Publications by authors named "Anna Varghese"

52 Publications

Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity.

Pancreatology 2021 Feb 6. Epub 2021 Feb 6.

Department of Medicine, Memorial Sloan Kettering Cancer Center, USA; Department of Medicine, Weill Cornell Medical College, USA; David M. Rubenstein Center for Pancreas Cancer Research, USA. Electronic address:

Background: /Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated.

Methods: Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed.

Results: Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months).

Conclusions: LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.
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http://dx.doi.org/10.1016/j.pan.2021.02.003DOI Listing
February 2021

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.

Clin Cancer Res 2021 Jan 27. Epub 2021 Jan 27.

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

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.

Patients And Methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.

Results: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients ( = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8 T lymphocyte activation, differentiation, and proliferation in patients with objective response.

Conclusion: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2474DOI Listing
January 2021

Clinical Calculator Based on Molecular and Clinicopathologic Characteristics Predicts Recurrence Following Resection of Stage I-III Colon Cancer.

J Clin Oncol 2021 Jan 13:JCO2002553. Epub 2021 Jan 13.

Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Clinical calculators and nomograms have been endorsed by the American Joint Committee on Cancer (AJCC), as they provide the most individualized and accurate estimate of patient outcome. Using molecular and clinicopathologic variables, a third-generation clinical calculator was built to predict recurrence following resection of stage I-III colon cancer.

Methods: Prospectively collected data from 1,095 patients who underwent colectomy between 2007 and 2014 at Memorial Sloan Kettering Cancer Center were used to develop a clinical calculator. Discrimination was measured with concordance index, and variability in individual predictions was assessed with calibration curves. The clinical calculator was externally validated with a patient cohort from Washington University's Siteman Cancer Center in St Louis.

Results: The clinical calculator incorporated six variables: microsatellite genomic phenotype; AJCC T category; number of tumor-involved lymph nodes; presence of high-risk pathologic features such as venous, lymphatic, or perineural invasion; presence of tumor-infiltrating lymphocytes; and use of adjuvant chemotherapy. The concordance index was 0.792 (95% CI, 0.749 to 0.837) for the clinical calculator, compared with 0.708 (95% CI, 0.671 to 0.745) and 0.757 (0.715 to 0.799) for the staging schemes of the AJCC manual's 5th and 8th editions, respectively. External validation confirmed robust performance, with a concordance index of 0.738 (95% CI, 0.703 to 0.811) and calibration plots of predicted probability and observed events approaching a 45° diagonal.

Conclusion: This third-generation clinical calculator for predicting cancer recurrence following curative colectomy successfully incorporates microsatellite genomic phenotype and the presence of tumor-infiltrating lymphocytes, resulting in improved discrimination and predictive accuracy. This exemplifies an evolution of a clinical calculator to maintain relevance by incorporating emerging variables as they become validated and accepted in the oncologic community.
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http://dx.doi.org/10.1200/JCO.20.02553DOI Listing
January 2021

Insertion of an Alu-like element in MLH1 intron 7 as a novel cause of Lynch syndrome.

Mol Genet Genomic Med 2020 12 15;8(12):e1523. Epub 2020 Oct 15.

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

Background: Lynch Syndrome (LS) is caused by germline mutations in the DNA mismatch repair (MMR) genes with mutations in MLH1 accounting for ~40% of LS-related alterations.

Methods: MSK-IMPACT analysis was performed on peripheral blood from a patient with early- onset colorectal cancer. Subsequently PCR and sequencing was performed to characterize the insertion. Immunohistochemistry for MMR genes and MLH1 promoter methylation were analyzed on patient's tumor.

Results: MSK-IMPACT germline testing revealed an insertion into c.588+8_588+9 of MLH1 intron 7. The insertion was further characterized as an AluSx-like element with ~115 bp in length. Functional studies demonstrated that the AluSx-like element led to complete disruption of mRNA splicing and probably resulted in transcriptional termination at the poly (A) region of the AluSx-like insertion.

Conclusions: The insertion of a truncated AluSx like element into MLH1 intron 7 results in aberrant splicing and transcription, thereby causing Lynch syndrome. This study confirms that retrotransposon insertions may be an important mechanism for cancer predisposition.
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http://dx.doi.org/10.1002/mgg3.1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767547PMC
December 2020

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

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

Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

Mod Pathol 2020 09 29;33(9):1822-1831. Epub 2020 Apr 29.

The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinical correlates of this cellular feature. After case selection, 516 conventional PDACs and 21 ASCs entered this study and ~45,000 HPFs (median 80 HPFs per sample) were reviewed; 549 entotic-CICs were detected through our cohort. We observed that entotic-CIC occurred more frequently in liver metastasis compared with primary in PDAC. Moreover, poorly differentiated adenocarcinoma or adenosquamous carcinoma had more entotic-CIC than well or moderately differentiated adenocarcinoma. With respect to genetic features TP53 mutations, KRAS amplification, and MYC amplification were significantly associated with entosis in PDAC tissues. From a clinical standpoint entotic CICs were independently associated with a poor prognosis by multivariate Cox regression analysis when considering all cases or primary PDACs specifically. These results provide a contextual basis for understanding entosis in PDAC, a highly aggressive cancer for which molecular insights are needed to improve survival.
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http://dx.doi.org/10.1038/s41379-020-0549-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452867PMC
September 2020

Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

Clin Cancer Res 2020 07 6;26(13):3271-3279. Epub 2020 Mar 6.

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

Purpose: Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.

Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.

Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline and mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (, 57% vs 36%; , 17% vs 9%; < 0.003).

Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348681PMC
July 2020

Phase I Study of Trifluridine/Tipiracil Plus Irinotecan and Bevacizumab in Advanced Gastrointestinal Tumors.

Clin Cancer Res 2020 04 10;26(7):1555-1562. Epub 2020 Jan 10.

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

Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC).

Patients And Methods: Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered.

Results: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m twice daily plus irinotecan 180 mg/m. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months).

Conclusions: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2743DOI Listing
April 2020

Radiation dose reference card for interventional radiology procedures: Experience in a tertiary referral centre.

Indian J Radiol Imaging 2019 Jul-Sep;29(3):247-252. Epub 2019 Oct 30.

Department of Radiology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.

Background: Fluoroscopy-guided interventions can potentially increase radiation risk to patients, if awareness on angiographic imaging technique and radiation dose is neglected.

Aim: To develop patient radiation dose reference card from standardized imaging techniques for various radiology interventions performed using flat detector based angiography system.

Materials And Methods: Real-time monitoring of angiographic exposure parameters and radiation dose were performed for 16 types of radiological interventions. Effective dose (ED) was estimated from dose area product (DAP) using PCXMC Monte Carlo simulation software. Radiation risk levels were estimated based on Biological Effects of Ionising radiation (BEIR) report VII predictive models for an Asian population.

Results: Pulse rates of 7.5 pps and 0.6 mm Copper filtration during fluoroscopy and 4 frames per second (fps) and 0.1-0.3 mm Cu filtration during image acquisitions were found to reduce radiation dose. Owing to increased number of image acquisitions, DAP was highest during diagnostic spinal angiography 186.7 Gycm (44.0-377.5). This resulted in highest ED of 59.4 mSv with moderate risk levels (1 in 1000 to 1 in 500). Most of the radiological interventions had low radiation risk levels (1 in 10,000 to 1 in 1000).

Conclusion: The patient radiation dose reference card is valuable to the medical community and can aid in patient counselling on radiation induced risk from radiological interventions.
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http://dx.doi.org/10.4103/ijri.IJRI_35_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857258PMC
October 2019

Development of Genome-Derived Tumor Type Prediction to Inform Clinical Cancer Care.

JAMA Oncol 2019 Nov 14. Epub 2019 Nov 14.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity.

Objective: To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy.

Design, Setting, And Participants: A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer.

Results: The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11 644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses.

Conclusions And Relevance: These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.
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http://dx.doi.org/10.1001/jamaoncol.2019.3985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865333PMC
November 2019

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

Contemporary Validation of a Nomogram Predicting Colon Cancer Recurrence, Revealing All-Stage Improved Outcomes.

JNCI Cancer Spectr 2019 Jun 25;3(2):pkz015. Epub 2019 Apr 25.

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

Background: The Memorial Sloan Kettering Cancer Center (MSK) colon cancer recurrence nomogram is a risk calculator that provides patients and clinicians with individualized prediction of recurrence following curative resection of colon cancer. Although validated on multiple separate cohorts, the nomogram requires periodic updating as patient care changes over time. The aim of this study was to evaluate the nomogram's accuracy in a contemporary cohort and modify the tool to reflect improvements in outcome related to advances in colon cancer therapy.

Methods: A contemporary patient cohort was compiled, including consecutive colon cancer patients undergoing curative resection for stage I-III colon adenocarcinoma at MSK from 2007 to 2014. The nomogram's predictive accuracy was assessed by concordance index and calibration plots of predicted vs actual freedom from recurrence at 5 years after surgery.

Results: Data from a total of 999 eligible patients with complete records were used for validation. Median follow-up among survivors was 37 months. The concordance index was 0.756 (95% confidence interval = 0.707 to 0.805), indicating continued discriminating power, but the calibration plot revealed that the nomogram overestimated recurrence risk. Recalibration of the nomogram by estimating a new baseline freedom-from-recurrence function restored the nomogram's accuracy.

Conclusion: The updated nomogram retains the original nomogram's variables but includes a lower baseline estimation of recurrence risk, reflecting improvements in outcomes for all stages of colon cancer, likely resulting from advances in imaging and integration of multiple treatment modalities.
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http://dx.doi.org/10.1093/jncics/pkz015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512350PMC
June 2019

Genomic profiling in pancreatic ductal adenocarcinoma and a pathway towards therapy individualization: A scoping review.

Cancer Treat Rev 2019 May 22;75:27-38. Epub 2019 Mar 22.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Context: Pancreatic cancer (PDAC) is one of the most challenging cancers to treat with modest recent improvements in survival from new systemic therapies. There is growing interest in individualized therapy underpinned by somatic and germline genomic alterations.

Objective: A systematic review of data on therapies targeting somatic and germline alterations, and their downstream pathways in PDAC.

Method: A systematic literature search was conducted using PRISMA guidelines to include relevant results published after January 1, 2008.

Results: A total of 71 relevant studies were included. We identified 36 studies targeting the KRAS-pathway, the most common being with MEK-inhibitor therapy. Twenty-two studies were identified that evaluated platinum-based chemotherapy and PARP inhibitors in patients with deleterious mutations in DNA damage repair genes and have shown encouraging results. Immunotherapy has demonstrated activity in patients with mismatch repair deficiency/microsatellite instability.

Conclusion: Evidence from translational and clinical research presents an exciting platform for genomic targeted therapy in PDAC. Validity for targeting BRCA with platinum and PARP inhibitors and microsatellite instability with immune therapy has been established, nonetheless, evidence for targeting the common driver oncogenes is lacking and much work is needed. Of importance is identifying the subgroup of KRAS -wild type PDAC (approximately 5%) where there is enrichment for targetable opportunities.
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http://dx.doi.org/10.1016/j.ctrv.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504563PMC
May 2019

Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes.

Cancer 2019 05 8;125(9):1441-1448. Epub 2019 Jan 8.

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

Background: Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Pathogenic germline alterations (PGAs) in BRCA2 and potentially targetable somatic alterations (SAs) in ERBB2 and ELF3 have been previously described in AC. Memorial Sloan Kettering Cancer Center has implemented an opt-in strategy for germline testing (GT) and somatic testing (ST) for patients with AC to further evaluate the spectrum of PGAs and SAs.

Methods: Forty-five patients with pathologically confirmed AC prospectively consented with the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) test (410-468 genes). A subset of the cohort (23 of the 45 patients) also consented to GT with MSK-IMPACT (76-88 genes). Germline data for 21 of the remaining 22 patients who had not consented to GT were obtained in a de-identified fashion without clinical correlation. Clinicopathologic features, treatment histories, and survival data for consenting patients were collected and analyzed.

Results: Pancreaticobiliary, intestinal, and mixed features of the 2 types were the primary pathologic subtypes of AC identified in this cohort. No difference in median overall survival was found between pathologic subtypes. Eight of 44 patients (18%) were identified as harboring pathogenic mutations in BRCA2, ATM, RAD50, and MUTYH. In addition, this study found a wide spectrum of SAs in genes such as KRAS, MDM2, ERBB2, ELF3, and PIK3CA. Two patients in the cohort underwent SA-targeted therapy, and 1 had a partial radiographic response.

Conclusions: Mutations in multiple somatic and germline genes were identified in this cohort. Significantly, actionable targets were identified in the tumors, and broader testing for PGAs and SAs should be considered for all patients with AC.
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http://dx.doi.org/10.1002/cncr.31951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467723PMC
May 2019

Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer.

J Clin Oncol 2019 02 30;37(4):286-295. Epub 2018 Oct 30.

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

Purpose: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status.

Methods: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed.

Results: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases.

Conclusion: MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.
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http://dx.doi.org/10.1200/JCO.18.00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553803PMC
February 2019

FOLFCIS Treatment and Genomic Correlates of Response in Advanced Anal Squamous Cell Cancer.

Clin Colorectal Cancer 2019 03 21;18(1):e39-e52. Epub 2018 Sep 21.

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

Background: Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC.

Patients And Methods: We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy - essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin - in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers.

Results: Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations.

Conclusions: FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.
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http://dx.doi.org/10.1016/j.clcc.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428631PMC
March 2019

A Study on the Use of Radiation-Protective Apron among Interventionists in Radiology.

J Clin Imaging Sci 2018 24;8:34. Epub 2018 Aug 24.

Department of Radiology, Christian Medical College, Vellore, Tamil Nadu, India.

Objective: Radiation-protective aprons are commonly used by interventionists to protect against the harmful effects of ionizing radiation. Choice of appropriate aprons with respect to lead equivalence and weight is necessary for effective protection and reduced physical strain. This study evaluates the knowledge and practice of using radiation-protective aprons by interventionists.

Materials And Methods: Ninety-one interventional radiologists who attended an annual interventional conference were provided with a questionnaire which included age, years of experience, area of expertise, type and weight of apron used, and physical strain caused due to the use of apron.

Results: About 14.3% of the interventionists practiced in an angiographic suite for less than an hour a day, 45% for 2-4 h, 21% for 4-6 h, 10% for 6-10 h, and the rest above 10 h/day. About 68% of the interventionists wore 0.5 mm lead-equivalent (Pb) aprons; 15.4% with 0.25 mm Pb; about 5.5% with 0.35 mm Pb aprons, and the remaining were not aware of the lead equivalence. About 47% reported that they had body aches due to wearing single-sided aprons. Interventionists working more than 10 h/day wearing single-sided lead apron predominantly complained of shoulder pain and back pain.

Conclusion: A large fraction of interventionists reported that they had physical strain. It is suggestive for interventionists to wear correct fit and light-weight aprons with appropriate lead equivalence.
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http://dx.doi.org/10.4103/jcis.JCIS_34_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118106PMC
August 2018

A simple quality control tool for assessing integrity of lead equivalent aprons.

Indian J Radiol Imaging 2018 Apr-Jun;28(2):258-262

Department of Radiology, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.

Background: Protective lead or lead-equivalent (Pbeq) aprons play a key role in providing necessary shielding from secondary radiation to occupational workers. Knowledge on the integrity of these shielding apparels during purchase is necessary to maintain adequate radiation safety.

Aim: The aim of the study was to evaluate the lead equivalence in aprons based on simple quality assessment tool.

Materials And Methods: 0.25 mm and 0.5 mm lead and lead-free aprons from 6 manufacturers were assessed using a calibrated digital X-ray unit. The percentage attenuation values of the aprons were determined at 100 kVp using an ionization chamber and the pixel intensities were analyzed using digital radiographic images of lead apron, copper step wedge tool, and 2 mm thick lead.

Results: Mean radiation attenuation of 90% and 97% was achieved in 0.25 mm and 0.5 mm lead or lead-free aprons respectively. The pixel intensities from 0.25 mm Pbeq apron correspond to 0.8-1.2 mm thickness of Cu while 0.5 mm Pbeq aprons correspond to 2.0-2.8 mm of Cu.

Conclusion: Pixel intensity increased with increase in the thickness of copper step wedge indicating a corresponding increase in lead equivalence in aprons. It is suggestive that aprons should be screened for its integrity from the time of purchase using computed tomography (CT), fluoroscopy, or radiography. It is recommended that this simple test tool could be used for checking lead equivalence if any variation in contrast is seen in the image during screening.
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http://dx.doi.org/10.4103/ijri.IJRI_374_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038217PMC
July 2018

Nanoliposomal irinotecan with fluorouracil for the treatment of advanced pancreatic cancer, a single institution experience.

BMC Cancer 2018 Jun 27;18(1):693. Epub 2018 Jun 27.

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, NY, USA.

Background: Effective treatment options for advanced pancreatic cancer are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of nanoliposomal irinotecan with fluorouracil/leucovorin (nal-IRI + 5-FU/LV) for the treatment of advanced pancreatic cancer following progression on gemcitabine-based chemotherapy. There are limited additional data on the safety and efficacy of nal-IRI + 5-FU/LV following FDA approval in October 2015. We examined the post-approval safety and effectiveness of nal-IRI + 5-FU/LV in advanced pancreatic cancer patients receiving treatment at Memorial Sloan Kettering Cancer Center.

Methods: A retrospective chart review was conducted of all patients beginning treatment with nal-IRI + 5-FU/LV from October 2015 through June 2017. Using the electronic medical record and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of treatment, adverse events, progression free survival (PFS), overall survival (OS) and treatment response.

Results: Fifty six patients were identified. Median progression free survival (PFS) was 2.9 months and median overall survival (OS) was 5.3 months. Patients with prior disease progression on irinotecan experienced PFS and OS of 2.2 and 3.9 mo, respectively. Patients without prior irinotecan exposure experienced significantly longer PFS (4.8 mo, p = 0.02) and OS (7.7 mo, p = 0.002), as did patients who received prior irinotecan without disease progression (PFS, 5.7 mo, p = 0.04; OS, 9.0 mo, p = .04). Progression on prior irinotecan was associated with greater lines of prior advanced disease chemotherapy (2 vs 1). Dose reductions (DR) were most frequently due to fatigue (42%) and diarrhea (37%), but were not associated with worse outcomes. In fact, patients with ≥1 DR experienced longer PFS (5.4 v 2.6 mo, p = 0.035). Sequential therapy with nab-paclitaxel + gemcitabine (nab-P + Gem) followed by nal-IRI + 5-FU/LV (n = 25) resulted in OS of 23.0 mo. Mutations in TP53 were associated with shorter PFS.

Conclusions: These data support the safety and efficacy of nal-IRI + 5-FU/LV, reinforcing results of NAPOLI-1. Patients without disease progression on prior irinotecan fared significantly better than patients with progression, when treated with nal-IRI + 5-FU/LV. Sequential therapy with nab-P + Gem followed by nal-IRI + 5-FU/LV demonstrates encouraging median OS. These findings provide guidance for patients most likely to benefit from nal-IRI + 5-FU/LV.
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http://dx.doi.org/10.1186/s12885-018-4605-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020418PMC
June 2018

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer.

Clin Cancer Res 2018 07 10;24(14):3253-3262. Epub 2018 Apr 10.

Stephenson Oklahoma Cancer Center/Sarah Cannon Research Institute, Oklahoma City, Oklahoma.

The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3421DOI Listing
July 2018

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

JAMA Oncol 2018 06 14;4(6):e180071. Epub 2018 Jun 14.

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

Importance: Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.

Objective: To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC.

Design, Setting, And Participants: A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified.

Exposures: Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT).

Main Outcomes And Measures: Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK.

Results: Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort.

Conclusions And Relevance: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.
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http://dx.doi.org/10.1001/jamaoncol.2018.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885165PMC
June 2018

Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.

J Natl Cancer Inst 2018 10;110(10):1067-1074

Department of Medicine.

Background: Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications.

Methods: Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410-468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an "identified" manner in 356 (57.9%) patients and in an "anonymized" manner in 259 (42.1%) patients, using an institutional review board-approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves.

Results: PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2.

Conclusions: PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.
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http://dx.doi.org/10.1093/jnci/djy024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186514PMC
October 2018

Incidence, Management, and Implications of Visceral Thrombosis in Pancreatic Ductal Adenocarcinoma.

Clin Colorectal Cancer 2018 06 31;17(2):121-128. Epub 2018 Jan 31.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Medicine, Weill Cornell Medicine, New York, NY. Electronic address:

Background: Visceral or splanchnic thrombosis is defined as thrombi within the hepatoportal venous system, including portal (PV), mesenteric (MV), and splenic vein (SV), as well as thrombi in renal or gonadal veins. There are limited data to evaluate the prognostic significance, incidence, and clinical management of visceral thromboses in patients with pancreatic ductal adenocarcinoma (PDAC).

Patients And Methods: We conducted an analysis of 95 patients treated at Memorial Sloan Kettering Cancer Center with PDAC who had a visceral thrombosis.

Results: A total of 153 visceral thromboses (VsT) were identified in 95 patients (n = 51, 54% woman). A total of 36 patients (37%) had locally advanced disease, and n = 59 (62%) had metastatic disease. Systemic therapies received included FOLFIRINOX (n = 57, 60%) and GC/PTX (n = 27, 28%). All VsT events were incidentally detected. Overall survival of cohort was 12.3 months (range, 10.2-14.4 months). Visceral thrombosis incidence in the cohort was as follows: portal vein (PV) (45%), MV (26%), SV (17%), and gonadal veins (8%). Time to develop first VsT was 4.3 months (range, 3-5.6 months), and time to death from VsT development was 1.87 months (range, 0.8-2.8 months). Forty-five patients (47%) developed a second VsT. Sixty percent had a Khorana risk score of > 3. Thirty-nine patients (41%) were treated with short-term anticoagulation (AC) (< 1 month) (low-molecular-weight heparin, n = 34). Forty-five patients (47%) were treated with long-term AC (> 1 month) (low-molecular-weight heparin, n = 32; 23 were transitioned to an oral anticoagulant). Twenty-two patients (23%) were not treated with AC. Eight patients (8%) had a bleeding complication from AC. Portal vein thrombosis had the shortest overall survival at 3.6 months (range, 2.3-4.8 months).

Conclusion: In PDAC, VsT can frequently present as an incidental finding on routine abdominal imaging. The most common location is PV, followed by MV and SV. We observed that AC is underutilized in this setting despite a low bleeding complication rate. PV was associated with the least overall survival of the VsT. Future large prospective studies should explore the role of AC and value in this setting.
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http://dx.doi.org/10.1016/j.clcc.2018.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382360PMC
June 2018

Radiation dose from percutaneous transluminal coronary angioplasty procedure performed using a flat detector for different clinical angiographic projections.

J Radiol Prot 2018 Jun 30;38(2):511-524. Epub 2018 Jan 30.

Department of Radiology, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, South India.

The radiation dose from complex cardiac procedures is of concern due to the lengthy fluoroscopic screening time and vessel complexities. This study intends to assess radiation dose based on angiographic projection and vessel complexities for clinical protocols used in the performance of percutaneous transluminal coronary angioplasty (PTCA). Dose-area product (DAP), reference air kerma (K ) and real-time monitoring of tube potentials and tube current for each angiographic projection and dose setting were evaluated for 66 patients who underwent PTCA using a flat detector system. The mean DAP and cumulative K were 32.71 Gy cm (0.57 Gy), 51.24 Gy cm (0.9 Gy) and 102.03 Gy cm (1.77 Gy) for single-, double- and triple-vessel PTCA, respectively. Among commonly used angiographic projections, left anterior oblique 45°-caudal 35° reached 2 Gy in 55 min using a low-dose fluoroscopy setting and 21 min for a medium-dose setting. Use of a low-dose setting for fluoroscopic screening showed a radiation dose reduction of 39% compared with a medium-dose setting.
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http://dx.doi.org/10.1088/1361-6498/aaab71DOI Listing
June 2018

Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations.

Clin Cancer Res 2018 03 24;24(6):1326-1336. Epub 2018 Jan 24.

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

Immune checkpoint inhibition has been shown to generate profound and durable responses in mismatch repair deficient (MMR-D) solid tumors and has elicited interest in detection tools and strategies to guide therapeutic decision-making. Herein we address questions on the appropriate screening, detection methods, patient selection, and initiation of therapy for MMR-D pancreatic ductal adenocarcinoma (PDAC) and assess the utility of next-generation sequencing (NGS) in providing additional prognostic and predictive information for MMR-D PDAC. Archival and prospectively acquired samples and matched normal DNA from = 833 PDAC cases were analyzed using a hybridization capture-based, NGS assay designed to perform targeted deep sequencing of all exons and selected introns of 341 to 468 cancer-associated genes. A computational program using NGS data derived the MSI status from the tumor-normal paired genome sequencing data. Available germline testing, IHC, and microsatellite instability (MSI) PCR results were reviewed to assess and confirm MMR-D and MSI status. MMR-D in PDAC is a rare event among PDAC patients (7/833), occurring at a frequency of 0.8%. Loss of MMR protein expression by IHC, high mutational load, and elevated MSIsensor scores were correlated with MMR-D PDAC. All 7 MMR-D PDAC patients in the study were found to have Lynch syndrome. Four (57%) of the MMR-D patients treated with immune checkpoint blockade had treatment benefit (1 complete response, 2 partial responses, 1 stable disease). An integrated approach of germline testing and somatic analyses of tumor tissues in advanced PDAC using NGS may help guide future development of immune and molecularly directed therapies in PDAC patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856632PMC
March 2018

Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.

Cancer Cell 2018 01;33(1):125-136.e3

Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Departments of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.
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http://dx.doi.org/10.1016/j.ccell.2017.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765991PMC
January 2018

Visceral Thromboses in Pancreas Adenocarcinoma: Systematic Review.

Clin Colorectal Cancer 2018 06 12;17(2):e207-e216. Epub 2017 Dec 12.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Weill Cornell Medicine, New York, NY. Electronic address:

Within gastrointestinal malignancies, primary hepatocellular carcinoma and pancreatic ductal adenocarcinoma (PDAC) are frequently associated with visceral thromboses (VT). Thrombus formation in the portal (PVT), mesenteric (MVT), or splenic vein (SVT) system leads to portal hypertension and intestinal ischemia. VT in PDAC may convey a risk of increased distal thrombosis and poses therapeutic uncertainty regarding the role of anticoagulation. An increasing number of reports describe VT associated with PDAC. It is possible that early diagnosis of these events may help reduce morbidity and speculatively improve oncologic outcomes. To perform a systematic review to study PVT, MVT, and SVT associated with PDAC, and to provide a comprehensive review. Medline/PubMed, Embase, Web of Science, Scopus, and the Cochrane Library. Data Extraction and Assessment: Two blinded independent observers extracted and assessed the studies for diagnosis of PVT, MVT, and SVT in PDAC. Studies were restricted to English-language literature published between 2007 and 2016. Eleven articles were identified. Five case reports and 7 retrospective studies were found, with a total of 127 patients meeting the inclusion criteria. The mean age at diagnosis was 64 years. PVT was found in 35% (n = 46), SVT in 52% (n = 65), and MVT in 13% (n = 15). Mean follow-up time was 26 months. Only 3 of the selected articles studied the impact of anticoagulation in VT. All patients with nonvisceral thrombosis (eg, deep-vein thrombosis, pulmonary emboli) were therapeutically treated; in contrast, patients with VT only rarely received treatment. VT in PDAC is a frequent finding at diagnosis or during disease progression. Evidence to guide treatment choices is limited, and current management is based on inferred experience from nononcologic settings. Anticoagulation appears to be safe in VT, with most of the large studies recommending a careful assessment for patients at a high risk of bleeding.
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http://dx.doi.org/10.1016/j.clcc.2017.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752720PMC
June 2018

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study.

Cancer Discov 2018 02 15;8(2):184-195. Epub 2017 Dec 15.

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

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with -, V600-, and non-V600 -mutant solid tumors. Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in - and V600- and non-V600-mutant solid-tumor malignancies. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1119DOI Listing
February 2018

Chimeric antigen receptor (CAR) T and other T cell strategies for pancreas adenocarcinoma.

Authors:
Anna M Varghese

Chin Clin Oncol 2017 Dec 24;6(6):66. Epub 2017 Oct 24.

Gastrointestinal Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.

Treatments in metastatic pancreas cancer remain based in cytotoxic chemotherapy, and novel treatment strategies are needed. Building on the emerging role of T cell therapy in hematologic malignancies and our understanding of the underlying biology of pancreas cancer, research is growing in the role of T cell therapy for patients with solid tumors in general and more specifically patients with pancreas cancer. This review will focus on describing the biology of T cell therapy and its current applications in pancreas cancer.
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http://dx.doi.org/10.21037/cco.2017.09.04DOI Listing
December 2017