Publications by authors named "Julio Garcia Aguilar"

154 Publications

Effect of a Predictive Model on Planned Surgical Duration Accuracy, Patient Wait Time, and Use of Presurgical Resources: A Randomized Clinical Trial.

JAMA Surg 2021 Jan 27. Epub 2021 Jan 27.

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

Importance: Accurate surgical scheduling affects patients, clinical staff, and use of physical resources. Although numerous retrospective analyses have suggested a potential for improvement, the real-world outcome of implementing a machine learning model to predict surgical case duration appears not to have been studied.

Objectives: To assess accuracy and real-world outcome from implementation of a machine learning model that predicts surgical case duration.

Design, Setting, And Participants: This randomized clinical trial was conducted on 2 surgical campuses of a cancer specialty center. Patients undergoing colorectal and gynecology surgery at Memorial Sloan Kettering Cancer Center who were scheduled more than 1 day before surgery between April 7, 2018, and June 25, 2018, were included. The randomization process included 29 strata (11 gynecological surgeons at 2 campuses and 7 colorectal surgeons at a single campus) to ensure equal chance of selection for each surgeon and each campus. Patients undergoing more than 1 surgery during the study's timeframe were enrolled only once. Data analyses took place from July 2018 to November 2018.

Interventions: Cases were assigned to machine learning-assisted surgical predictions 1 day before surgery and compared with a control group.

Main Outcomes And Measures: The primary outcome measure was accurate prediction of the duration of each scheduled surgery, measured by (arithmetic) mean (SD) error and mean absolute error. Effects on patients and systems were measured by start time delay of following cases, the time between cases, and the time patients spent in presurgical area.

Results: A total of 683 patients were included (mean [SD] age, 55.8 [13.8] years; 566 women [82.9%]); 72 were excluded. Of the 683 patients included, those assigned to the machine learning algorithm had significantly lower mean (SD) absolute error (control group, 59.3 [72] minutes; intervention group, 49.5 [66] minutes; difference, -9.8 minutes; P = .03) compared with the control group. Mean start-time delay for following cases (patient wait time in a presurgical area), dropped significantly: 62.4 minutes (from 70.2 minutes to 7.8 minutes) and 16.7 minutes (from 36.9 minutes to 20.2 minutes) for patients receiving colorectal and gynecology surgery, respectively. The overall mean (SD) reduction of wait time was 33.1 minutes per patient (from 49.4 minutes to 16.3 minutes per patient). Improved accuracy did not adversely inflate time between cases (surgeon wait time). There was marginal improvement (1.5 minutes, from a mean of 70.6 to 69.1 minutes) in time between the end of cases and start of to-follow cases using the predictive model, compared with the control group. Patients spent a mean of 25.2 fewer minutes in the facility before surgery (173.3 minutes vs 148.1 minutes), indicating a potential benefit vis-à-vis available resources for other patients before and after surgery.

Conclusions And Relevance: Implementing machine learning-generated predictions for surgical case durations may improve case duration accuracy, presurgical resource use, and patient wait time, without increasing surgeon wait time between cases.

Trial Registration: ClinicalTrials.gov Identifier: NCT03471377.
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http://dx.doi.org/10.1001/jamasurg.2020.6361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841577PMC
January 2021

Rectal cancer with complete endoscopic response after neoadjuvant therapy: what is the meaning of a positive MRI?

Eur Radiol 2021 Jan 15. Epub 2021 Jan 15.

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

Objectives: To determine the short-term outcomes of discordant tumor assessments between DWI-MRI and endoscopy in patients with treated rectal cancer when tumor-bed diffusion restriction is present ("+DWI").

Methods: In this HIPPA-compliant, IRB-approved retrospective study, rectal MRI and endoscopic reports were reviewed for patients with locally advanced primary rectal adenocarcinoma (LARC) treated with chemoradiotherapy or total neoadjuvant therapy and imaged between January 2016 and December 2019. Eligible patients had a +DWI and endoscopy within 2 weeks of each other. True positive MRI were those with tumor on endoscopy and/or biopsy (TP) or in whom endoscopy was negative for tumor, but subsequent 3-month follow-up endoscopy and DWI were both positive (TP). The positive predictive value of DWI-MRI was calculated on a per-scan and per-patient basis. DWI-negative MRI exams were not explored in this study.

Results: In total, 397 patients with nonmetastatic primary LARC were analyzed. After exclusions, 90 patients had 98 follow-up rectal MRI studies with +DWI. Seventy-six patients underwent 80 MRI scans and had concordant findings at endoscopy (TPa). Seventeen patients underwent 18 MRI scans and had discordant findings at endoscopy (FP); among these, 4 scans in 4 patients were initially false positive (FP) but follow-up MRI remained +DWI and the endoscopy turned concordantly positive (TP). PPV was 0.86 per scan and per patient. In 4/18 (22%) scans and 4/17 (24%) patients with discordances, MRI detected tumor regrowth before endoscopy.

Conclusions: Although most +DWI exams discordant with endoscopy are false positive, 22% will reveal that DWI-MRI detects tumor recurrence before endoscopy.

Key Points: • Most often, in post-treatment assessment for rectal cancer when DWI-MRI shows restriction in the tumor bed and endoscopy shows no tumor, +DWI MRI will be proven false positive. • Conversely, our study demonstrated that, allowing for sequential follow-up at a 3-month maximum interval, DWI-MRI may detect tumor presence in the treated tumor bed before endoscopy in 22% of discordant findings between DWI-MRI and endoscopy. • Our results showed that a majority of DWI-MRI-positive scans in treated rectal cancer concur with the presence of tumor on endoscopy performed within 2 weeks.
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http://dx.doi.org/10.1007/s00330-020-07657-0DOI 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

Comparative analysis of the Memorial Sloan Kettering Bowel Function Instrument and the Low Anterior Resection Syndrome Questionnaire for assessment of bowel dysfunction in rectal cancer patients after low anterior resection.

Colorectal Dis 2021 Feb 10;23(2):451-460. Epub 2021 Feb 10.

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

Aim: Neoadjuvant therapy and total mesorectal excision (TME) for rectal cancer are associated with bowel dysfunction symptoms known as low anterior resection syndrome (LARS). Our study compared the only two validated instruments-the LARS Questionnaire (LARS-Q) and the Memorial Sloan Kettering Bowel Function Instrument (MSK-BFI)-in rectal cancer patients undergoing sphincter-preserving TME.

Methods: One hundred and ninety patients undergoing sphincter-preserving TME for Stage I-III rectal cancer completed the MSK-BFI and LARS-Q simultaneously at a median time of 12 (range 1-43) months after restoration of bowel continuity. Associations between the MSK-BFI total/subscale scores and the LARS-Q score were investigated using Spearman rank correlation (r ). Discriminant validity for the two questionnaires was assessed, and the questionnaires were compared with the European Quality of Life Instrument.

Results: Major LARS was identified in 62% of patients. The median MSK-BFI scores for no LARS, minor LARS and major LARS were 76.5, 70 and 57, respectively. We found a strong association between MSK-BFI and LARS-Q (r -0.79). The urgency/soilage subscale (r -0.7) and the frequency subscale (r -0.68) of MSK-BFI strongly correlated with LARS-Q. Low correlation was observed between the MSK-BFI diet subscale and LARS-Q (r -0.39). On multivariate analysis, both questionnaires showed worse bowel function in patients with distal tumours. A low to moderate correlation with the European Quality of Life Instrument was observed for both questionnaires.

Conclusions: The MSK-BFI and LARS-Q showed good correlation and similar discriminant validity. As the LARS-Q is easier to complete, it may be considered the preferred tool to screen for bowel dysfunction.
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http://dx.doi.org/10.1111/codi.15515DOI Listing
February 2021

Primary Tumor-Related Complications and Salvage Outcomes in Patients with Metastatic Rectal Cancer and an Untreated Primary Tumor.

Dis Colon Rectum 2021 Jan;64(1):45-52

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

Background: For rectal cancer with unresectable metastases, current practice favors omitting interventions directed at the primary tumor in asymptomatic patients.

Objective: This study aimed to determine the proportion of patients with primary tumor-related complications, characterize salvage outcomes, and measure survival in patients with metastatic rectal cancer who did not undergo upfront intervention for their primary tumor.

Design: This is a retrospective analysis.

Setting: This study was conducted at a comprehensive cancer center.

Patients: Patients who presented between January 1, 2008, and December 31, 2015, with synchronous stage IV rectal cancer, an unresected primary tumor, and no prior primary tumor-directed intervention were selected.

Main Outcome Measures: The main outcome measured was the rate of primary tumor-related complications in the cohort that did not receive any primary tumor-directed intervention. The Kaplan-Meier method and Cox regression analysis were used to determine whether complications are associated with survival.

Results: The cohort comprised 358 patients with a median age of 56 years (22-92). Median follow-up was 26 months (range, 1-93 months). Among the 168 patients (46.9%) who eventually underwent elective resection of the primary tumor, the surgery was performed with curative intent in 66 patients (18.4%) and preemptive intent in 102 patients (28.5%). Of the 190 patients who did not undergo an upfront or elective intervention for the primary tumor, 68 (35.8%) experienced complications. Nonsurgical intervention for complications was attempted in 34 patients with an overall success rate of 61.8% (21/34). Surgical intervention was performed in 47 patients (including 13 patients for whom nonsurgical intervention failed): diversion in 26 patients and resection in 21 patients. Of those 47 patients, 42 (89.4%) ended up with a colostomy or ileostomy.

Limitations: This study was conducted at a single center.

Conclusion: A significant proportion of patients with metastatic rectal cancer and untreated primary tumor experience primary tumor-related complications. These patients should be followed closely, and preemptive intervention (resection, diversion, or radiation) should be considered if the primary tumor progresses despite systemic therapy. See Video Abstract at http://links.lww.com/DCR/B400. COMPLICACIONES RELACIONADAS CON EL TUMOR PRIMARIO Y RESULTADOS DE RESCATE EN PACIENTES CON CÁNCER DE RECTO METASTÁSICO Y UN TUMOR PRIMARIO NO TRATADO: Para el cáncer de recto con metástasis no resecables, la práctica actual favorece la omisión de las intervenciones dirigidas al tumor primario en pacientes asintomáticos.Determinar la proporción de pacientes con complicaciones relacionadas con el tumor primario, caracterizar los resultados de rescate y medir la supervivencia en pacientes con cáncer rectal metastásico que no se sometieron a una intervención inicial para su tumor primario.Análisis retrospectivo.Centro oncológico integral.Pacientes que se presentaron entre el 1 de enero de 2008 y el 31 de diciembre de 2015 con cáncer de recto en estadio IV sincrónico, un tumor primario no resecado y sin intervención previa dirigida al tumor primario.Tasa de complicaciones relacionadas con el tumor primario en la cohorte que no recibió ninguna intervención dirigida al tumor primario. Se utilizó el método de Kaplan-Meier y el análisis de regresión de Cox para determinar si las complicaciones están asociadas con la supervivencia.La cohorte estuvo compuesta por 358 pacientes con una mediana de edad de 56 años (22-92). La mediana de seguimiento fue de 26 meses (rango, 1 a 93 meses). Entre los 168 pacientes (46,9%) que finalmente se sometieron a resección electiva del tumor primario, la cirugía se realizó con intención curativa en 66 pacientes (18,4%) y con intención preventiva en 102 pacientes (28,5%). De los 190 pacientes que no se sometieron a una intervención inicial o electiva para el tumor primario, 68 (35,8%) experimentaron complicaciones. Se intentó una intervención no quirúrgica para las complicaciones en 34 pacientes con una tasa de éxito global del 61,8% (21 de 34). La intervención quirúrgica se realizó en 47 pacientes (incluidos 13 pacientes en los que falló la intervención no quirúrgica): derivación en 26 pacientes y resección en 21 pacientes. De esos 47 pacientes, 42 (89,4%) terminaron con una colostomía o ileostomía.Único centro.Una proporción significativa de pacientes con cáncer de recto metastásico y primario no tratado experimentan complicaciones relacionadas con el tumor primario. Se debe hacer un seguimiento estrecho de estos pacientes y considerar la posibilidad de una intervención preventiva (resección, derivación o radiación) si el tumor primario progresa a pesar de la terapia sistémica. Consulte Video Resumen en http://links.lww.com/DCR/B400.
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http://dx.doi.org/10.1097/DCR.0000000000001803DOI Listing
January 2021

Quantitative assessment of tumor-infiltrating lymphocytes in mismatch repair proficient colon cancer.

Oncoimmunology 2020 11 11;9(1):1841948. Epub 2020 Nov 11.

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

Tumor infiltrating lymphocytes (TIL), which represent host adaptive response to the tumor, were first identified at scanning magnification to select areas with the highest counts on hematoxylin and eosin slides, quantitated per high-power field (HPF), and analyzed for association with recurrence-free survival (RFS) in 848 patients. Highest TIL in a single HPF was analyzed as a continuous and categorical variable, and optimal cutoff analysis was performed to predict RFS. Highest TIL count in a single HPF ranged from 0 to 45, and the optimal cutoff for TIL high vs TIL low was determined to be ≥ 3 vs < 3 with a concordance probability estimate of 0.74. In the entire cohort, 5-year RFS was 90.2% (95% CI = 83.7-94.2) in TIL high compared to 78.9% (95% CI = 74.1-82.9) in TIL low (log rank < .0001). TIL remained significant in the mismatch repair-proficient (pMMR) cohort where 5-year RFS was 94.6% (95% CI = 88.3-97.5) in TIL high compared to 77.9% (95% CI = 69.2-84.4) in TIL low ( = .008). On multivariable analysis, TIL and AJCC Stage were independently associated with RFS in the pMMR cohort. Qualitatively in the pMMR cohort, RFS in Stage II TIL high patients was similar to that in Stage I patients and RFS in Stage III TIL high was similar to that in Stage II TIL low patients. Assessment of TIL in a single HPF using standard H&E slides provides important prognostic information independent of MMR status and AJCC stage.
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http://dx.doi.org/10.1080/2162402X.2020.1841948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671050PMC
November 2020

Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma.

Clin Cancer Res 2021 Mar 16;27(5):1429-1437. Epub 2020 Nov 16.

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

Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.

Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (, and ). Clinical variables were correlated with MMR/MSI status.

Results: Twenty-six percent (26/100; 95% confidence interval, 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome ( = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group ( = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group ( = 0.0002).

Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2892DOI Listing
March 2021

Monitoring an Ongoing Enhanced Recovery After Surgery (ERAS) Program: Adherence Improves Clinical Outcomes in a Comparison of Three Thousand Colorectal Cases.

Clin Surg 2020 Aug 10;5. Epub 2020 Aug 10.

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

Aim: In 2014, Memorial Sloan Kettering Cancer Center was identified as an outlier for increased length of stay (LOS) after colorectal surgery. We subsequently implemented a comprehensive Enhanced Recovery After Surgery (ERAS) program in January 2016, which is continually monitored to target areas for improvement. The primary aim of this study was to evaluate the impact of a newly established ERAS program in a high-volume colorectal center over time.

Method: This was a retrospective cohort study, comparing 3000 sequential cancer patients who underwent elective colorectal surgery before and after ERAS implementation. Patients were divided into three groups (Pre-, Early, and Late ERAS). Adherence to ERAS process measures and outcomes (LOS, complications, and 30-day readmission) were compared among the three time periods.

Results: Adherence to ERAS metrics significantly increased over time, from a median of 25% Pre-ERAS to 67% Early and 75% Late ERAS ( < 0.0001). Mean LOS decreased from 5.2 days Pre-ERAS to 4.5 Early and 4.0 Late ERAS ( < 0.0001). There were no differences in rates of complications or readmissions, and patients with shorter LOS had lower readmission rates. With ERAS, the readmission rate was 4.4% for patients discharged within 3 days, versus >10% for LOS ≥5 days ( < 0.0001).

Conclusion: Initiation of an ERAS program at a high-volume colorectal center was associated with decreased LOS, without increasing morbidity. Increased ERAS adherence was associated with a further decrease in LOS. Multidisciplinary monitoring to promote protocol adherence is necessary for maintaining a safe and effective ERAS program.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643765PMC
August 2020

Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline.

Pract Radiat Oncol 2021 Jan-Feb;11(1):13-25. Epub 2020 Oct 21.

Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas. Electronic address:

Purpose: This guideline reviews the evidence and provides recommendations for the indications and appropriate technique and dose of neoadjuvant radiation therapy (RT) in the treatment of localized rectal cancer.

Methods: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on the use of RT in preoperative management of operable rectal cancer. These questions included the indications for neoadjuvant RT, identification of appropriate neoadjuvant regimens, indications for consideration of a nonoperative or local excision approach after chemoradiation, and appropriate treatment volumes and techniques. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.

Results: Neoadjuvant RT is recommended for patients with stage II-III rectal cancer, with either conventional fractionation with concurrent 5-FU or capecitabine or short-course RT. RT should be performed preoperatively rather than postoperatively. Omission of preoperative RT is conditionally recommended in selected patients with lower risk of locoregional recurrence. Addition of chemotherapy before or after chemoradiation or after short-course RT is conditionally recommended. Nonoperative management is conditionally recommended if a clinical complete response is achieved after neoadjuvant treatment in selected patients. Inclusion of the rectum and mesorectal, presacral, internal iliac, and obturator nodes in the clinical treatment volume is recommended. In addition, inclusion of external iliac nodes is conditionally recommended in patients with tumors invading an anterior organ or structure, and inclusion of inguinal and external iliac nodes is conditionally recommended in patients with tumors involving the anal canal.

Conclusions: Based on currently published data, the American Society for Radiation Oncology task force has proposed evidence-based recommendations regarding the use of RT for rectal cancer. Future studies will look to further personalize treatment recommendations to optimize treatment outcomes and quality of life.
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http://dx.doi.org/10.1016/j.prro.2020.08.004DOI Listing
October 2020

Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies.

Fam Cancer 2020 Oct 9. Epub 2020 Oct 9.

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

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one-and not all-PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.
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http://dx.doi.org/10.1007/s10689-020-00210-4DOI Listing
October 2020

Correction to: Primary Tumor Location and Outcomes After Cytoreductive Surgery and Intraperitoneal Chemotherapy for Peritoneal Metastases of Colorectal Origin.

Ann Surg Oncol 2020 Dec;27(Suppl 3):987

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

In the original article there is a reference missing, in addition to its citations in the text. The reference is as follows.
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http://dx.doi.org/10.1245/s10434-020-09191-1DOI Listing
December 2020

Primary Tumor Location and Outcomes After Cytoreductive Surgery and Intraperitoneal Chemotherapy for Peritoneal Metastases of Colorectal Origin.

Ann Surg Oncol 2021 Feb 25;28(2):1109-1117. Epub 2020 Aug 25.

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

Background: The aim of this study is to evaluate outcomes in patients with peritoneal metastasis of colorectal cancer (pmCRC) who underwent cytoreductive surgery and intraperitoneal chemotherapy (CRS/IPC) in relation to the location of the primary tumor. Regional therapy, including cytoreductive surgery and intraperitoneal chemotherapy, has been associated with improved survival in patients with pmCRC. Location of the primary tumor has been shown to be prognostic in patients with metastasis.

Patients And Methods: A retrospective review was performed for all patients who underwent complete cytoreduction and intraperitoneal chemotherapy from 2010 to 2017, examining patient and tumor characteristics, overall and recurrence-free survival, recurrence patterns, and tumor mutational profiles.

Results: Ninety-three patients were included in the study: 49 (53%) with a right-sided and 44 (47%) with a left-sided primary tumor. Patients with a right-sided tumor had significantly shorter recurrence-free survival (median, 6.3 months; 95% CI, 4.7-8.1 months vs 12.3 months; 95% CI, 3.6-21.7 months; P = 0.02) and overall survival (median, 36.6 months; 95% CI, 26.4-46.9 months vs 83.3 months; 95% CI 44.2-122.4 months; P = 0.03). BRAF and KRAS mutations were more frequent in right-sided tumors, and APC and TP53 mutations were more frequent in left-sided tumors, which were more chromosomally instable. BRAF mutations were associated with early recurrence.

Conclusions: Tumor sidedness is a predictor of oncological outcomes after CRS/IPC. Tumor sidedness and molecular characteristics should be considered when counseling patients regarding expected outcomes and when selecting or stratifying pmCRC patients for clinical trials of regional therapy.
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http://dx.doi.org/10.1245/s10434-020-08993-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855731PMC
February 2021

L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer.

Nat Cancer 2020 Jan 13;1(1):28-45. Epub 2020 Jan 13.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAM cells partially overlap with LGR5 stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin-REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAM to an L1CAM state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.
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http://dx.doi.org/10.1038/s43018-019-0006-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351134PMC
January 2020

Non Surgical Treatment in Patients With Advanced Rectal Cancer.

Cir Esp 2020 Jul 2. Epub 2020 Jul 2.

Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Nueva York, Estados Unidos. Electronic address:

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http://dx.doi.org/10.1016/j.ciresp.2020.06.003DOI Listing
July 2020

Outcome measures in multimodal rectal cancer trials.

Lancet Oncol 2020 05;21(5):e252-e264

Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany; Frankfurt Cancer Institute, Frankfurt Germany.

There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.
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http://dx.doi.org/10.1016/S1470-2045(20)30024-3DOI Listing
May 2020

Watch and Wait in Rectal Cancer or More Wait and See?

JAMA Surg 2020 07;155(7):657-658

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

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http://dx.doi.org/10.1001/jamasurg.2020.0226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483390PMC
July 2020

Confirmation of complete mesocolic excision with central vascular ligation.

Eur J Surg Oncol 2020 07 18;46(7):1386-1387. Epub 2020 Apr 18.

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

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http://dx.doi.org/10.1016/j.ejso.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372914PMC
July 2020

Management of Locally Advanced Rectal Cancer During The COVID-19 Pandemic: A Necessary Paradigm Change at Memorial Sloan Kettering Cancer Center.

Adv Radiat Oncol 2020 Jul-Aug;5(4):687-689. Epub 2020 Apr 22.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

The COVID-19 pandemic will consume significant health care resources. Given the concerns for rapidly increasing infection rates in the United States, impending staffing shortages, and the potential for resource reallocation, we rapidly reevaluated our rectal cancer practice policies during this public health emergency. Before the pandemic, we commonly used total neoadjuvant therapy with a strong preference for long-course chemoradiation. In the setting of the ongoing pandemic, we now mandate short-course radiation therapy (SCRT). Despite multiple randomized trials demonstrating no difference in locoregional recurrence, distant recurrence, or overall survival between SCRT and long-course chemoradiation, the adaptation of SCRT in the United States has been low given concerns for less tumor downstaging and increased toxicity. In the setting of the ongoing and likely prolonged COVID-19 pandemic, we feel that these concerns must be reevaluated, because SCRT presents a well-validated alternative that will allow us to meet the needs of a greater number of potentially curable patients at a time when resources are severely and acutely constrained.
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http://dx.doi.org/10.1016/j.adro.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175910PMC
April 2020

Organ Preservation in Rectal Cancer.

J Gastrointest Surg 2020 Aug 20;24(8):1880-1888. Epub 2020 Apr 20.

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

A proportion of patients with rectal cancer who undergo neoadjuvant treatment end up with a complete pathological response. Because these patients have excellent oncological outcomes, many have questioned if surgical treatment in this population constitutes overtreatment. There is growing interest in watch and wait with selective organ preservation for rectal cancer patients. We review the fundamentals and key considerations of this approach including patient selection, available treatment regimens, assessment of response, long-term monitoring of response, and long-term oncological and functional outcomes.
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http://dx.doi.org/10.1007/s11605-020-04583-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390702PMC
August 2020

Clinical utility of radiomics at baseline rectal MRI to predict complete response of rectal cancer after chemoradiation therapy.

Abdom Radiol (NY) 2020 11;45(11):3608-3617

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Purpose: To investigate the value of T2-radiomics combined with anatomical MRI staging criteria from pre-treatment rectal MRI in predicting complete response to neoadjuvant chemoradiation therapy (CRT).

Methods: This retrospective study included patients with locally advanced rectal cancer who underwent rectal MRI before neoadjuvant CRT from October 2011 to January 2015 and then surgery. Surgical histopathologic analysis was used as the reference standard for pathologic complete response. Anatomical MRI staging criteria were extracted from our institutional standardized radiology report. In radiomics analysis, one radiologist manually segmented the primary tumor on T2-weighted images for all 102 patients (i.e., training set); two different radiologists independently segmented 66/102 patients (i.e., validation set). 108 radiomics features were extracted. Then, scanner-independent features were identified and least absolute shrinkage operator analysis was used to extract a radiomics score. Finally, a support vector machine model combining the radiomics score and anatomical MRI staging criteria was compared against both anatomical MRI-only and radiomics-only models using the deLong test.

Results: The study included 102 patients (42 women; median age = 61 years).The radiomics score produced an area under the curve (AUC) of 0.75. Comparable results were found using the validation set (AUCs = 0.75 and 0.71 for each radiologist, respectively). The anatomical MRI-only model had an accuracy of 67% (sensitivity 42%, specificity 72%); when adding the radiomics score, the accuracy increased to 74% (sensitivity 58%, specificity 77%).

Conclusion: Combining T2-radiomics and anatomical MRI staging criteria from pre-treatment rectal MRI may help to stratify patients based on the prediction of treatment response to neoadjuvant therapy.
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http://dx.doi.org/10.1007/s00261-020-02502-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572430PMC
November 2020

Patient-Reported Bowel Function in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy After Neoadjuvant Therapy: A Case-Control Study.

Dis Colon Rectum 2020 07;63(7):897-902

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

Background: A watch-and-wait strategy is a nonoperative alternative to sphincter-preserving surgery for patients with locally advanced rectal cancer who achieve a clinical complete response after neoadjuvant therapy. There are limited data about bowel function for patients undergoing this organ-preservation approach.

Objective: The purpose of this study was to compare bowel function in patients with rectal cancer managed with a watch-and-wait approach with bowel function in patients who underwent sphincter-preserving surgery (total mesorectal excision).

Design: This was a retrospective case-control study using patient-reported outcomes.

Settings: The study was conducted at a comprehensive cancer center.

Patients: Twenty-one patients underwent a watch-and-wait approach and were matched 1:1 with 21 patients from a pool of 190 patients who underwent sphincter-preserving surgery, based on age, sex, and tumor distance from the anal verge.

Main Outcome Measures: Bowel function was measured using the Memorial Sloan Kettering Cancer Center Bowel Function Instrument.

Results: Patients in the watch-and-wait arm had better bowel function on the overall scale (median total score, 76 vs 55; p < 0.001) and on all of the subscales, with the greatest difference on the urgency/soilage subscale (median score, 20 vs 12; p < 0.001).

Limitations: The study was limited by its retrospective design, small sample size, and temporal variability between surgery and time of questionnaire completion.

Conclusions: A watch-and-wait strategy correlated with overall better bowel function when compared with sphincter-preserving surgery using a comprehensive validated bowel dysfunction tool. See Video Abstract at http://links.lww.com/DCR/B218. FUNCIÓN EVACUATORIA INFORMADA POR PACIENTES EN CÁNCER RECTAL MANEJADO CON UNA ESTRATEGIA DE OBSERVAR Y ESPERAR DESPUÉS DE LA TERAPIA NEOADYUVANTE: UN ESTUDIO DE CASOS Y CONTROLES: Observar y esperar es una alternativa no operativa a la cirugía de preservación del esfínter para pacientes con cáncer rectal localmente avanzado que logran una respuesta clínica completa después de la terapia neoadyuvante. Hay datos limitados sobre la función evacuatoria en pacientes sometidos a este abordaje para preservación de órganos.Evaluar la función evacuatoria en pacientes con cáncer rectal manejados con observar y esperar comparado a pacientes sometidos a cirugía de preservación de esfínteres (escisión mesorrectal total).Estudio retrospectivo de casos y controles utilizando resultados reportados por pacientes.Centro especializado oncológico.21 pacientes se sometieron a observar y esperar y se compararon con 21 pacientes de un grupo de 190 pacientes que se sometieron a cirugía de preservación de esfínteres controlando por edad, sexo y la distancia del tumor al borde anal.Función evacuatoria utilizando un instrumento de valoración del Centro de Cáncer Memorial Sloan Kettering.Los pacientes de observar y esperar demostraron mejor función evacuatoria en la escala general (puntuación total media, 76 versus 55; p <0,001) y en todas las subescalas, con la mayor diferencia en la subescala de urgencia / ensuciamiento fecal (puntuación media, 20 versus 12; p <0,001).Diseño retrospectivo, numero de muestra pequeño y variabilidad temporal entre la cirugía y el tiempo de finalización del cuestionario.Observar y esperar se correlacionó con mejor función evacuatoria en general en comparación con la cirugía de preservación del esfínter utilizando una herramienta integral validada para la disfunción evacuatoria. Consulte Video Resumen en http://links.lww.com/DCR/B218. (Traducción-Dr. Adrián Ortega).
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http://dx.doi.org/10.1097/DCR.0000000000001646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274891PMC
July 2020

Intracorporeal Anastomoses in Minimally Invasive Right Colectomies Are Associated With Fewer Incisional Hernias and Shorter Length of Stay.

Dis Colon Rectum 2020 05;63(5):685-692

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

Background: Intracorporeal anastomosis is associated with several short-term benefits. However, it is a technically challenging procedure with potential risk OBJECTIVE:: The purpose of this study was to investigate differences in short-term complications and long-term incisional hernia rates after robotic right colectomy with intracorporeal versus extracorporeal anastomoses and standardized extraction sites.

Design: This was a historical cohort study.

Settings: The study was conducted at a single institution.

Patients: All of the patients undergoing robotic right colectomy with intracorporeal anastomosis and a Pfannenstiel extraction site or extracorporeal anastomosis with a vertical midline extraction site from 2013 to 2017 were eligible. Exclusion criteria were conversion to laparotomy for tumor-related reasons or lack of follow-up.

Intervention: Intracorporeal or extracorporeal anastomosis was performed, based on availability of the robotic stapler and appropriate bedside assistance.

Main Outcome Measures: The primary outcome was incisional hernia, diagnosed either clinically or on postoperative imaging, and analyzed using time-to-event analysis. A Cox proportional hazards model was used for multivariable analysis. Secondary outcomes were analyzed using parametric and nonparametric tests. Statistical significance was set at p < 0.05.

Results: Of 164 patients who met all inclusion criteria, 67 had intracorporeal and 97 had extracorporeal anastomoses. Median follow-up time was similar in both groups (14 vs 15 mo; p = 0.73). The 1-year estimated incisional hernia rate was 12% for extracorporeal and 2% for intracorporeal anastomoses (p = 0.007); this difference was confirmed by multivariable modeling. The severity of postoperative complications was similar between the groups, but there was an increase in incisional infections and a shorter length of stay (1 day) for intracorporeal cases.

Limitations: The study was limited by its retrospective, single-surgeon nature.

Conclusions: Right colectomy with intracorporeal anastomosis and a Pfannenstiel extraction site may reduce the rate of incisional hernias compared with extracorporeal anastomosis with a vertical midline extraction site. The intracorporeal approach was also associated with a decreased length of stay but an increase in incisional surgical site infections. These findings have implications for healthcare use and patient-centered outcomes. See Video Abstract at http://links.lww.com/DCR/B147. ANASTOMOSIS INTRACORPÓREAS EN COLECTOMÍAS DERECHAS MÍNIMAMENTE INVASIVAS SE ASOCIAN CON MENOS HERNIAS INCISIONALES Y UNA ESTADÍA HOSPITALARIA MÁS BREVE: nastomosis intracorpórea se asocia con varios beneficios a corto plazo. Sin embargo, es un procedimiento técnicamente desafiante con riesgos potenciales.nvestigar las diferencias en las complicaciones a corto plazo y las tasas de hernia incisional a largo plazo después de la colectomía robótica derecha con anastomosis intracorpórea versus extracorpórea y sitios de extracción estandarizados.Estudio de cohorte histórico.cirujano individual, institución única.Todos los pacientes sometidos a colectomía robótica derecha con anastomosis intracorpórea y un sitio de extracción de Pfannenstiel o anastomosis extracorpórea con un sitio de extracción vertical de la línea media de 2013-2017 fueron elegibles. Los criterios de exclusión fueron la conversión a laparotomía por razones relacionadas con el tumor o la falta de seguimiento.nastomosis intracorpórea o extracorpórea, según la disponibilidad de grapadora robótica y la asistencia adecuada quirúrgica.El resultado primario fue la hernia incisional, diagnosticada clínicamente o en imágenes postoperatorias, y analizada mediante análisis de tiempo hasta el evento. Se usó un modelo de riesgos proporcionales de Cox para el análisis multivariable. Los resultados secundarios se analizaron mediante pruebas paramétricas y no paramétricas. La significación estadística se estableció en p < 0,05.De 164 pacientes que cumplieron con todos los criterios de inclusión, 67 tenían anastomosis intracorpóreas y 97 tenían anastomosis extracorpóreas. La mediana del tiempo de seguimiento fue similar en ambos grupos (14 versus 15 meses, p = 0,73). La tasa de hernia incisional estimada para un año fue del 12% para las anastomosis extracorpóreas y del 2% para las anastomosis intracorpóreas (p = 0,007); esta diferencia fue confirmada por el modelado multivariable. La gravedad de las complicaciones postoperatorias fue similar entre los grupos, pero hubo un aumento de las infecciones incisionales y una estancia más corta (un día) para los casos intracorpóreos.Retrospectiva, cirujano único.a colectomía derecha con anastomosis intracorpórea y un sitio de extracción de Pfannenstiel puede reducir la tasa de hernias incisionales en comparación con la anastomosis extracorpórea con un sitio de extracción vertical en la línea media. El enfoque intracorpóreo también se asoció con una disminución de la duración de la estadía, pero con un aumento de las infecciones del sitio quirúrgico incisional. Estos hallazgos tienen implicaciones para la utilización de recursos médicos y beneficios para pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B147. (Traducción-Dr. Adrian Ortega).
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http://dx.doi.org/10.1097/DCR.0000000000001612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148181PMC
May 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

Risk of Metachronous Colorectal Neoplasm after a Segmental Colectomy in Lynch Syndrome Patients According to Mismatch Repair Gene Status.

J Am Coll Surg 2020 04 30;230(4):669-675. Epub 2020 Jan 30.

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

Background: Because of increased risk of metachronous colorectal cancer (CRC), all patients with Lynch syndrome (LS) are offered a total colectomy. However, because metachronous CRC rate by mismatch repair (MMR) gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy.

Study Design: Single-center, retrospective cohort study in patients with an earlier colectomy for CRC and an MMR germline mutation in MLH1, MSH2, MSH6, or PMS2 followed prospectively in a hereditary CRC family registry. All patients underwent surveillance colonoscopy. Metachronous CRC was defined as one detected more than 1 year after index resection. Primary end point was cumulative incidence of metachronous CRC overall and by MMR gene.

Results: One hundred and ten patients were included: 35 with MLH1 likely pathogenic/pathogenic (LP/P) variants (32%), 42 MSH2 (38%), 20 MSH6 (18%), and 13 PMS2 (12%). Median follow-up 4.26 years (range 0.53 to 19.92 years). Overall, metachronous CRC developed in 22 patients (20%). At 10-year follow-up, incidence was 12% (95% CI 6% to 23%), with no metachronous CRC detected in patients with a PMS2 or MSH6 LP/P variant.

Conclusions: After index segmental resection, metachronous CRC is less likely to develop in LS patients with MSH6 or PMS2 LP/P variant than in MLH1 or MSH2 carriers. Our data support segmental resection and long-term colonoscopic surveillance rather than total colectomy in carefully selected, well-informed LS patients with MSH6 or PMS2 LP/P variant.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104918PMC
April 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

A rectal cancer organoid platform to study individual responses to chemoradiation.

Nat Med 2019 10 7;25(10):1607-1614. Epub 2019 Oct 7.

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

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.
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http://dx.doi.org/10.1038/s41591-019-0584-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385919PMC
October 2019

Genomic stratification beyond Ras/B-Raf in colorectal liver metastasis patients treated with hepatic arterial infusion.

Cancer Med 2019 11 10;8(15):6538-6548. Epub 2019 Sep 10.

Department of Medicine, MSKCC, New York City, New York, USA.

Background: Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit.

Methods: We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK-IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels.

Results: Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver-restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B-Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co-alteration of Ras/B-Raf and TP53 had worse OS. Similar findings were observed in a validation cohort.

Conclusions: Concurrently altered Ras/B-Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B-Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B-Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI.
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http://dx.doi.org/10.1002/cam4.2415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825986PMC
November 2019

Lateral Nodal Features on Restaging Magnetic Resonance Imaging Associated With Lateral Local Recurrence in Low Rectal Cancer After Neoadjuvant Chemoradiotherapy or Radiotherapy.

JAMA Surg 2019 09 18;154(9):e192172. Epub 2019 Sep 18.

Department of Surgery, Amsterdam University Medical Centers, location VUmc, Amsterdam, the Netherlands.

Importance: Previously, it was shown in patients with low rectal cancer that a short-axis (SA) lateral node size of 7 mm or greater on primary magnetic resonance imaging (MRI) resulted in a high lateral local recurrence (LLR) rate after chemoradiotherapy or radiotherapy ([C]RT) with total mesorectal excision (TME) and that this risk was lowered by a lateral lymph node dissection (LLND). The role of restaging MRI after (C)RT with regard to LLR risk and which specific patients might benefit from an LLND is not fully understood.

Objective: To determine the factors on primary and restaging MRI that are associated with LLR in low rectal cancer after (C)RT and to formulate specific guidelines on which patients might benefit from an LLND.

Design, Setting, And Participants: In this retrospective, multicenter, pooled cohort study, patients who underwent surgery for cT3 or cT4 low rectal cancer with a curative intent from 12 centers in 7 countries from January 2009 to December 2013 were included. All patients' MRIs were rereviewed according to a standardized protocol, with specific attention to lateral nodal features. The original cohort included 1216 patients. For this study, patients who underwent (C)RT and had a restaging MRI were selected, leaving 741 for analyses across 10 institutions, including 651 who underwent (C)RT with TME and 90 who underwent (C)RT with TME and LLND.

Main Outcomes And Measures: The main purpose was to identify the factors on primary and restaging MRI associated with LLR after (C)RT with TME. Whether high-risk patients might benefit in terms of LLR reduction from an LLND was also studied.

Results: Of the 741 included patients, 480 (64.8%) were male, and the mean (SD) age was 60.4 (12.0) years. An SA lateral node size of 7 mm or greater on primary MRI resulted in a 5-year LLR rate of 17.9% after (C)RT with TME. At 3 years, there were no LLRs in 28 patients (29.2%) with lateral nodes that were 4 mm or less on restaging MRI. Nodes that were 7 mm or greater on primary MRI and greater than 4 mm on restaging MRI in the internal iliac compartment resulted in a 5-year LLR rate of 52.3%, significantly higher compared with nodes in the obturator compartment of that size (9.5%; hazard ratio, 5.8; 95% CI, 1.6-21.3; P = .003). Compared with (C)RT with TME alone, treatment with (C)RT with TME and LLND in these unresponsive internal nodes resulted in a significantly lower LLR rate of 8.7% (hazard ratio, 6.2; 95% CI, 1.4-28.5; P = .007).

Conclusions And Relevance: Restaging MRI is important in clinical decision making in lateral nodal disease. In patients with shrinkage of lateral nodes from an SA node size of 7 mm or greater on primary MRI to an SA node size of 4 mm or less on restaging MRI, which occurs in about 30% of cases, LLND can be avoided. However, persistently enlarged nodes in the internal iliac compartment indicate an extremely high risk of LLR, and an LLND lowered LLR in these cases.
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http://dx.doi.org/10.1001/jamasurg.2019.2172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613303PMC
September 2019

Looking Forward, Not Backward, on Watch and Wait for Rectal Cancer-In Reply.

JAMA Oncol 2019 Jun 27. Epub 2019 Jun 27.

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

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http://dx.doi.org/10.1001/jamaoncol.2019.1887DOI Listing
June 2019

Assessment of the Value of Comorbidity Indices for Risk Adjustment in Colorectal Surgery Patients.

Ann Surg Oncol 2019 Sep 17;26(9):2797-2804. Epub 2019 Jun 17.

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

Background And Purpose: Comorbidity indices (CIs) are widely used in retrospective studies. We investigated the value of commonly used CIs in risk adjustment for postoperative complications after colorectal surgery.

Methods: Patients undergoing colectomy without stoma for colonic neoplasia at a single institution from 2009 to 2014 were included. Four CIs were calculated or obtained for each patient, using administrative data: Charlson-Deyo (CCI-D), Charlson-Romano (CCI-R), Elixhauser Comorbidity Score, and American Society of Anesthesiologists classification. Outcomes of interest in the 90-day postoperative period were any surgical complication, surgical site infection (SSI), Clavien-Dindo (CD) grade 3 or higher complication, anastomotic leak or abscess, and nonroutine discharge. Base models were created for each outcome based on significant bivariate associations. Logistic regression models were constructed for each outcome using base models alone, and each index as an additional covariate. Models were also compared using the DeLong and Clarke-Pearson method for receiver operating characteristic (ROC) curves, with the CCI-D as the reference.

Results: Overall, 1813 patients were included. Postoperative complications were reported in 756 (42%) patients. Only 9% of patients had a CD grade 3 or higher complication, and 22.8% of patients developed an SSI. Multivariable modeling showed equivalent performance of the base model and the base model augmented by the CIs for all outcomes. The ROC curves for the four indices were also similar.

Conclusions: The inclusion of CIs added little to the base models, and all CIs performed similarly well. Our study suggests that CIs do not adequately risk-adjust for complications after colorectal surgery.
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http://dx.doi.org/10.1245/s10434-019-07502-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684474PMC
September 2019