Publications by authors named "Vinod Balachandran"

104 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

Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

Nat Commun 2021 02 1;12(1):729. Epub 2021 Feb 1.

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

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.
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http://dx.doi.org/10.1038/s41467-021-20935-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851155PMC
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

The association between tumor mutational burden and prognosis is dependent on treatment context.

Nat Genet 2021 01 4;53(1):11-15. Epub 2021 Jan 4.

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

In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICIs). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types before/without ICI treatment or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.
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http://dx.doi.org/10.1038/s41588-020-00752-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796993PMC
January 2021

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

Prognostic Factors After Neoadjuvant Imatinib for Newly Diagnosed Primary Gastrointestinal Stromal Tumor.

J Gastrointest Surg 2020 Nov 9. Epub 2020 Nov 9.

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

Introduction: Neoadjuvant imatinib (Neo-IM) therapy may facilitate R0 resection in primary gastrointestinal stromal tumors (GISTs) that are large or in difficult anatomic locations. While response to preoperative tyrosine kinase inhibitors is associated with better outcome in metastatic GIST, little is known about prognostic factors after Neo-IM in primary GIST.

Study Design: Patients with primary GIST with or without synchronous metastases who underwent Neo-IM were retrospectively analyzed from a prospective maintained institutional database for Response Evaluation Criteria in Solid Tumors (RECIST), tumor viability, and mitotic rate. Overall survival (OS) was estimated by Kaplan-Meier and compared by log-rank test. Cox proportionate hazard models were used for univariate and multivariate analysis.

Results: One hundred and fifty patients were treated for a median of 7.1 months (range 0.2-160). By RECIST, partial response, stable disease, and progressive disease were seen in 40%, 51%, and 9%, respectively. By pathologic analysis, ≤ 50% of the tumor was viable in 72%, and the mitotic rate was ≤ 5/50HPF in 74%. On multivariate analysis, RECIST response and tumor viability were not associated with OS, while post-treatment high mitotic rate (hazard ratio (HR) for death 5.3, CI 2.3-12.4), R2 margins (HR 6.0, CI 2.3-15.5), and adjuvant imatinib (HR 0.4, CI 0.2-0.9) were (p < 0.05). Five-year OS was 81 vs. 38% for low vs. high mitotic rate; 81, 59, and 39% for R0, R1, and R2 margins; and 75 vs 61% for adjuvant vs. no adjuvant imatinib therapy (p < 0.05).

Conclusions: In primary GIST undergoing Neo-IM therapy, progression was uncommon, but substantial down-sizing occurred in the minority. High tumor mitotic rate and incomplete resection following Neo-IM were associated with poor outcome, while adjuvant imatinib was associated with prolonged survival.
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http://dx.doi.org/10.1007/s11605-020-04843-9DOI 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

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

Authors:
Ayuko Hoshino Han Sang Kim Linda Bojmar Kofi Ennu Gyan Michele Cioffi Jonathan Hernandez Constantinos P Zambirinis Gonçalo Rodrigues Henrik Molina Søren Heissel Milica Tesic Mark Loïc Steiner Alberto Benito-Martin Serena Lucotti Angela Di Giannatale Katharine Offer Miho Nakajima Caitlin Williams Laura Nogués Fanny A Pelissier Vatter Ayako Hashimoto Alexander E Davies Daniela Freitas Candia M Kenific Yonathan Ararso Weston Buehring Pernille Lauritzen Yusuke Ogitani Kei Sugiura Naoko Takahashi Maša Alečković Kayleen A Bailey Joshua S Jolissant Huajuan Wang Ashton Harris L Miles Schaeffer Guillermo García-Santos Zoe Posner Vinod P Balachandran Yasmin Khakoo G Praveen Raju Avigdor Scherz Irit Sagi Ruth Scherz-Shouval Yosef Yarden Moshe Oren Mahathi Malladi Mary Petriccione Kevin C De Braganca Maria Donzelli Cheryl Fischer Stephanie Vitolano Geraldine P Wright Lee Ganshaw Mariel Marrano Amina Ahmed Joe DeStefano Enrico Danzer Michael H A Roehrl Norman J Lacayo Theresa C Vincent Martin R Weiser Mary S Brady Paul A Meyers Leonard H Wexler Srikanth R Ambati Alexander J Chou Emily K Slotkin Shakeel Modak Stephen S Roberts Ellen M Basu Daniel Diolaiti Benjamin A Krantz Fatima Cardoso Amber L Simpson Michael Berger Charles M Rudin Diane M Simeone Maneesh Jain Cyrus M Ghajar Surinder K Batra Ben Z Stanger Jack Bui Kristy A Brown Vinagolu K Rajasekhar John H Healey Maria de Sousa Kim Kramer Sujit Sheth Jeanine Baisch Virginia Pascual Todd E Heaton Michael P La Quaglia David J Pisapia Robert Schwartz Haiying Zhang Yuan Liu Arti Shukla Laurence Blavier Yves A DeClerck Mark LaBarge Mina J Bissell Thomas C Caffrey Paul M Grandgenett Michael A Hollingsworth Jacqueline Bromberg Bruno Costa-Silva Hector Peinado Yibin Kang Benjamin A Garcia Eileen M O'Reilly David Kelsen Tanya M Trippett David R Jones Irina R Matei William R Jarnagin David Lyden

Cell 2020 08 13;182(4):1044-1061.e18. Epub 2020 Aug 13.

Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address:

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.
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http://dx.doi.org/10.1016/j.cell.2020.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522766PMC
August 2020

Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases.

Clin Exp Metastasis 2020 10 20;37(5):593-605. Epub 2020 Jul 20.

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

Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study evaluates whether HGPs can predict the effectiveness of adjuvant CTx in patients with resected CRLM. Two main types of HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000-2016). A total of 656 patients (53.1%) patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.37-0.73, p < 0.001), and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75-4.21, p = 0.19). In pretreated patients no significant effect of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49-1.42, p = 0.50) nor in the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71-1.29, p = 0.79). Similar results were found for DFS, with a superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55-0.93, p < 0.001) that were not pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this effect was only observed in patients that were not treated with chemotherapy.
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http://dx.doi.org/10.1007/s10585-020-10048-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497305PMC
October 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

Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.

Clin Cancer Res 2020 07 22;26(13):3239-3247. Epub 2020 May 22.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.

Experimental Design: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: , and HRm status was grouped as: (i) germline versus somatic; (ii) core ( and versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.

Results: Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.

Conclusions: Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380542PMC
July 2020

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

ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity.

Nature 2020 03 19;579(7797):130-135. Epub 2020 Feb 19.

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

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues. Although ILC2s are found in cancers of these tissues, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8 T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1 TILC2s and PD-1 T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.
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http://dx.doi.org/10.1038/s41586-020-2015-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060130PMC
March 2020

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases.

HPB (Oxford) 2020 Sep 27;22(9):1271-1279. Epub 2019 Dec 27.

Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, 10065 NY, New York, United States. Electronic address:

Background: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).

Methods: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.

Results: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001).

Conclusion: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.
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http://dx.doi.org/10.1016/j.hpb.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890567PMC
September 2020

Intraductal Papillary Mucinous Neoplasms: Have IAP Consensus Guidelines Changed our Approach?: Results from a Multi-institutional Study.

Ann Surg 2019 Dec 5. Epub 2019 Dec 5.

Department of Surgery, Hepatopancreatobiliary Service, Duke, University School of Medicine, Durham, NC.

Objective: To evaluate the influence of consensus guidelines on the management of intraductal papillary mucinous neoplasms (IPMN) and the subsequent changes in pathologic outcomes.

Background: Over time, multiple guidelines have been developed to identify high-risk IPMN. We hypothesized that the development and implementation of guidelines should have increased the percentage of resected IPMN with high-risk disease.

Methods: Memorial Sloan-Kettering (MSK), Johns Hopkins (JH), and Massachusetts General Hospital (MGH) databases were queried for resected IPMN (2000-2015). Patients were categorized into main-duct (MD-IPMN) versus branch-duct (BD-IPMN). Guideline-specific radiographic/endoscopic features were recorded. High-risk disease was defined as high-grade dysplasia/carcinoma. Fisher's exact test was used to detect differences between institutions. Logistic regression evaluated differences between time-points [preguidelines (pre-GL, before 2006), Sendai (SCG, 2006-2012), Fukuoka (FCG, after 2012)].

Results: The study included 1210 patients. The percentage of BD-IPMN with ≥1 high-risk radiographic feature differed between centers (MSK 69%, JH 60%, MGH 45%; P < 0.001). In MD-IPMN cohort, the presence of radiographic features such as solid component and main pancreatic duct diameter ≥10 mm also differed (solid component: MSK 38%, JH 30%, MGH 18%; P < 0.001; duct ≥10 mm: MSK 49%, JH 32%, MGH 44%; P < 0.001). The percentage of high-risk disease on pathology, however, was similar between institutions (BD-IPMN: P = 0.36, MD-IPMN: P = 0.48). During the study period, the percentage of BD-IPMN resected with ≥1 high-risk feature increased (52% pre-GL vs 67% FCG; P = 0.005), whereas the percentage of high-risk disease decreased (pre-GL vs FCG: 30% vs 20%). For MD-IPMN, there was not a clear trend towards guideline adherence, and the rate of high-risk disease was similar over the time (pre-GL vs FCG: 69% vs 67%; P = 0.63).

Conclusion: Surgical management of IPMN based on radiographic criteria is variable between institutions, with similar percentages of high-risk disease. Over the 15-year study period, the rate of BD-IPMN resected with high-risk radiographic features increased; however, the rate of high-risk disease decreased. Better predictors are needed.
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http://dx.doi.org/10.1097/SLA.0000000000003703DOI Listing
December 2019

Histopathological growth patterns and positive margins after resection of colorectal liver metastases.

HPB (Oxford) 2020 06 15;22(6):911-919. Epub 2019 Nov 15.

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

Background: Histopathological growth patterns (HGPs) of colorectal liver metastases (CRLM) may be an expression of biological tumour behaviour impacting the risk of positive resection margins. The current study aimed to investigate whether the non-desmoplastic growth pattern (non-dHGP) is associated with a higher risk of positive resection margins after resection of CRLM.

Methods: All patients treated surgically for CRLM between January 2000 and March 2015 at the Erasmus MC Cancer Institute and between January 2000 and December 2012 at the Memorial Sloan Kettering Cancer Center were considered for inclusion.

Results: Of all patients (n = 1302) included for analysis, 13% (n = 170) had positive resection margins. Factors independently associated with positive resection margins were the non-dHGP (odds ratio (OR): 1.79, 95% confidence interval (CI): 1.11-2.87, p = 0.016) and a greater number of CRLM (OR: 1.15, 95% CI: 1.08-1.23 p < 0.001). Both positive resection margins (HR: 1.41, 95% CI: 1.13-1.76, p = 0.002) and non-dHGP (HR: 1.57, 95% CI: 1.26-1.95, p < 0.001) were independently associated with worse overall survival.

Conclusion: Patients with non-dHGP are at higher risk of positive resection margins. Despite this association, both positive resection margins and non-dHGP are independent prognostic indicators of worse overall survival.
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http://dx.doi.org/10.1016/j.hpb.2019.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888172PMC
June 2020

Coaltered and Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer.

Clin Cancer Res 2020 03 12;26(5):1077-1085. Epub 2019 Nov 12.

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

Purpose: We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer.

Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year ( = 17) and ≥10-year ( = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I-IV patients.

Results: In the extremes-of-survivorship cohort, significant co-occurrence of hotspot mutations and alterations was observed in ≤2-year survivors ( < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic (i.e., either , or ) and alteration generated three prognostic clusters: (i) -altered alone (median OS, 132 months); (ii) -altered alone (65 months) or - and pan-wild-type (60 months); and (iii) coaltered - (40 months; < 0.0001). Coaltered - was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered - was associated with worse OS in patients with liver ( = 490) and lung ( = 172) but not peritoneal surface ( = 149) metastases. Moreover, coaltered - tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.

Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered - and its association with distinct patterns of colorectal cancer metastasis.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056517PMC
March 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