Publications by authors named "Philip Paty"

235 Publications

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

J Clin Oncol 2021 Mar 13;39(8):911-919. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02553DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000001803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931667PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925361PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643765PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08993-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855731PMC
February 2021

Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage.

Metabolites 2020 Jun 19;10(6). Epub 2020 Jun 19.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers ( = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon ( = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/metabo10060257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345993PMC
June 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamasurg.2020.0226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483390PMC
July 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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000001646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274891PMC
July 2020

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.

Sci Rep 2020 03 17;10(1):4905. Epub 2020 Mar 17.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.

Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-61851-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078199PMC
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-3728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348681PMC
July 2020

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis.

Elife 2019 12 16;8. Epub 2019 Dec 16.

Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States.

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with leflunomide substantially impaired CRC liver metastatic colonization and hypoxic growth. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis under hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in CRC metastatic progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.52135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299340PMC
December 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056517PMC
March 2020

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity.

Cancer Res 2020 03 5;80(5):1219-1227. Epub 2019 Nov 5.

Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.

Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities. Here, we established a protocol for irradiating organoids that delivers radiation profiles simulating the organ of origin. This technique yielded highly similar dose-survival curves of small and large intestinal crypts and their cognate organoids analyzed by the single-hit multi-target (SHMT) algorithm, outcomes reflecting the inherent radiation profile of their respective Lgr5 stem cell populations. As this technological advance is quantitative, it will be useful for accurate evaluation of intestinal (patho)physiology and drug screening. SIGNIFICANCE: These findings establish standards for irradiating organoids that deliver radiation profiles that phenocopy the organ of origin..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-0312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056505PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-019-0584-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385919PMC
October 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.

View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07502-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684474PMC
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jncics/pkz015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512350PMC
June 2019

Induction Chemotherapy Reduces Patient-reported Toxicities During Neoadjuvant Chemoradiation with Intensity Modulated Radiotherapy for Rectal Cancer.

Clin Colorectal Cancer 2019 09 6;18(3):167-174. Epub 2019 Apr 6.

Department of Radiation Oncology, University of Colorado Denver School of Medicine, Denver, CO. Electronic address:

Background: Initial treatment with either neoadjuvant chemoradiation (CRT) or induction FOLFOX (5-Fluorouracil, leucovorin, and oxaliplatin) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer. We compared patient-reported outcomes (PRO) during CRT in patients who had received induction chemotherapy versus those who did not.

Patients And Methods: We reviewed records of patients with locally advanced rectal cancer who were treated with CRT between September 2009 and October 2014, and who had completed ≥ 4 PRO assessments during treatment. Clinician- and patient-reported toxicities were collected each week during treatment. We fit binomial generalized linear models to maximum toxicity scores across all patients' visits.

Results: Of 123 patients with ≥ 4 PRO assessments, 87 (71%) patients reported a clinically meaningful PRO score of 3 or higher for diarrhea, and 91 (74%) patients reported a PRO score of ≥ 3 for urgency, during 1 or more weeks of treatment, corresponding to 'very frequent' or worse. Of 116 patients who had also completed ≥ 4 clinician-reported assessments for descriptive analysis, clinically significant diarrhea (Common Terminology Criteria for Adverse Events grade ≥ 2) was reported in 9% of patients, and grade 2 proctitis and cystitis were reported in 20% and 4%, respectively. Eighty-four (68%) patients had undergone induction chemotherapy prior to CRT. Patients who received induction chemotherapy had 68% lower odds of experiencing significant urgency (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11-0.95; P = .04), 76% lower odds of bleeding (OR, 0.24; 95% CI, 0.1-0.62; P < .01), and 75% lower odds of tenesmus (OR, 0.25; 95% CI, 0.11-0.6; P < .01) versus those treated with upfront CRT.

Conclusion: Based on PROs, a high proportion of patients experienced clinically significant symptoms during pelvic CRT, with diarrhea and urgency being most commonly reported. This appears to be under-reported on clinician-reported assessments. Delivery of induction chemotherapy was associated with lower odds of experiencing urgency, bleeding, and tenesmus on PROs during subsequent CRT, with no significant impact on diarrhea and rectal pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817304PMC
September 2019

Reducing the Morbidity of Rectal Cancer Treatment.

JAMA Oncol 2019 07;5(7):940-941

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2019.0181DOI Listing
July 2019

Role of the Interval from Completion of Neoadjuvant Therapy to Surgery in Postoperative Morbidity in Patients with Locally Advanced Rectal Cancer.

Ann Surg Oncol 2019 Jul 8;26(7):2019-2027. Epub 2019 Apr 8.

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

Background: Increasing the interval from completion of neoadjuvant therapy to surgery beyond 8 weeks is associated with increased response of rectal cancer to neoadjuvant therapy. However, reports are conflicting on whether extending the time to surgery is associated with increased perioperative morbidity.

Methods: Patients who presented with a tumor within 15 cm of the anal verge in 2009-2015 were grouped according to the interval between completion of neoadjuvant therapy and surgery: < 8 weeks, 8-12 weeks, and 12-16 weeks.

Results: Among 607 patients, the surgery was performed at < 8 weeks in 317 patients, 8-12 weeks in 229 patients, and 12-16 weeks in 61 patients. Patients who underwent surgery at 8-12 weeks and patients who underwent surgery at < 8 weeks had comparable rates of complications (37% and 44%, respectively). Univariable analysis identified male sex, earlier date of diagnosis, tumor location within 5 cm of the anal verge, open operative approach, abdominoperineal resection, and use of neoadjuvant chemoradiotherapy alone to be associated with higher rates of complications. In multivariable analysis, male sex, tumor location within 5 cm of the anal verge, open operative approach, and neoadjuvant chemoradiotherapy administered alone were independently associated with the presence of a complication. The interval between neoadjuvant therapy and surgery was not an independent predictor of postoperative complications.

Conclusions: Delaying surgery beyond 8 weeks from completion of neoadjuvant therapy does not appear to increase surgical morbidity in rectal cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-019-07340-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579536PMC
July 2019

Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy.

JAMA Oncol 2019 Apr 11;5(4):e185896. Epub 2019 Apr 11.

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

Importance: The watch-and-wait (WW) strategy aims to spare patients with rectal cancer unnecessary resection.

Objective: To analyze the outcomes of WW among patients with rectal cancer who had a clinical complete response to neoadjuvant therapy.

Design, Setting, And Participants: This retrospective case series analysis conducted at a comprehensive cancer center in New York included patients who received a diagnosis of rectal adenocarcinoma between January 1, 2006, and January 31, 2015. The median follow-up was 43 months. Data analyses were conducted from June 1, 2016, to October 1, 2018.

Exposures: Patients had a clinical complete response after completing neoadjuvant therapy and agreed to a WW strategy of active surveillance and possible salvage surgery (n = 113), or patients underwent total mesorectal excision and were found to have a pathologic complete response (pCR) at resection (n = 136).

Main Outcomes And Measures: Kaplan-Meier estimates were used for analyses of local regrowth and 5-year rates of overall survival, disease-free survival, and disease-specific survival.

Results: Compared with the 136 patients in the pCR group, the 113 patients in the WW group were older (median [range], 67.2 [32.1-90.9] vs 57.3 [25.0-87.9] years, P < .001) with cancers closer to the anal verge (median [range] height from anal verge, 5.5 [0.0-15.0] vs 7.0 [0.0-13.0] cm). All 22 local regrowths in the WW group were detected on routine surveillance and treated by salvage surgery (20 total mesorectal excisions plus 2 transanal excisions). Pelvic control after salvage surgery was maintained in 20 of 22 patients (91%). No pelvic recurrences occurred in the pCR group. Rectal preservation was achieved in 93 of 113 patients (82%) in the WW group (91 patients with no local regrowths plus 2 patients with local regrowths salvaged with transanal excision). At 5 years, overall survival was 73% (95% CI, 60%-89%) in the WW group and 94% (95% CI, 90%-99%) in the pCR group; disease-free survival was 75% (95% CI, 62%-90%) in the WW group and 92% (95% CI, 87%-98%) in the pCR group; and disease-specific survival was 90% (95% CI, 81%-99%) in the WW group and 98% (95% CI, 95%-100%) in the pCR group. A higher rate of distant metastasis was observed among patients in the WW group who had local regrowth vs those who did not have local regrowth (36% vs 1%, P < .001).

Conclusions And Relevance: A WW strategy for select rectal cancer patients who had a clinical complete response after neoadjuvant therapy resulted in excellent rectal preservation and pelvic tumor control; however, in the WW group, worse survival was noted along with a higher incidence of distant progression in patients with local regrowth vs those without local regrowth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2018.5896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459120PMC
April 2019

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

Clin Cancer Res 2019 03 26;25(6):1948-1956. Epub 2018 Dec 26.

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

Purpose: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death. A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.

Results: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all < 0.04). SMAD4 loss was associated with worse RFS ( = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS ( = 0.002 and = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival.

Conclusions: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421131PMC
March 2019

Author Correction: Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

Nat Commun 2018 11 13;9(1):4827. Epub 2018 Nov 13.

Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL 60637, USA.

In the originally published version of this Article, the affiliation details for Kevin P. White inadvertently omitted 'Tempus Labs, Chicago, IL, 60654, USA'. This has now been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07303-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233186PMC
November 2018

Outcomes of Low-Grade Appendiceal Mucinous Neoplasms with Remote Acellular Mucinous Peritoneal Deposits.

Ann Surg Oncol 2019 Jan 12;26(1):118-124. Epub 2018 Nov 12.

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

Background: Occasionally, low-grade appendiceal mucinous neoplasms (LAMN) present with mucinous peritoneal deposits (MPD) localized to periappendiceal tissue or diffused throughout the peritoneum.

Objective: This study was aimed at evaluating the relevance of mucin cellularity for predicting outcomes of LAMN with remote MPD.

Methods: The records of patients with LAMN and remote MPD who underwent initial assessment at a comprehensive cancer center from 1990 to 2015 were reviewed, and diagnostic procedures, treatments, and outcomes were analyzed.

Results: Of 48 patients included in the analysis, 19 had cellular MPD (CMPD) and 29 had acellular MPD. Of 33 patients who underwent cytoreductive surgery, 30 had a complete cytoreduction; the 3 patients with an incomplete cytoreduction had CMPD. In the follow-up period (median, 4 years), 6 patients died of the disease, all of whom had CMPD. Of 11 patients who had progression of disease, 10 had CMPD.

Conclusion: Cellularity of remote MPD is an important determinant of disease outcome in LAMN. Approaches such as active surveillance may have a role in selected patients with LAMN and AMPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-018-7003-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339600PMC
January 2019

Effect of Neoadjuvant Systemic Chemotherapy With or Without Chemoradiation on Bowel Function in Rectal Cancer Patients Treated With Total Mesorectal Excision.

J Gastrointest Surg 2019 04 22;23(4):800-807. Epub 2018 Oct 22.

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

Background: Neoadjuvant chemoradiation (CRT) impairs bowel function in patients with rectal cancer treated with total mesorectal excision (TME). The impact of other forms of neoadjuvant therapy such as neoadjuvant chemotherapy alone (NC) and induction chemotherapy followed by CRT (total neoadjuvant therapy or TNT) on postoperative bowel function has not been investigated.

Methods: We conducted a retrospective review of 176 rectal cancer patients treated between November 1, 2011, and August 31, 2017. All patients completed the MSKCC Bowel Function Instrument (BFI), a validated bowel function questionnaire, at least 6 months after TME and/or ileostomy reversal. Differences in BFI scores were compared across four groups (surgery alone, CRT, NC, and TNT) and also according to exposure to neoadjuvant RT and neoadjuvant chemotherapy. A multivariable linear regression model was used to evaluate the independent relationship between exposure to neoadjuvant RT or chemotherapy and BFI.

Results: BFI total scores were significantly different between the four groups (p = 0.008). Exposure to RT correlated with worse BFI total scores (p = 0.002), and no differences were found in BFI total score after exposure to neoadjuvant chemotherapy (p = 0.92). In a linear regression model, only exposure to RT (β = - 5.1; 95% CI - 8.9 to - 1.3; p = 0.008) and tumor distance from the anal verge (β = 1.23; 95% CI 0.48 to 1.97; p = 0.001) were significantly correlated with BFI total score.

Conclusion: NC, whether administered alone or added to CRT, does not seem to impair bowel function. These data should be used to counsel rectal cancer patients when discussing neoadjuvant therapy options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11605-018-4003-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430650PMC
April 2019

Use of the Xi robotic platform for total abdominal colectomy: a step forward in minimally invasive colorectal surgery.

Surg Endosc 2019 03 22;33(3):966-971. Epub 2018 Oct 22.

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

Background: The use of the da Vinci robotic platform for total colectomy has been limited by the need to reposition the patient-side surgical cart from one side of the patient to the other, which increases operative time. In this study, we examined the feasibility of robotic total colectomy using the da Vinci Xi model, which offers a rotating boom-mounted system and laser-targeted trocar positioning.

Methods: The study cohort consisted of 23 patients who underwent minimally invasive total colectomy for cancer or polyposis syndromes at a comprehensive cancer center between 2015 and 2017. Of the 23 colectomies, 15 were robotic and eight were laparoscopic. For the robotic colectomies, trocars were placed in the supraumbilical region and all four quadrants. The da Vinci Xi robot was placed between the patient's legs, and the boom was rotated from left to right and then to the middle in order to work sequentially on the right colon, the left colon, and the pelvis. Operating time and short-term outcomes were compared between the patients who underwent robotic surgery and the patients who underwent laparoscopic surgery.

Results: The two groups of patients were comparable in age, gender, BMI, physical status, and disease types. In the robotic group, median length of stay (4 vs. 6 days, p = 0.047) was significantly shorter and median operative time (243 vs. 263 min, p = 0.97) and median estimated blood loss (50 vs. 100 ml; p = 0.08) were similar between the groups.

Conclusions: With the da Vinci Xi boom-mounted system, total abdominal colectomy can be performed without the need to move the patient-side surgical cart and is associated with shorter length of stay and similar operative time compared to the laparoscopic approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00464-018-6529-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377813PMC
March 2019

A perioperative multidisciplinary care bundle reduces surgical site infections in patients undergoing synchronous colorectal and liver resection.

HPB (Oxford) 2019 02 1;21(2):181-186. Epub 2018 Aug 1.

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

Background: Surgical site infections (SSIs) are a major cause of morbidity, mortality, and healthcare costs, and patients undergoing simultaneous colorectal/liver resections are at an especially high SSI risk.

Methods: Data were collected on all patients undergoing synchronous colorectal/liver resection from 2011 to 2016 (n = 424). The intervention, implemented in 2013, included 13 multidisciplinary perioperative components. The primary endpoints were superficial/deep and organ space SSIs. Secondary endpoints were hospital length of stay (LOS) and 30-day readmission rate. To control for changes in SSI rates independent of the intervention, interrupted time series analysis was conducted.

Results: Overall, superficial/deep, and organ space SSIs decreased by 60.5% (p < 0.001), 80.6% (p < 0.001), and 47.6% (p = 0.008), respectively. In the pre-intervention cohort (n = 231), there were 79 (34.2%), 31 (13.4%), and 48 (20.8%) total, superficial/deep, and organs space SSIs, respectively. In the post-intervention cohort (n = 193), there were 26 (13.5%), 5 (2.6%), and 21 (10.9%) total, superficial/deep, and organs space SSIs, respectively. Median LOS decreased from 9 to 8 days (p < 0.001). Readmission rates did not change (p = 0.6). Interrupted time series analysis found no significant trends in SSI rate within the pre-intervention (p = 0.35) and post-intervention (p = 0.55) periods.

Conclusion: In combined colorectal/liver resection patients, implementation of a multidisciplinary care bundle was associated with a 61% reduction in SSIs, with the greatest impact on superficial/deep SSI, and modest reduction in LOS. The absence of trends within each time period indicated that the intervention was likely responsible for SSI reduction. Future efforts should target further reduction in organ space SSI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hpb.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358518PMC
February 2019

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

Nat Commun 2018 05 4;9(1):1793. Epub 2018 May 4.

Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA.

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-04278-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935683PMC
May 2018