He was a co-founder of Seragon, purchased by Genentech/Roche in 2014. J.M. is a science advisor and owns company stock in Scholar Rock. H.C. is an inventor on several patents related to organoid technology. S.W.L. is a co-founder and scientific advisory board member for ORIC Pharm, Blueprint, and Mirimus. He also serves on the scientific advisory board for Constellation, Petra, and PMV and has recently served as a consultant for Forma, Boehringer Ingelheim, and Aileron. J.G.-A. has received support from Medtronic (honorarium for consultancy with Medtronic), Johnson & Johnson (honorarium for delivering a talk), and Intuitive Surgical (honorarium for participating in a webinar by Intuitive Surgical). P.B.R. has received honorarium from Corning to discuss 3D cell culture techniques, has served as a consultant for AstraZeneca, and is a consultant for EMD Serono for work on radiation sensitizers.

Objective We aimed to describe the mortality burden and macroeconomic effects of head and neck cancer as well as delineate the role of surgical workforce in improving head and neck cancer outcomes. Study Design Statistical and economic analysis. Setting Research group. Subjects and Methods We conducted a statistical analysis on data from the World Development Indicators and the 2016 Global Burden of Disease study to describe the relationship between surgical workforce and global head and neck cancer mortality-to-incidence ratios. A value of lost output model was used to project the global macroeconomic effects of head and neck cancer. Results Significant differences in mortality-to-incidence ratios existed between Global Burden of Disease study superregions. An increase of surgical, anesthetic, and obstetric provider density by 10% significantly correlated with a reduction of 0.76% in mortality-to-incidence ratio ( P < .0001; adjusted R2 = 0.84). There will be a projected global cumulative loss of $535 billion US dollars (USD) in economic output due to head and neck cancer between 2018 and 2030. Southeast Asia, East Asia, and Oceania will suffer the greatest gross domestic product (GDP) losses at $180 billion USD, and South Asia will lose $133 billion USD. Conclusion The mortality burden of head and neck cancer is increasing and disproportionately affects those in low- and middle-income countries and regions with limited surgical workforces. This imbalance results in large and growing economic losses in countries that already face significant resource constraints. Urgent investment in the surgical workforce is necessary to ensure access to timely surgical services and reverse these negative trends.

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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). Patientderived xenografts from SMAD4-deficient and SMAD4retained 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 ¼ 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P ¼ 0.002 and P ¼ 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.

Purpose Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG. Methods and Materials A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items “diffuse intrinsic pontine glioma” and 221 articles using search items “diffuse brainstem glioma radiotherapy.” Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT. Results We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months. Conclusions As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.

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 (n ¼ 17) and 10-year (n ¼ 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 KRAS hotspot mutations and TP53 alterations was observed in 2-year survivors (P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS, or BRAF) and TP53 alteration generated three prognostic clusters: (i) TP53-altered alone (median OS, 132 months); (ii) Ras/B-raf-altered alone (65 months) or Ras/ B-raf-and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf-TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf-TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered Ras/B-raf-TP53 was associated with worse OS in patients with liver (n ¼ 490) and lung (n ¼ 172) but not peritoneal surface (n ¼ 149) metastases. Moreover, coaltered Ras/B-raf-TP53 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 Ras/B-raf-TP53 and its association with distinct patterns of colorectal cancer metastasis.

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 ANTECEDENTES: 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. OBJETIVO: 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). DISEÑO: Estudio retrospectivo de casos y controles utilizando resultados reportados por pacientes. ENTORNO CLINICO: Centro especializado oncológico. PACIENTES: 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. PRINCIPALES MEDIDAS DE VOLARACION: Función evacuatoria utilizando un instrumento de valoración del Centro de Cáncer Memorial Sloan Kettering. RESULTADOS: 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). LIMITACIONES: Diseño retrospectivo, numero de muestra pequeño y variabilidad temporal entre la cirugía y el tiempo de finalización del cuestionario. CONCLUSIONES: 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)

Background The value of intravenous acetaminophen in postoperative pain management remains debated. The authors tested the hypothesis that intravenous acetaminophen use, in isolation and in comparison to oral, would be associated with decreased opioid utilization (clinically significant reduction defined as 25%) and opioid-related adverse effects in open colectomy patients. Methods Using national claims data from open colectomy patients (Premier Healthcare Database, Premier Healthcare Solutions, Inc., USA; 2011 to 2016; n = 181,640; 602 hospitals), we separately categorized oral and intravenous acetaminophen use: 1 (1,000 mg) or more than 1 dose on the day of surgery, postoperative day 1, or later. Multilevel models measured associations between intravenous or oral acetaminophen and (1) opioid utilization and (2) opioid-related adverse effects. Percent change and multiplicity-adjusted 99.5% CI are reported. Results Overall, 25.1% of patients received intravenous acetaminophen, of whom 48.0% (n = 21,878) received 1 dose on the day of surgery. In adjusted analyses, particularly more than 1 dose of intravenous acetaminophen (versus nonuse) on postoperative day 1 was associated with a −12.4% (99.5% CI, −15.2 to −9.4%) change in opioid utilization. In comparison, a stronger reduction was seen in those receiving more than 1 oral acetaminophen dose: −22.6% (99.5% CI, −26.2 to −18.9%). Unadjusted group medians were 550 and 490 oral morphine equivalents, respectively. Intravenous versus oral differences were less pronounced among those receiving more than 1 acetaminophen dose on the day of surgery: −8.0% (99.5% CI, −11.0 to −4.9%) median 499 oral morphine equivalents versus −8.7% (99.5% CI, −14.4 to −2.7%) median 445 oral morphine equivalents, respectively; all statistically significant, but none clinically significant. Comparable outcome patterns existed for opioid-related adverse effects. Conclusions The demonstrated marginal effects do not support routine use of intravenous acetaminophen given alternative nonopioid analgesic options.