4.3 to 50.3). For POD1 DFA ≤5,000 U/L, early drain removal was associated with fewer CR-POPFs (2.8% vs 23.5%; p < 0.001), and substantiated by multivariable analysis (odds ratio 0.09; 95% CI, 0.03 to 0.28). Surgeon adherence was inversely related to CR-POPF rate (R = 0.846).

Conclusions: This extended experience validates a dynamic drain management protocol, providing a model for better drain management and individualized patient care after pancreaticoduodenectomy. This study confirms that drains can be safely omitted from negligible/low-risk patients, and moderate/high-risk patients benefit from early drain removal.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.01.028DOI Listing
May 2020

The North American Neuroendocrine Tumor Society Consensus Paper on the Surgical Management of Pancreatic Neuroendocrine Tumors.

Pancreas 2020 01;49(1):1-33

Department of Surgery, Oregon Health & Science University, Portland, OR.

This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the surgical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The group reviewed a series of questions of specific interest to surgeons taking care of patients with pancreatic neuroendocrine tumors, and for each, the available literature was reviewed. What follows are these reviews for each question followed by recommendations of the panel.
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http://dx.doi.org/10.1097/MPA.0000000000001454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029300PMC
January 2020

Epithelial to mesenchymal plasticity and differential response to therapies in pancreatic ductal adenocarcinoma.

Proc Natl Acad Sci U S A 2019 12 16. Epub 2019 Dec 16.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114;

Transcriptional profiling has defined pancreatic ductal adenocarcinoma (PDAC) into distinct subtypes with the majority being classical epithelial (E) or quasi-mesenchymal (QM). Despite clear differences in clinical behavior, growing evidence indicates these subtypes exist on a continuum with features of both subtypes present and suggestive of interconverting cell states. Here, we investigated the impact of different therapies being evaluated in PDAC on the phenotypic spectrum of the E/QM state. We demonstrate using RNA-sequencing and RNA-in situ hybridization (RNA-ISH) that FOLFIRINOX combination chemotherapy induces a common shift of both E and QM PDAC toward a more QM state in cell lines and patient tumors. In contrast, Vitamin D, another drug under clinical investigation in PDAC, induces distinct transcriptional responses in each PDAC subtype, with augmentation of the baseline E and QM state. Importantly, this translates to functional changes that increase metastatic propensity in QM PDAC, but decrease dissemination in E PDAC in vivo models. These data exemplify the importance of both the initial E/QM subtype and the plasticity of E/QM states in PDAC in influencing response to therapy, which highlights their relevance in guiding clinical trials.
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http://dx.doi.org/10.1073/pnas.1914915116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936349PMC
December 2019

Defining the Safety Profile for Performing Pancreatoduodenectomy in the Setting of Hyperbilirubinemia.

Ann Surg Oncol 2020 May 5;27(5):1595-1605. Epub 2019 Nov 5.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Hyperbilirubinemia is commonly observed in patients requiring pancreatoduodenectomy (PD). Thus far, literature regarding the danger of operating in the setting of hyperbilirubinemia is equivocal. What remains undefined is at what specific level of bilirubin there is an adverse safety profile for undergoing PD. The aim of this study is to identify the optimal safety profile of patients with hyperbilirubinemia undergoing PD.

Patients And Methods: The present work analyzed 803 PDs from 2004 to 2018. A generalized additive model was used to determine cutoff values of total serum bilirubin (TB) that were associated with increases in adverse outcomes, including 90-day mortality. Subgroup comparisons and biliary stent-specific analyses were performed for patients with TB below and above the cutoff.

Results: TB of 13 mg/dL was associated with an increase in 90-day mortality (P = 0.043) and was the dominant risk factor on multivariate logistic regression [odds ratio (OR) 8.193, P = 0.001]. Increased TB levels were also associated with reoperations, number of complications per patient, and length of stay. Patients with TB greater than or equal to 13 mg/dL (TB ≥ 13) who received successful biliary decompression through stenting had less combined death and serious morbidity (P = 0.048).

Conclusions: Preoperative TB ≥ 13 mg/dL was associated with increased 90-day mortality after PD. Reducing a TB ≥ 13 is generally recommended before proceeding to surgery.
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http://dx.doi.org/10.1245/s10434-019-08044-wDOI Listing
May 2020

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, Setting, And Participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main Outcomes And Measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions And Relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2019.3718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824231PMC
October 2019

Prediction of Recurrence Patterns from Hepatic Parenchymal Disease After Resection of Colorectal Liver Metastases.

Ann Surg Oncol 2020 Jan 15;27(1):188-195. Epub 2019 Oct 15.

Department of Surgery, Hepatopancreatobiliary Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Obesity and metabolic syndrome are associated with inflammatory hepatic parenchymal disease (HPD) and increased risk for recurrence after resection of colorectal liver metastases (CRLM). The independent impact of HPD on recurrence patterns has not been well defined.

Methods: The nonalcoholic fatty liver disease activity score (NAS) was used to quantify HPD including steatosis and fibrosis for all patients with completely resected CRLM between April 2003 and March 2007. Clinicopathologic factors, perioperative history, and outcomes were compared with the NAS. Fisher's exact test was used to examine the association between severe HPD (NAS ≥ 3) with clinical and perioperative characteristics. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS). The cumulative incidences of recurrence [any intrahepatic recurrence (IHR), extrahepatic recurrence only (EHR), and death without recurrence (DWR)] were estimated using competing risks methods.

Results: Among the 357 patients included in this study, microsteatosis was noted in 124 (35%) patients, severe HPD in 31 (9%), steatohepatitis in 14 (4%), and sinusoidal injury in 36 (10%). After median follow-up of 127 months (range 4-175 months), 10-year RFS was 22% [95% confidence interval (CI) 17-27%]. Ten-year cumulative incidence for IHR, EHR, and DWR was 37%, 30%, and 12%, respectively. After controlling for confounders, NAS ≥ 3 was independently associated with higher risk of IHR [hazard ratio (HR) 1.76, 95% CI 1.07-2.90, p = 0.027] and lower risk of EHR (HR 0.18, 95% CI 0.04-0.75, p = 0.019) on multivariable analysis.

Conclusions: Severe HPD was associated with increased IHR risk and decreased EHR risk. Future investigation into whether improving HPD from reversible etiologies can reduce the risk for IHR is warranted.
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http://dx.doi.org/10.1245/s10434-019-07934-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061284PMC
January 2020

Lending a hand for laparoscopic distal pancreatectomy: the optimal approach?

HPB (Oxford) 2020 05 7;22(5):690-701. Epub 2019 Oct 7.

Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address:

Background: Both minimally invasive surgery (MIS) and open approaches for distal pancreatectomy are acceptable. MIS options include total laparoscopic/robotic (TLR) and hand-assist laparoscopy (HAL). When considering safety profile and specimen quality, the optimal approach is unknown.

Methods: Patients who underwent distal pancreatectomy from 2010-2018 at two major academic institutions were included. Converted procedures were categorized into final approach. Ninety-day perioperative/pathologic outcomes of MIS and open were compared. Subset analyses between TLR vs HAL and HAL vs open were performed. Intent-to-treat analysis was performed.

Results: Among 1006 patients, resection was performed by MIS in 35% (n = 352), open in 65% (n = 654). MIS had similar patient comorbidity profile as open but had increased operative time (183 vs 162 min; p < 0.01), lower estimated-blood-loss (EBL; 131 vs 341 mL; p < 0.01), fewer intraoperative blood transfusions (1.4 vs 5%; p < 0.01), shorter LOS (5.2 vs 7.2 days; p < 0.01). Tumor size was smaller (3.2 vs 4.4 cm; p < 0.01) with lower lymph node (LN) yield (14 vs 16; p < 0.01). When comparing HAL (n = 109) to TLR (n = 243), despite increased prior abdominal operations (60 vs 43%; p = 0.008), HAL had shorter operative time (167 vs 191 min; p < 0.01), similar length-of-stay (LOS; 5.4 vs 5.1 days; p = 0.27), and readmission rate (15 vs 13%; p = 0.47). When comparing HAL to open, the advantages of TLR approach persisted including lower EBL (171 vs 342 mL; p < 0.01), and shorter LOS (5.4 vs 7.2 days; p < 0.01). Although HAL had smaller tumors, it had a similar LN yield (16 vs 16; p = 0.80), and higher R0-rate (97 vs 83%; p < 0.01).

Conclusion: Hand-assist laparoscopy is safe and feasible for distal pancreatectomy as operative time, complication profile, lymph node yield, and R0-rates are similar to open procedures, while maintaining the associated the advantages of a total laparoscopic/robotic approach with reduced blood loss and shorter length-of-stay.
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http://dx.doi.org/10.1016/j.hpb.2019.09.007DOI Listing
May 2020

Recurrence Patterns After Resection of Colorectal Liver Metastasis are Modified by Perioperative Systemic Chemotherapy.

World J Surg 2020 03;44(3):876-886

Department of Surgery, Erasmus MC Cancer Institute, Erasmus University, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Background: This study investigated the impact of perioperative systemic chemotherapy on the recurrence rate and pattern following resection of colorectal liver metastases.

Methods: A retrospective cohort study was conducted in two centers. Rates and patterns of recurrence and overall survival (OS) were compared between patients treated with and without perioperative systemic chemotherapy. The clinical risk score (CRS) was used to stratify patients in low risk (CRS 0-2) and high risk (CRS 3-5) of recurrence.

Results: A total of 2020 patients were included, of whom 1442 (71%) received perioperative systemic chemotherapy. The median follow-up was 88 months, and 1289 patients (64%) developed a recurrence. The recurrence pattern was independent of chemotherapy in low-risk patients: intrahepatic recurrences (30% vs. 30%, p = 0.97) and extrahepatic recurrences (38% vs. 39%, p = 0.52). In high-risk patients, no difference in intrahepatic recurrences was found (48% vs. 50%, p = 0.59). However, a lower rate of extrahepatic recurrences (43% vs. 55%, p = 0.007) was observed with perioperative systemic chemotherapy, mainly due to a reduction in pulmonary recurrences (25% vs. 35%, p = 0.007). In competing risk analysis, the cumulative incidence of extrahepatic recurrence was significantly lower with perioperative systemic chemotherapy in high-risk patients only (5-year cumulative incidence 44% vs. 59%, p < 0.001). Perioperative chemotherapy was associated with improved OS in high-risk patients (adjusted HR 0.73, 95% CI 0.57-0.94, p = 0.02), but not in low-risk patients (adjusted HR 0.99, 95% CI 0.82-1.19, p = 0.90).

Conclusions: Perioperative systemic chemotherapy had no association with intrahepatic recurrence, but was associated with fewer pulmonary recurrences and superior OS in high-risk patients only.
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http://dx.doi.org/10.1007/s00268-019-05121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668197PMC
March 2020

CT radiomics associations with genotype and stromal content in pancreatic ductal adenocarcinoma.

Abdom Radiol (NY) 2019 09;44(9):3148-3157

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, C-276F, New York, NY, 10065, USA.

Purpose: The aim of this study was to investigate the relationship between CT imaging phenotypes and genetic and biological characteristics in pancreatic ductal adenocarcinoma (PDAC).

Methods: In this retrospective study, consecutive patients between April 2015 and June 2016 who underwent PDAC resection were included if previously consented to a targeted sequencing protocol. Mutation status of known PDAC driver genes (KRAS, TP53, CDKN2A, and SMAD4) in the primary tumor was determined by targeted DNA sequencing and results were validated by immunohistochemistry (IHC). Radiomic features of the tumor were extracted from the preoperative CT scan and used to predict genotype and stromal content.

Results: The cohort for analysis consisted of 35 patients. Genomic and IHC analysis revealed alterations in KRAS in 34 (97%) patients, and changes in expression of CDKN2A in 29 (83%), SMAD4 in 16 (46%), and in TP53 in 29 (83%) patients. Models created from radiomic features demonstrated associations with SMAD4 status and the number of genes altered. The number of genes altered was the only significant predictor of overall survival (p = 0.016). By linear regression analysis, a prediction model for stromal content achieved an R value of 0.731 with a root mean square error of 19.5.

Conclusions: In this study, we demonstrate that in PDAC SMAD4 status and tumor stromal content can be predicted using radiomic analysis of preoperative CT imaging. These data show an association between resectable PDAC imaging features and underlying tumor biology and their potential for future precision medicine.
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http://dx.doi.org/10.1007/s00261-019-02112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692205PMC
September 2019