Validation of a Clinical Calculator Predicting Freedom From Colon Cancer Recurrence After Surgery on the Basis of Molecular and Clinical Variables.

BACKGROUND: The Memorial Sloan Kettering clinical calculator for estimating the likelihood of freedom from colon cancer recurrence on the basis of clinical and molecular variables was developed at a time when testing for microsatellite instability was performed selectively, based on patient age, family history, and histologic features. Microsatellite stability was assumed if no testing was done. OBJECTIVE: This study aimed to validate the calculator in a cohort of patients who had all been tested for microsatellite instability. DESIGN: Retrospective cohort analysis. SETTINGS: Comprehensive cancer center. PATIENTS: This study included consecutive patients who underwent curative resection for stage I, II, or III colon cancer between 2017 and 2019. INTERVENTION: Universal testing of mircrosatellite phenotype in all cases. MAIN OUTCOME MEASURES: The calculator's predictive accuracy was assessed using the concordance index and a calibration plot of predicted versus actual freedom from recurrence at 3 years after surgery. For a secondary sensitivity analysis, the presence of a tumor deposit(s) (disease category N1c) was considered equivalent to one positive lymph node (category N1a). RESULTS: With a median follow-up of 32 months among survivors, the concordance index for the 745 patients in the cohort was 0.748 (95% CI, 0.693-0.801), and a plot of predicted versus observed recurrences approached the 45° diagonal, indicating good discrimination and calibration. In the secondary sensitivity analysis for tumor deposits, the concordance index was 0.755 (95% CI, 0.700-0.806). LIMITATIONS: This study was limited by its retrospective, single-institution design. CONCLUSIONS: These results, based on inclusion of actual rather than imputed microsatellite stability status and presence of tumor deposits, confirm the predictive accuracy and reliability of the calculator. See Video Abstract . VALIDACIN DE UNA CALCULADORA CLNICA QUE PREDICE LA AUSENCIA DE RECURRENCIA POSTQUIRURGICA DEL CNCER DE COLON SOBRE LA BASE DE VARIABLES MOLECULARES Y CLNICAS: ANTECEDENTES:La calculadora clínica del Memorial Sloan Kettering para la estimación de la probabilidad de ausencia de recurrencia del cáncer de colon sobre la base de variables clínicas y moleculares, se desarrolló en un momento en que las pruebas para la inestabilidad de microsatélites se realizaban de forma selectiva, basadas en la edad del paciente, los antecedentes familiares y las características histológicas. Se asumía la estabilidad micro satelital si no se realizaba ninguna prueba.OBJETIVO:El objetivo de este estudio fue validar la calculadora en una cohorte de pacientes a los que se les había realizado la prueba de inestabilidad de microsatélites.DISEÑO:Análisis de cohorte retrospectivo.AJUSTE:Centro integral de cáncer.PACIENTES:Pacientes consecutivos con cáncer de colon que fueron sometidos a resección curativa por cáncer de colon en estadios I, II o III entre los años 2017 y 2019.PRINCIPALES MEDIDAS DE RESULTADO:La precisión predictiva de la calculadora fue evaluada mediante el índice de concordancia y un gráfico de calibración de la ausencia de recurrencia predecida versus la real a los 3 años tras la cirugía. A los efectos de un análisis secundario de sensibilidad, la presencia de depósito(s) tumoral(es) (categoría de enfermedad N1c) se consideró equivalente a un ganglio linfático positivo (categoría N1a).RESULTADOS:Con una mediana de seguimiento de 32 meses entre los supervivientes, el índice de concordancia para los 745 pacientes de la cohorte fue de 0,748 (intervalo de confianza del 95 %, 0,693 a 0,801), y una gráfica de recurrencias previstas versus observadas se acercó a la diagonal de 45°, indicando una buena discriminación y calibración. En el análisis secundario de sensibilidad para depósitos tumorales, el índice de concordancia fue de 0,755 (intervalo de confianza del 95 %, 0,700 a 0,806).LIMITACIONES:Diseño retrospectivo, institución única.CONCLUSIONES:Estos resultados, basados en la inclusión real del estado de estabilidad de microsatélites en lugar de imputado y la presencia de depósitos tumorales, confirman la precisión predictiva y la confiabilidad de la calculadora. (Traducción-Dr Osvaldo Gauto ).

Characteristics of Mismatch Repair-Deficient Colon Cancer in Relation to Mismatch Repair Protein Loss, Hypermethylation Silencing, and Constitutional and Biallelic Somatic Mismatch Repair Gene Pathogenic Variants.

BACKGROUND: Mismatch repair-deficient colon cancer is heterogeneous. Differentiating inherited constitutional variants from somatic genetic alterations and gene silencing is important for surveillance and genetic counseling. OBJECTIVE: This study aimed to determine the extent to which the underlying mechanism of loss of mismatch repair influences molecular and clinicopathologic features of microsatellite instability-high colon cancer. DESIGN: This is a retrospective analysis. SETTINGS: This study was conducted at a comprehensive cancer center. PATIENTS: Patients with microsatellite instability-high colon cancer of stage I, II, or III were included. INTERVENTION: Patients underwent a curative surgical resection. MAIN OUTCOME MEASURES: The main outcome measures were hypermethylation of the MLH1 promoter, biallelic inactivation, constitutional pathogenic variants, and loss of specific mismatch repair proteins. RESULTS: Of the 157 identified tumors with complete genetic analysis, 66% had hypermethylation of the MLH1 promoter, 18% had constitutional pathogenic variants, (Lynch syndrome), 11% had biallelic somatic mismatch repair gene pathogenic variants, and 6% had unexplained high microsatellite instability. The distribution of mismatch repair loss was as follows: MLH1 and PMS2 co-loss, 79% of the tumors; MSH2 and MSH6 co-loss, 10%; MSH6 alone, 3%; PMS2 alone, 2%; other combinations, 2%; no loss, 2%. Tumor mutational burden was lowest in MLH1- and PMS2-deficient tumors. MSH6-deficient tumors had the lowest levels of tumor-infiltrating lymphocytes, lowest MSI scores, and fewest frameshift deletions. Patients with MLH1 promoter hypermethylation were significantly more likely to be older and female and to have right-sided colon lesions than patients with biallelic inactivation. Mutation was the most prevalent second hit in tumors with biallelic inactivation and tumors of patients with Lynch syndrome. LIMITATIONS: This study was limited by potential selection or referral bias, missing data for some patients, and relatively small sizes of some subgroups. CONCLUSIONS: Clinical characteristics of mismatch repair-deficient colon cancer vary with the etiology of microsatellite instability, and its molecular characteristics vary with the affected mismatch repair protein. See Video Abstract at http://links.lww.com/DCR/B984 . CARACTERSTICAS DEL CNCER DE COLON CON DEFICIENCIA EN LA REPARACIN DE ERRORES DE EMPAREJAMIENTO EN RELACIN CON LA PRDIDA DE PROTENAS MMR, SILENCIAMIENTO DE LA HIPERMETILACIN Y LAS VARIANTES PATGENAS SOMTICAS DE GENES MMR CONSTITUCIONAL Y BIALLICO: ANTECEDENTES:El cáncer de colon deficiente en la reparación de errores de emparejamiento es heterogéneo. La diferenciación de las variantes constitucionales heredadas de las alteraciones genéticas somáticas y el silenciamiento de genes es importante para la vigilancia y el asesoramiento genético.OBJETIVO:Determinar hasta qué punto el mecanismo subyacente de pérdida de reparación de desajustes influye en las características moleculares y clinicopatológicas del cáncer de colon con alta inestabilidad de microsatélites.DISEÑO:Análisis retrospectivo.ESCENARIO:Centro integral de cáncer.PACIENTES:Pacientes con cáncer de colon con inestabilidad de microsatélites alta en estadio I, II, o III.INTERVENCIÓN:Resección quirúrgica con intención curativa.PRINCIPALES RESULTADOS Y MEDIDAS:Hipermetilación del promotor MLH1, inactivación bialélica, variante patógena constitucional y pérdida de proteínas específicas reparadoras de desajustes.RESULTADOS:De los 157 tumores identificados con un análisis genético completo, el 66 % tenía hipermetilación del promotor MLH1, el 18 % tenía una variante patogénica constitucional (síndrome de Lynch), el 11 % tenía variantes patogénicas somáticas bialélicas de algún gen MMR y el 6 % tenía una alta inestabilidad de microsatélites sin explicación. La distribución de la pérdida según la proteína de reparación del desajuste fue la siguiente: pérdida conjunta de MLH1 y PMS2, 79 % de los tumores; co-pérdida de MSH2 y MSH6, 10%; MSH6 solo, 3%; PMS2 solo, 2%; otras combinaciones, 2%; sin pérdida, 2%. La carga mutacional del tumor fue más baja en los tumores deficientes en MLH1 y PMS2. Los tumores con deficiencia de MSH6 tenían los niveles más bajos de linfocitos infiltrantes de tumores, las puntuaciones más bajas del sensor de IMS y la menor cantidad de deleciones por cambio de marco. Los pacientes con hipermetilación del promotor MLH1 tenían significativamente más probabilidades de ser mayores y mujeres y de tener lesiones en el colon derecho que los pacientes con inactivación bialélica. La mutación fue el segundo golpe más frecuente en tumores con inactivación bialélica y tumores de pacientes con síndrome de Lynch.LIMITACIONES:Sesgo potencial de selección o referencia, datos faltantes para algunos pacientes y tamaños relativamente pequeños de algunos subgrupos.CONCLUSIONES:Las características clínicas del cáncer de colon deficiente en reparación de desajustes varían con la etiología de la inestabilidad de microsatélites, y sus características moleculares varían con la proteína de reparación de desajustes afectada. Vea Resumen de video en http://links.lww.com/DCR/B984 . (Traducción-Dr. Felipe Bellolio ).

Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

MRI at Restaging After Neoadjuvant Therapy for Rectal Cancer Overestimates Circumferential Resection Margin Proximity as Determined by Comparison With Whole-Mount Pathology.

BACKGROUND: Current guidelines recommend restaging with MRI after neoadjuvant therapy for rectal cancer, but the accuracy of restaging MRI in estimating circumferential margin involvement requires additional clarification. OBJECTIVE: The objective of this study was to measure the accuracy of circumferential resection margin assessment by MRI after neoadjuvant therapy and identify characteristics associated with accuracy. DESIGN: MRI data were retrospectively analyzed for concordance with the findings of whole-mount pathology analysis of the corresponding surgical specimens. Univariate and multivariate logistic regression analyses were performed to identify characteristics associated with accuracy. SETTING: This study was conducted at a comprehensive cancer center. PATIENTS: Included in the study were consecutive patients who underwent total mesorectal excision for rectal cancer between January 2018 and March 2020 after receiving neoadjuvant therapy and undergoing restaging with MRI. MAIN OUTCOME MEASURES: The primary outcome of this study included accuracy, sensitivity, specificity, and positive and negative predictive values for categorizing the circumferential resection margin as threatened; mean and paired mean differences were in proximity of the margin. RESULTS: Of the 94 patients included in the analysis, 39 (41%) had a threatened circumferential resection margin according to MRI at restaging, but only 17 (18%) had a threatened margin based on pathology. The accuracy of MRI in identifying a threatened margin was 63.8%, with margin proximity overestimated by 0.4 cm on average. In multivariate logistic regression, anterior location of the margin and tumor proximity to the anal verge were independently associated with reduced MRI accuracy. LIMITATIONS: A limitation was the retrospective design at a single institution. CONCLUSIONS: The knowledge that MRI-based restaging after neoadjuvant therapy overestimates circumferential margin proximity may render some surgical radicality unnecessary and thereby help avoid the associated morbidity. With the recognition that MRI-based assessment of margin proximity may not be reliable for anterior margin and for distal tumors, radiologists may want to use greater caution in interpreting images of tumors with these characteristics and to acknowledge the uncertainty in their reports. See Video Abstract at http://links.lww.com/DCR/B814. LA IRM EN LA REESTADIFICACIN LUEGO DE TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO SOBRESTIMA LA PROXIMIDAD DEL MARGEN DE RESECCIN CIRCUNFERENCIAL SEGN LO DETERMINADO COMPARATIVAMENTE CON LA PIEZA DE ANATOMOPATOLOGA: ANTECEDENTES:Las pautas actuales recomiendan la re-estadificación por medio de la resonancia magnética luego de terapia neoadyuvante en los casos de cáncer de recto, pero la precisión de la reevaluación con la IRM para estimar el grado de implicación del margen circunferencial requiere aclaraciones adicionales.OBJETIVO:Medir el grado de exactitud en la evaluación del margen de resección circunferencial mediante resonancia magnética después de la terapia neoadyuvante e identificar las características asociadas con la precisión.DISEÑO:Se analizaron retrospectivamente los datos de resonancia magnética para determinar la concordancia entre los hallazgos del análisis de la pieza de anatamopatología y las muestras quirúrgicas correspondientes. Se realizó el análisis de regresión logística univariada y multivariada para identificar las características asociadas con la exactitud.AJUSTE:Centro oncológico integral.PACIENTES:Todos aquellos que se sometieron consecutivamente a una excisión total del mesorrecto por cáncer rectal entre Enero 2018 y Febrero 2020 luego de recibir terapia neoadyuvante y someterse a una re-estadificación por imágenes de resonancia magnética (IRM).PRINCIPALES MEDIDAS DE RESULTADO:La exactitud, la sensibilidad y especificidad; los valores predictivos positivos y negativos para categorizar el margen de resección circunferencial como amenazado; la diferencia media y las medias pareadas de proximidad a los margenes.RESULTADOS:De los 94 pacientes incluidos en el análisis, 39 (41%) tenían un margen de resección circunferencial amenazado según la resonancia magnética en la re-estadificación, pero solo 17 (18%) tenían un margen amenazado basado en la patología. La precisión de la resonancia magnética para identificar un margen amenazado fue del 63,8%, con la proximidad del margen sobreestimada en 0,4 cm en promedio. En la regresión logística multivariada, la ubicación anterior de los bordes de resección y la proximidad del tumor al margen anal se asociaron de forma independiente con la reducción en la precisión de la resonancia magnética.LIMITACIONES:Diseño retrospectivo en una institución única.CONCLUSIONES:El saber que la re-estadificación basada en la IRM, luego de terapia neoadyuvante sobreestima la proximidad de la lesión a los márgenes circunferenciales, hace innecesaria cierta radicalidad quirúrgica complementaria, lo que ayuda a evitar morbilidad asociada. Reconociendo que la evaluación de proximidad de los márgenes de resección basada en la resonancia magnética, no puede ser confiable en casos de márgenes anteriores y en casos de tumores distales. Los radiólogos recomiendan tener más precaución en la interpretación de imágenes de tumores con estas características y reconocen cierto desasosiego en sus informes. Consulte Video Resumen en http://links.lww.com/DCR/B814.

Development and Assessment of a Clinical Calculator for Estimating the Likelihood of Recurrence and Survival Among Patients With Locally Advanced Rectal Cancer Treated With Chemotherapy, Radiotherapy, and Surgery.

Importance: Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. Objective: To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. Design, Setting, and Participants: This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Exposures: Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Main Outcomes and Measures: Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Results: Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). Conclusions and Relevance: In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

Phase II trial of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma after disease progression on sorafenib.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) who received second line sorafenib plus doxorubicin following disease progression on sorafenib were shown retrospectively to have improved progression free survival (PFS) and overall survival (OS). Sorafenib plus doxorubicin combination may synergistically promote ASK-1 mediated apoptosis in cancer cells through RAF-1 inhibition. Thus, we conducted this phase II study of sorafenib and doxorubicin combination following progression on sorafenib. METHODS: Patients with histologically confirmed advanced HCC, confirmed radiologic progression on sorafenib, Karnofsky performance status (KPS) ≥70%, and Child-Pugh A liver cirrhosis were eligible. Patients received sorafenib 400 mg twice daily and doxorubicin 60 mg/m2 once every 3-weeks. The primary endpoint was OS at 6 months (OS6). Secondary endpoints included safety, PFS, OS, response rate (RR) by RECIST 1.1. Additional endpoints included baseline and on-treatment tumor ASK-1 and pERK expression levels by immunohistochemistry (IHC) and the correlation with PFS, RR, and OS. RESULTS: Thirty patients were enrolled in the study, 86% were male, median age was 64 years. OS6 was 76.6% (95%CI: 57.2%-88.1%). Median OS was 8.6 (95%CI: 7.3-12) months, and median PFS reached 3.9 (95%CI: 2.4-4.6) months. Three (11%) partial responses were observed and 17 patients (61%) had stable disease. Pertinent grade 3-4 adverse events that occurred in more than 10% of patients included neutropenia (16%), febrile neutropenia (10%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). No association with the difference in baseline and post-treatment ASK-1 and pERK level of expression by IHC and survival outcomes was detected. CONCLUSION: Sorafenib plus doxorubicin following progression on sorafenib did not show any improved outcome. We do not recommend further development or use of this combination in HCC.

Pathology definitions and resection strategies for early colorectal neoplasia: Eastern versus Western approaches in the post-Vienna era.

There is a well-known discrepancy between East and West classifications of colorectal neoplasm, especially "intramucosal carcinoma," categorized as subgroup 4.4 in the Vienna classification, usually recognized as high-grade dysplasia in the United States and as carcinoma in situ in Japan. Focusing on management, in the current National Comprehensive Cancer Network algorithm, high-grade dysplasia, carcinoma in situ, and intramucosal carcinoma are managed similarly, whereas submucosal invasion by carcinoma requires en bloc resection. To bridge the differences with regard to these conceptual problems in the definition and management of carcinoma in situ and intramucosal carcinoma, endoscopists and pathologists from Japan and the United States gathered and discussed from their perspectives how to accurately assess specimens of en bloc/piecemeal resection and to effectively predict lymph node metastasis risk.

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

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.

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

PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: 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 P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 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.

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

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.

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

Importance: Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. Objective: To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. Design, Setting, and Participants: A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. Exposures: Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Main Outcomes and Measures: Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. Results: Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. Conclusions and Relevance: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Gastric Carcinomas With Lymphoid Stroma: An Evaluation of the Histopathologic and Molecular Features.

Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus (EBV) positivity and mismatch repair (MMR) deficiency. We performed this study to evaluate molecular alterations in this morphologically homogeneous subtype and compare them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. We identified 31 study cases and subjected them to in situ hybridization for EBV-encoded RNAs and assessment for MMR status. Immunostains for PD-L1, ß-catenin, and HER2 were performed; extracted DNA was sequenced with a Comprehensive Cancer Panel. Most study patients were older adult men with stage I or II disease (76%). Tumors were classified as EBV/MMR-proficient (MMR-P) (n=7), EBV/MMR deficient (n=12), and EBV/MMR-P (n=12). EBV/MMR-P tumors were usually located in the proximal stomach (83%) and showed heterogenous growth patterns with glandular differentiation (83%). Tumors in all groups showed numerous tumor infiltrating lymphocytes and PD-L1 expression, infrequent nuclear ß-catenin accumulation (10%), and lacked both membranous HER2 staining and HER2 amplification. EBV/MMR-deficient tumors showed significantly higher tumor mutation burden (P=0.001) and KRAS alterations (56%) compared with EBV/MMR-P tumors (9%, P=0.05). TP53 variants were more common among EBV/MMR-P tumors (82%) compared with EBV/MMR proficient (0%, P=0.01) and EBV/MMR-deficient (11%, P<0.01) tumors. Alterations in KRAS, ARID1A, PIK3CA, and TP53 followed similar patterns of distribution compared with The Cancer Genome Atlas dataset. We conclude that gastric carcinomas with lymphoid stroma show a spectrum of molecular changes and frequent PD-L1 expression, raising the possibility that this subgroup of tumors may be susceptible to checkpoint inhibitors and/or agents that target receptor tyrosine kinase-mediated signaling.

Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial.

PURPOSE: Although neoadjuvant chemoradiotherapy achieves low local recurrence rates in clinical stages II to III rectal cancer, it delays administration of optimal chemotherapy. We evaluated preoperative infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/bevacizumab with selective rather than consistent use of chemoradiotherapy. PATIENTS AND METHODS: Thirty-two patients with clinical stages II to III rectal cancer participated in this single-center phase II trial. All were candidates for low anterior resection with total mesorectal excision (TME). Patients were to receive six cycles of FOLFOX, with bevacizumab included for cycles 1 to 4. Patients with stable/progressive disease were to have radiation before TME, whereas responders were to have immediate TME. Postoperative radiation was planned if R0 resection was not achieved. Postoperative FOLFOX × 6 was recommended, but adjuvant regimens were left to clinician discretion. The primary outcome was R0 resection rate. RESULTS: Between April 2007 and December 2008, 32 (100%) of 32 study participants had R0 resections. Two did not complete preoperative chemotherapy secondary to cardiovascular toxicity. Both had preoperative chemoradiotherapy and then R0 resections. Of 30 patients completing preoperative chemotherapy, all had tumor regression and TME without preoperative chemoradiotherapy. The pathologic complete response rate to chemotherapy alone was 8 of 32 (25%; 95% CI, 11% to 43%). The 4-year local recurrence rate was 0% (95% CI, 0% to 11%); the 4-year disease-free survival was 84% (95% CI, 67% to 94%). CONCLUSION: For selected patients with clinical stages II to III rectal cancer, neoadjuvant chemotherapy and selective radiation does not seem to compromise outcomes. Preoperative Radiation or Selective Preoperative Radiation and Evaluation Before Chemotherapy and TME (PROSPECT), a randomized phase III trial to validate this experience, is now open in the US cooperative group network.

Preoperative chemotherapy and the risk of hepatotoxicity and morbidity after liver resection for metastatic colorectal cancer: a single institution experience.

BACKGROUND: Patients undergoing liver resection for colorectal cancer liver metastasis (CRCLM) are often treated with chemotherapy before surgery. However, the associations between chemotherapy, liver injury, perioperative outcomes, and other confounding factors remain unclear. This study investigates the effect of preoperative chemotherapy for CRCLM on nontumoral liver histology and perioperative outcomes in a contemporary cohort. STUDY DESIGN: Five hundred six patients underwent hepatic resection for CRCLM between April 2003 and March 2007. Histologic evaluation of nontumoral liver parenchyma for sinusoidal dilatation, steatosis, and steatohepatitis was performed in 384 cases for which tissue was available. Patient factors, tumor characteristics, chemotherapy regimens, histology of nontumoral liver, and perioperative morbidity were analyzed. RESULTS: Two hundred fifty patients (65%) received preoperative chemotherapy for a median duration of 24 weeks. Irinotecan, increased body mass index (BMI), and diabetes mellitus (DM) were associated with hepatic steatosis and steatohepatitis. Sinusoidal dilatation was not associated with chemotherapy or any clinicopathologic factors. Perioperative blood transfusion was independently associated with an increased risk of any complication. Major postoperative complications were independently associated with major (≥ 3 segments) resections (57%) and perioperative blood transfusion. The use of any preoperative chemotherapy decreased the odds of major complications. Liver-related complications were independently associated with major resection and blood transfusion, but not with chemotherapy. Three postoperative deaths (0.8%) occurred, all in patients who were not treated with chemotherapy and had no evidence of liver injury. CONCLUSIONS: With appropriate patient selection, liver resection for CRCLM can be safely performed in patients treated with preoperative chemotherapy.

FDG-PET assessment of rectal cancer response to neoadjuvant chemoradiotherapy is not associated with long-term prognosis: a prospective evaluation.

BACKGROUND: At present there is no defined role for routine FDG-PET in the preoperative evaluation of nonmetastatic rectal cancer. OBJECTIVE: The primary objective of this study was to evaluate the ability of FDG-PET to predict long-term prognosis based on the response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. DESIGN: This was a prospective study. SETTINGS: This study was performed at an academic, tertiary care, comprehensive cancer center. PATIENTS: One hundred twenty-seven patients with locally advanced rectal cancer were enrolled between September 1999 and December 2005. INTERVENTIONS: All patients underwent FDG-PET scans before and after neoadjuvant chemoradiotherapy. MAIN OUTCOME MEASURES: FDG-PET parameters were evaluated by at least 2 study board-certified nuclear medicine physicians, and included mean standard uptake value, maximum standard uptake value, total lesion glycolysis, and visual response score. The main outcome measures were time to recurrence and disease-specific survival. RESULTS: Of 127 patients, 82 (65%) were men, the median age was 60 years (range, 27-82), 110 patients had stage II/III disease, and 17 patients had stage IV disease. Median follow-up among survivors was 77 months (range, 1-115 months). Nine patients had unresectable metastatic disease and were excluded from the time-to-recurrence analysis. At 5 years, 74% (95% CI = 66%-81%) of patients had not had recurrences (locally and/or distantly). The 5-year disease-specific survival was 89% (95% CI = 81%-93%). On univariate analysis, visual response score and time to recurrence came closest to having an association (HR = 0.83, 95% CI = 0.68-1.01, p = 0.06). On multivariate analysis, the visual response score was not significant (p = 0.85). No FDG-PET parameter was associated with disease-specific survival. CONCLUSIONS: Assessment of rectal cancer response to neoadjuvant chemoradiotherapy by FDG-PET provides no prognostic information. Therefore, serial FDG-PET before and after neoadjuvant chemoradiotherapy should not be performed for this purpose.

A single arm phase II study of a Far-Eastern traditional herbal formulation (sho-sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatitis C is a major public health problem internationally. Many patients cannot benefit from the current treatment regimen (interferon/ribavirin combinations) due to its side effects or ineffectiveness. Xiao-Chai-Hu-Tang or Sho-sai-ko-to (SST), a compound of seven botanical extracts used for liver diseases traditionally in East Asia, was shown to reduce transaminases and the incidence of hepatocellular carcinoma in hepatitis B patients. We conducted a phase II trial of SST in hepatitis C patients who were not candidates for interferon-based therapy to determine whether this agent is worthy of further study. MATERIALS AND METHODS: Twenty four chronic hepatitis C patients received SST at 2.5 g per os (p.o.) three times daily (t.i.d.) for 12 months. Liver function, hepatitis C virus (HCV) viral load and liver biopsy histology were assessed before and after the intervention. RESULTS: Improvement of aspartate aminotransferase (AST) was observed in 16 (67%) of study participants. Improvement of alanine aminotransferase (ALT) was seen in 18 (75%) patients. Viral load response was mixed, with 7 patients showing reductions, 10 increases and 7 indeterminate due to assay limitations. Among the 9 (38%) subjects who showed improvement per Knodell's histology activity index (HAI) scores in paired comparison of pre- and post-treatment liver biopsy (the primary endpoints of the study), 5 (21%) showed an improvement of 2 points or greater, meeting the pre-defined criteria for "response. CONCLUSIONS: Sho-sai-ko-to (SST or Xiao Chai Hu Tang) may improve liver pathology in selected hepatitis C patients who are not candidates for interferon based treatment. Larger, controlled studies of this botanical formulation may be warranted.

Squamous-cell carcinoma of the rectum: a rare but curable tumor.

PURPOSE: This study was designed to evaluate one institution's experience with treatment outcomes for rectal squamous-cell carcinoma. METHODS: Using our prospective Colorectal Database, we identified patients diagnosed with rectal squamous-cell carcinoma at our institution between 1983 and 2005. Pathology was rereviewed, tumor immunophenotype was compared to control cases of anal squamous-cell carcinoma and rectal adenocarcinoma, treatment modalities and outcomes were analyzed. RESULTS: Twelve patients were identified (10 females median age, 58 years). Median distal extent of tumors was 7 (range, 5-8) cm from the anal verge. Treatment included chemotherapy only (n = 1), chemoradiation only (n = 2), induction chemotherapy followed by chemoradiation and surgery (n = 2), chemoradiation followed by surgery (n = 5), and surgery followed by chemoradiation (n = 2). The chemotherapy regimen was 5-fluorouracil-based. Radiotherapy total dose was 50.4 Gy (1.8 Gy/day, daily x 5) external iliac and inguinal nodes were not included in the radiation field. Complete clinical responders to chemoradiation (n = 2) received no further treatment. All seven partial responders underwent surgery; six had complete pathologic response; nodal status in two of six was unknown because they had local excision. Immunophenotypical analysis showed similar keratin expression profile between rectal squamous-cell carcinoma (n = 5) and rectal adenocarcinoma (n = 5), which is different from anal squamous-cell carcinoma (n = 10). All patients were alive without evidence of disease at follow-up (median follow-up, 2.6 (range, 0.5-16) years). CONCLUSIONS: Our data suggest that most patients treated with upfront chemoradiation therapy followed by surgery did well. Sphincter-preserving surgery is usually feasible. Clinical judgment of tumor response after chemoradiation is not completely reliable. Immunohistochemistry suggests a common cellular origin for rectal squamous-cell carcinoma and rectal adenocarcinoma, which is different from anal squamous-cell carcinoma.