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Human papillomavirus (HPV) types 6 and 11 can infect the squamous epithelium of the respiratory tract. Up to 8·9% of patients with HPV-associated recurrent respiratory papillomatosis (RRP) have pulmonary involvement. Pulmonary manifestations of HPV infection are associated with considerable morbidity, in part because treatment options and management guidelines are lacking. Patients with pulmonary RRP have a 32-times increased lifetime risk of malignant transformation compared with the overall RRP population. We review the clinical and radiographic presentation, pathological features, and genetics of pulmonary RRP, and we provide management algorithms based on our clinical experience with this complex patient population. In patients with suspected pulmonary involvement, tissue-sparing procedures to address growing lesions might be warranted given the chronicity and multifocality of the disease over a patient's lifetime. However, malignant transformation of pulmonary lesion(s) warrants standard-of-care treatment for primary lung squamous cell carcinoma. Large cohort studies are needed to understand the clinical course of pulmonary RRP and to identify molecular markers of increased risk of malignant transformation in order to develop guidelines for optimal and standardised surveillance and treatment.

Recurrent laryngeal nerve (RLN) invasion by thyroid carcinoma represents an advanced disease status with potentially significant co-morbidity.In a retrospective single-center study, we included patients with invaded RLNs operated on while using nerve monitoring techniques. We studied pre-, intra-, and postoperative parameters associated with postoperative vocal cord paralysis (VCP); 5-year recurrence-free survival (RFS); and 5-year overall survival (OS) in addition to two subgroup analyses of postoperative VCP in patients without preoperative VCP and based on source of RLN invasion.Of 65 patients with 66 nerves-at-risk, 39.3% reported preoperative voice complaints. Preoperative VCP was documented in 43.5%. The RLN was invaded by primary tumor in 59.3% and nodal metastasis in 30.5%. Papillary thyroid carcinoma was the most common pathologic subtype (80%). After 6 months, 81.8% had VCP. Complete tumor resection of the RLN was not associated with 5-year RFS (p = 0.24) or 5-year OS (p = 0.9). Resecting the RLN did not offer statistically significant benefit on 5-year RFS (p = 0.5) or 5-year OS (p = 0.38). Radioactive Iodine (RAI) administration was associated with improvement in 5-year RFS (p = 0.006) and 5-year OS (p = 0.004). Patients without preoperative VCP had higher IONM amplitude compared with patients with VCP. After a mean follow-up of 65.8 months, 35.9% of patients had distant metastases, whereas 36.4% had recurrence.Preoperative VCP accompanies less than half of patients with RLN invasion. Invaded RLNs may have existent electrophysiologic stimulability. Complete tumor resection and RLN resection were not associated with better 5-year RFS or OS, but postoperative RAI was.4 Laryngoscope, 132:2285-2292, 2022.

Distribution of colorectal cancer cases according to SMAD4 expression status and immune response to the tumor in validation cohort

Kaplan-Meier graphs in the validation cohort with number of subjects at risk showing colorectal cancer-specific survival according to SMAD4 status.

Kaplan-Meier graphs with number of subjects at risk comparing recurrence-free survival (RFS) by (a) TIL status, or (b) PLA status, with arrows indicating patients whose tumors were also SMAD4 loss.

Clinical, pathological, and molecular characteristics of colorectal cancer cases according to SMAD4 expression status in validation cohort

Supplementary Methods, References, and Figures

Genomic and clinical information of MSKCC validation cohort (n=935) with corresponding data dictionary

Ordinal logistic regression analyses to assess the association of SMAD4 expression status with lymphocytic reaction patterns in validation cohort

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.

Kaplan-Meier graph with number of subjects at risk comparing (a) SMAD4, (b) TIL, and (c) PLA status, separately, as well as (d) SMAD4 and TIL, and (e) SMAD4 and PLA, together, with recurrence-free survival (RFS) among only the MMR-proficient patients.

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 (n = 17) and ≥10-year (n = 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 = 490) and lung (n = 172) but not peritoneal surface (n = 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.

Supplementary Figures 1 - 3

Objective To evaluate the association between pre-hospitalization antiplatelet medication use and COVID-19 disease severity. Design Retrospective cohort study. Setting Inpatient units at The Mount Sinai Hospital. Patients Adults age ≥18 admitted between March 1, 2020 and April 9, 2020 with confirmed COVID-19 infection with at least 28 days follow-up. Measurements We captured baseline demographic, pre-hospitalization antiplatelet medication use, and clinical encounter data for all patients who met inclusion criteria. The primary endpoint was peak score on a 6-point modified ordinal scale (MOS), which is based on World Health Organization blueprint R&S groups, used to grade severity of illness through clinical outcomes of interest. Scores indicate the following: 1 – COVID-19 infection not requiring hospitalization, 2 – requiring hospitalization but not supplemental oxygen, 3 – hospitalization requiring supplemental oxygen, 4 – hospitalization requiring high-flow nasal cannula (HFNC) or non-invasive positive pressure ventilation (NIPPV), 5 – hospitalization requiring intubation or extracorporeal membrane oxygenation (ECMO), 6 – death. Multivariable adjusted partial proportional odds model (PPOM) was performed to examine the association between pre-hospitalization antiplatelet medication use and likelihood of each MOS score. Main Results Of 762 people admitted with COVID-19, 239 (31.4%) used antiplatelet medications pre-hospitalization while 523 (68.6%) did not. Antiplatelet users were older and had more co-morbidities at baseline. Before adjusting for covariates, patients who used antiplatelet medications pre-hospitalization were more likely than non-users to have peak MOS score 6 (death, OR 1.75, 95% CI 1.21–2.52), peak MOS score ≥5 (intubation/ECMO or death, OR 1.4, 95% CI 1.00–1.98) and peak MOS score ≥4 (HFNC, NIPPV, intubation/ECMO or death, OR 1.40, 95% CI 1.01–1.94). On multivariable adjusted PPOM analysis controlling for 13 covariates, there were no longer any significant differences in peak MOS scores between users and non-users. Conclusions After adjusting for covariates, pre-hospital antiplatelet use was not associated with COVID-19 severity in hospitalized patients.

PURPOSE: To compare the characteristics and outcomes of rectal cancer patients with local recurrence at a perianastomotic site (PA), a surgical field (SF) site, or in lateral lymph nodes (LLN). METHODS: A total of 114 consecutive patients who underwent surgery for recurrent, non-metastatic rectal cancer at a single comprehensive cancer center between 1997 and 2012 were grouped on the basis of radiographic assessment of type of recurrence: PA, 76 (67%) patients; SF, 25 (22%) patients; LLN, 13 (11%) patients. Demographic, clinical, and pathological features were compared between the three groups, as were disease-free survival (DFS) and overall survival (OS). RESULTS: Recurrence type was associated with positive circumferential margin in the primary resection (PA, 4 [6%]; SF, 4 [19%]; LLN, 3 [25%]; P = 0.027), prior neoadjuvant therapy for the primary tumor (PA, 57 [75%]; SF, 18 [72%]; LLN, 4 [31%]; P = 0.007) and location of the primary tumor in the upper rectum (PA, 33 [45%]; SF, 5 [23%]; LLN, 1 [8%]; P < 0.001). Patients with PA had longer median DFS (PA, 5.1 years; SF, 1.5 years; LLN, 1.2 years; P = 0.036). There was a non-significant trend toward longer OS and higher rates of R0 resection for PA. CONCLUSION: Type of recurrence after salvage surgery for locally recurrent rectal cancer is associated with longer DFS in patients with PA recurrence.

Background The optimal extent of surgery and/or radiation to the contralateral lymph node region is unknown in early-stage human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). Methods To investigate the pathologic incidence of and risk factors for contralateral nodal disease (CND) in cT1-T2 HPV-related OPSCC treated with transoral robotic surgery (TORS) and bilateral neck dissection (BND), the records of 120 patients were reviewed. Results Eleven patients displayed pathologic contralateral nodal disease (pCND), including 7.1% of tonsil and 10.9% of base of tongue (BOT) cases. Medial hemistructure involvement and cN2 disease were significantly associated with pCND. Zero cN0 patients had pCND, and on multivariate analysis only cN classification remained significantly associated with pCND. Four percent of BOT patients and 2% of tonsil patients with a well-lateralized primary and cN0/N1 neck demonstrated pCND. Conclusions HPV-related OPSCC that are cN0-N1 have exceedingly low rates of pCND. Well-lateralized HPV-related BOT primaries with limited clinical nodal disease may be candidates for ipsilateral only treatment.

Global health has evolved to focus on reducing health inequity and obtaining the highest attainable standard of health for all people. To do this, a range of actors now pursue interventions and policy with an eye toward global targets that place strong emphasis on improving health systems. Within global health, global surgery has sought to delineate the burden of surgical disease and propose policy to improve access to surgery. Oral and maxillofacial surgery has been underrepresented in global health but has a vital role in reducing the global health inequity attributable to the impact of oral and craniofacial conditions.

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. FUNCION EVACUATORIA INFORMADA POR PACIENTES EN CANCER RECTAL MANEJADO CON UNA ESTRATEGIA DE OBSERVAR Y ESPERAR DESPUES DE LA TERAPIA NEOADYUVANTE: UN ESTUDIO DE CASOS Y CONTROLES: Observar y esperar es una alternativa no operativa a la cirugia de preservacion del esfinter para pacientes con cancer rectal localmente avanzado que logran una respuesta clinica completa despues de la terapia neoadyuvante. Hay datos limitados sobre la funcion evacuatoria en pacientes sometidos a este abordaje para preservacion de organos.Evaluar la funcion evacuatoria en pacientes con cancer rectal manejados con observar y esperar comparado a pacientes sometidos a cirugia de preservacion de esfinteres (escision mesorrectal total).Estudio retrospectivo de casos y controles utilizando resultados reportados por pacientes.Centro especializado oncologico.21 pacientes se sometieron a observar y esperar y se compararon con 21 pacientes de un grupo de 190 pacientes que se sometieron a cirugia de preservacion de esfinteres controlando por edad, sexo y la distancia del tumor al borde anal.Funcion evacuatoria utilizando un instrumento de valoracion del Centro de Cancer Memorial Sloan Kettering.Los pacientes de observar y esperar demostraron mejor funcion evacuatoria en la escala general (puntuacion total media, 76 versus 55; p

Introduction To improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins. Methods Half maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status. Results TMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines. Conclusions DAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

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 (n = 17) and ≥10-year (n = 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 = 490) and lung (n = 172) but not peritoneal surface (n = 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.

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.Statistical and economic analysis.Research group.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.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 (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.

Background Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. Methods We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. Results Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. Conclusions Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI., Patients with colorectal liver metastases receiving hepatic arterial infusion chemotherapy who have either resectable disease with concurrently altered Ras/B‐Raf and SMAD4 mutations, or unresectable disease with concurrent Ras/B‐Raf and TP53 alterations had worse survival. Mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 status may be useful for prognostic stratification in these patients.

Introduction The benefits of simulation-based medical training are well described. The most effective way to plant and scale simulation training in rural locations remains undescribed. We sought to plant simulation training programmes for anaesthesia emergencies in two rural Indian hospitals. Methods Two Indian consultant anaesthetists without experience in medical simulation underwent a 3-day course at the Boston Children’s Hospital’s (BCH) Simulator Program. They returned to their institutions and launched simulation programmes with an airway manikin and mock patient monitor. The 1-year experience was evaluated using individual, in-depth interviews of simulation facilitators. Three staff members (responsible for facilitating medical simulations over the prior year) at two rural hospitals in India were interviewed. None attended the BCH training; instead, they received on-the-job training from the BCH-trained, consultant anaesthetist colleagues. Results Successes included organisational adoption of simulation training with exercises 1 year after the initial BCH-training, increased interdisciplinary teamwork and improved clinical competency in managing emergencies. Barriers to effective, local implementation of simulation programmes fell into three categories: time required to run simulations, fixed and rigid roles, and variable resources. Thematic improvement requests were for standardised resources to help train simulation facilitators and demonstrate to participants a well-run simulation, in addition to context-sensitive scenarios. Conclusion An in-person training of simulation facilitators to promote medical simulation programmes in rural hospitals produced ongoing simulation programmes 1 year later. In order to make these programmes sustainable, however, increased investment in developing simulation facilitators is required. In particular, simulation facilitators must be prepared to formally train other simulation facilitators, too.

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.

Global health has evolved to focus on reducing health inequity and obtaining the highest attainable standard of health for all people. To do this, a range of actors now pursue interventions and policy with an eye toward global targets that place strong emphasis on improving health systems. Within global health, global surgery has sought to delineate the burden of surgical disease and propose policy to improve access to surgery. Oral and maxillofacial surgery has been underrepresented in global health but has a vital role in reducing the global health inequity attributable to the impact of oral and craniofacial conditions.

The COVID-19 pandemic poses significant challenges for otolaryngologists practicing in low- and middle-income countries (LMICs). This commentary highlights some of the particular challenges in low resource settings, including limited testing, insufficient personal protective equipment, small numbers of surgeons, and competing socio-economic demands. The commentary focuses on specific examples from around the world to draw attention to these challenges and also highlight examples of success and innovation. Amidst the crisis an opportunity exists for otolaryngologists from around the world to share resources, ideas, and innovations to best serve patients and improve the health system globally for the future.

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.

OBJECTIVES/HYPOTHESIS Patients who present to the emergency department (ED) with various otolaryngologic disorders are frequently referred to an otolaryngologist for follow-up care. Our aim was to further characterize this group as it has not been well described in the literature. STUDY DESIGN Cross-sectional retrospective study. METHODS We reviewed the charts of patients seen during an 18-month period in an urban public hospital trauma center adult ED and referred to an otolaryngology clinic for follow-up care. RESULTS Seven hundred thirty-eight patients were seen and referred; the most common diagnoses made by ED providers were peripheral vertigo (12%), otitis externa (8%), and nasal fractures (8%). Nine percent of patients were evaluated during their ED visit by an otolaryngology provider. Three hundred seventy-two (50%) patients returned for their otolaryngology clinic visit; facial trauma patients were least likely to return. The most common diagnoses made by otolaryngology providers were otitis externa (12%), peripheral vertigo (12%), and nasal fractures (7%). There was 50% concordance between patients' diagnoses made by ED and otolaryngology providers. The most common differences were otitis media versus otitis externa (10%) and acute pharyngitis versus laryngopharyngeal reflux (8%). During 37% of follow-up visits, an in-office procedure was performed, most commonly flexible fiberoptic laryngoscopy, cerumen removal, and nasal endoscopy. CONCLUSIONS Our analysis reports comprehensive characteristics of this referral group, identifying potential areas for improvement in patient management, resident education and efficiency. Otolaryngologists covering EDs should be familiar with this population in terms of types of cases that may affect their practices. LEVEL OF EVIDENCE 4. Laryngoscope, 128:1062-1067, 2018.

Purpose To validate the finding of an association between single nucleotide polymorphisms (SNPs) and toxicity during chemoradiotherapy (CRT) in rectal cancer patients, in an independent population. Methods and Materials The cohort consisted of 165 patients who received CRT for rectal cancer from 2006 to 2012. Prospectively recorded toxicity information, graded according to the Common Terminology Criteria for Adverse Events version 3.0, was retrieved from the medical record. Additionally, a subset of 52 patients recorded their gastrointestinal symptoms weekly during CRT, using the 7-item Bowel Problems Scale. Deoxyribonucleic acid was extracted from normal tissue in the proctectomy specimens and screened for 3 SNPs: XRCC1 R399Q, XPD K751Q, and TGFβ1 R25P. Univariable and multivariable logistic regression models were constructed. Results The median radiation dose was 50.4 Gy, and all patients received concurrent chemotherapy. Toxicities measured by the Common Terminology Criteria for Adverse Events were closely associated with patient-reported outcomes for the patients who completed the 7-item Bowel Problems Scale. Grade ≥3 toxicity occurred during CRT in 14 patients (8%). All 14 patients had either XRCC1 R399Q or TGFβ1 R25P polymorphisms. The TGFβ1 R25P polymorphism was significantly associated with grade ≥3 toxicity (odds ratio [OR] 3.47, P =.04) and, in patients who completed the Bowel Problems Scale, with grade ≥4 toxicity (OR 5.61, P =.02). The latter finding persisted in a multivariable logistic regression model controlling for ethnicity, age, and sex (adjusted OR 1.83, P =.02). Conclusions We have validated the correlation between the TGFβ1 R25P SNP and acute toxicity during CRT in an independent cohort using both clinician- and patient-reported toxicity. The information from our study could be used as a basis to formulate a prospective trial testing the utility of this SNP as a biomarker of acute toxicity during neoadjuvant treatment in locally advanced rectal cancer.

Introducción: la estabilidad es uno de los principales objetivos del tratamiento de ortodoncia, y la fibrotomía supracrestal circunferencial es una de las alternativas para prevenir la recidiva en casos de rotaciones dentales, apiñamiento y dientes con inclinación; sin embargo, no se tienen estudios que demuestren la efectividad de este tratamiento, así como sus efectos en la condición periodontal. El objetivo de esta revisión sistemática (RS) consistió en evaluar la efectividad de la fibrotomía supracrestal circunferencial (FSC) como procedimiento coadyuvante en la estabilidad del tratamiento de ortodoncia durante la retención, así como los efectos en la condición periodontal posterior a su realización. Métodos: la búsqueda de estudios relacionados con el tema se realizó mediante las bases de datos PubMed y EMBASE hasta octubre de 2018. Los estudios fueron considerados elegibles si abarcaban el uso de la FSC durante el periodo de retención y si reportaban la condición periodontal con un tiempo de seguimiento mayor o igual a un año. Para la evaluación del riesgo de sesgos en los estudios elegidos, se aplicó la escala Newcastle-Ottawa en los estudios observacionales y la herramienta de colaboración Cochrane para los ensayos clínicos aleatorizados (ECA) y ensayos clínicos controlados (ECC). Resultados: la estrategia de búsqueda arrojó 85 posibles artículos elegibles, de los cuales 5 fueron incluidos en laRS. Cuatro de los cinco estudios reportaron un índice de irregularidad menor en los pacientes que tuvieron FSC cuando se compararon con un grupo control. Con respecto a la condición periodontal, no se reportaron cambios en índice de placa, índice gingival, niveles de inserción, profundidad al sondaje y cantidad de encía queratinizada. Conclusiones: la fibrotomía es un método eficaz para evitar la recidiva de dientes previamente rotados y no genera alteraciones a nivel periodontal. Sin embargo, es importante tener en cuenta que la calidad metodológica de los estudios no fue alta.

Innovation ecosystems and emerging technologies can potentially accelerate the access to safe, affordable surgical care in low-resource settings. There is a need to develop localised innovation ecosystems that can establish an initial culture and catalyse the creation, adoption and diffusion of innovation. The surgathon model outlines one approach to seeding surgical innovation ecosystems. International academic institutions collaborated on six global surgery, innovation and ethics-themed hackathons (‘surgathons’) across India and Rwanda between 2016 and 2019. Over 1598 local multidisciplinary students participated, learning about challenges in the delivery of surgical care and ideating solutions that could leverage appropriate technology and resources for impact. Pursuing student ideas and evaluating their implementation past the surgathons continues to be an active effort. Surgathons have unfolded in different permutations based on local faculty, institution and health system context. The surgathon model is a novel method of priority setting challenges in global surgery and utilises locally driven expertise and innovation capacity to derive ethical solutions. The model offers a path for low-resource setting students and faculty to learn, advocate and innovate for improved surgical care.

Objectives Recommendations for polysomnography (PSG) in pediatric sleep disordered breathing (SDB) vary between the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the American Academy of Pediatrics (AAP). We determined the rates of preoperative PSG in children without risk factors outlined in the AAO-HNS Clinical Practice Guidelines and described the postoperative course of those patients following T&A. Methods Patients aged 3–17 undergoing T&A for SDB or OSA who did not have an indication for preoperative PSG were included. We conducted retrospective review to describe the rate, type, and timing of respiratory complications for patients with and without PSG following T&A, and discuss cases where disposition was changed due to PSG results. Results 1135 patients without risk factors underwent T&A for SDB or OSA. 196 (17%) had a preoperative PSG, of whom 85 (43.3%) had AHI >10 and 38 (24.8%) had an O2 nadir Conclusion PSG in children without risk factors results in admission of otherwise healthy patients following T&A who would have otherwise undergone ambulatory surgery. PSG alone in pediatric patients with no AAO-HNS risk factors should not influence postoperative disposition. These patients should be monitored for 3 h post-T&A and discharged in the absence of complications. Evidence level 2b

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 individual patients. We established a biorepository of 32 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 theirex vivoresponses to clinically relevant chemotherapy and radiation treatment correlate well with responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive rectal cancer followed by metastasis to lung and liver. Importantly, engrafted tumors closely reflected 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,in vitroplatform coupled with endoluminal propagation in animals.

Background With increasing adoption of transoral robotic surgery (TORS) for oropharyngeal cancer (OPC), more patients may receive trimodality therapy. We sought to investigate outcomes and toxicities in this cohort. Methods A retrospective study of patients with OPC treated with trimodality therapy at a tertiary-care hospital, comparing those receiving bilateral vs unilateral neck radiation. Results Four hundred thirty-six patients underwent TORS, 17% receiving adjuvant chemoradiation. Of the 46 patients completing adjuvant treatment in-house, contralateral neck was spared in 20%. There were no significant differences in survival, and patient-reported outcomes in salivary function, mood, and anxiety were superior in those patients receiving unilateral neck radiation and directly correlated with mean dose to local structures. Conclusions Surgery for OPC offers the potential for reduction in radiation volumes by omitting the contralateral neck in those who may have required definitive chemoradiation. Even in patients receiving concurrent chemotherapy, unilateral neck radiation has a favorable toxicity profile without compromising survival.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with

Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival. A subset of patients with intact MMR but a similar immune microenvironment to MMR-deficient patients was identified and found to universally express high levels of PD-L1, suggesting that they may represent a currently untreated, checkpoint inhibitor-responsive population. Further, PD-L1 expression on antigen-presenting cells (APCs) in the tumor microenvironment (TME) resulted in impaired CTL/EC engagement and enhanced infiltration and engagement of Tregs. Characterization of the TME by mfIHC highlights the interconnection between immunity and immunosuppression in metastatic colon cancer and may better stratify patients for receipt of immunotherapies.

The legend of the Figure currently reads: "A formula for advancing surgical system strengthening and World Health Assembly resolution 68.15 through the World Health Organization's thirteenth General Programme of Work (GPW-13). This graphic depicts the three strategic shifts outlined in GPW-13 and ties them to specific avenues for surgical system strengthening to achieve overarching goals. GPW-13 = Thirteenth General Programme of Work; NSOAPs = National Surgical, Obstetric, and Anesthesia Plans; PHC = primary healthcare; SDG 3 = Sustainable Development Goal 3; UHC = universal health coverage; WHA 68.18 = World Health Assembly resolution 68.15. " The corrected Figure legend should read: A formula for advancing surgical system strengthening and World Health Assembly resolution 68.15 through the World Health Organization's thirteenth General Programme of Work (GPW-13). This graphic depicts the three strategic shifts outlined in GPW-13 and ties them to specific avenues for surgical system strengthening to achieve overarching goals. GPW-13 = Thirteenth General Programme of Work; NSOAPs = National Surgical, Obstetric, and Anesthesia Plans; PHC = primary healthcare; SDG 3 = Sustainable Development Goal 3; UHC = universal health coverage; WHA 68.15 = World Health Assembly resolution 68.15.

Introduction: the objective of this study was to evaluate the periodontal effects of fixed retainers in the long term. Methods: a search in electronic databases (PubMed, Cochrane Library, Science Direct, Embase, ProQuest, Ebsco, Biomed Central, Medline, Lilacs, and Google Scholar) and a manual search with no language restrictions. The inclusion criteria were: randomized clinical trials and meta-analysis, prospective and retrospective studies, studies in humans, clinical and radiographical studies evaluating the periodontium, performed during the 1987-2014 period, up to 10 years of follow-up. Four authors extracted data from the selected studies independently. Results: after applying the inclusion criteria, we selected 4 studies in which a total of 405 patients were evaluated. All the studies were longitudinal and retrospective. There was a greater prevalence of gingival recessions, especially in mandibular incisors, which are more vulnerable. There were no significant changes in terms of alveolar bone index or calculus index. The survival rate of fixed retainers was 50% or higher. Due to the heterogeneity of the selected studies, including difference in study population, differences in methods to assess the intervention, and follow-up periods, it was impossible to quantify the variables to perform a meta-analysis. Conclusions: the selected studies had a middle level of evidence. The greatest gingival recessions occurred with the use of fixed retainers in a long time; however, there is no alteration of the alveolar bone level. The studies recommend encouraging patients to maintain good oral hygiene. The findings of this review should be cautiously taken due to the resulting level of evidence, and the general recommendation for clinicians is that, in the long run, these retainers appear to be safe to maintain the alignment of mandibular incisors, although more studies with greater scientific rigor are required. There were no conflicts of interest and this study did not have any kind of financial support. RESUMEN. Introducción: el objetivo del presente estudio consistió en evaluar los efectos periodontales de los retenedores fijos a largo plazo. Métodos: se realizó una búsqueda en bases de datos electrónicas (PubMed, Cochrane Library, Science Direct, Embase, ProQuest, Ebsco, Biomed Central, Medline, Lilacs y Google Scholar) y una búsqueda manual sin restricción de lenguaje. Los criterios de inclusión fueron: ensayos clínicos aleatorizados y metaanálisis, estudios prospectivos y retrospectivos, estudios en humanos, estudios en los que se evaluara clínica y radiográficamente el periodonto, periodo comprendido entre 1987 y 2014, seguimiento hasta 10 años. Cuatro autores extrajeron independientemente los datos de los estudios seleccionados. Resultados: después de aplicar los criterios de inclusión, se seleccionaron 4 estudios en los que se evaluaron un total de 405 pacientes. Todos los estudios fueron longitudinales retrospectivos. Se encontró una mayor prevalencia de recesiones gingivales, especialmente de los incisivos mandibulares, que son más vulnerables. No mostraron cambios significativos ni el índice de hueso alveolar ni el índice de cálculo. La tasa de supervivencia de los retenedores fijos fue mayor del 50%. Debido a la heterogeneidad de los estudios seleccionados, entre los cuales se encuentra la diferencia en la población de estudio, diferencias en los métodos para evaluar la intervención y el tiempo de seguimiento, fue imposible cuantificar las variables para realizar un metaanálisis. Conclusiones: los estudios seleccionados tuvieron un nivel de evidencia medio. Se presentan mayores recesiones gingivales con el uso de los retenedores fijos a largo plazo; sin embargo, no hay alteración del nivel óseo alveolar. Los estudios recomiendan incentivar al paciente para que mantenga una buena higiene oral. Los resultados de esta revisión se deben tomar con cautela por el nivel de evidencia que arrojaron, y la recomendación general para el clínico es que, a largo plazo, estos retenedores parecen ser seguros para mantener el alineamiento de incisivos mandibulares, aunque se requieren más estudios con mayor rigor científico. No hubo conflictos de intereses y la investigación no contó con ningún tipo de financiamiento.

RESUMEN. Antecedentes: A través del tiempo se han propuesto diferentes técnicas para realizar la remoción del adhesivo y resina remanentes luego de retirar los brackets, pero no existe un consenso entre los diferentes autores. Objetivo: el propósito de esta revisión sistemática fue identificar cuál es la técnica más adecuada para evitar injuria al esmalte durante la remoción de la resina remanente después de retirados los brackets. Métodos: Esta revisión sistemática se basó en los lineamientos de PRISMA, Para recolectar la evidencia publicada se realizó una búsqueda electrónica en diferentes bases de datos. Resultados: Se encontraron 8 artículos con una evidencia media (> de 9) los cuales fueron considerados en esta revisión sistemática. Al parecer la remoción de resina y adhesivo remanentes con ultrasonido, fresa de carburo de tungsteno de alta velocidad y piedras blancas generan la mayor pérdida de esmalte, mientras que 6 artículos proponen la fresa de tungsteno de baja velocidad como la mejor técnica. Conclusiones: Se requieren estudios aleatorizados, con grupo control, doble-ciego y una técnica de análisis del esmalte estandarizada para poder generar un nivel de evidencia alto y dar recomendaciones más acertadas para el clínico.ABSTRACT. Background: Over time different techniques have been proposed for the removal of the remaining adhesive and resin after the removal of brackets, but there is no consensus among authors. Objective: Evaluate the most appropriate technique to prevent injury to the enamel during the removal of the remaining resin after the brackets are removed. Methods: This systematic review is based on the guidelines of PRISMA, to collect the published evidence there was a various electronic databases search. Results: There were only 8 items with medium evidence (> 9) which were considered in this systematic review. Apparently removing remaining adhesive resin with ultrasound, tungsten carbide cutter high speed and white stones generate the greatest loss of enamel, while 6 articles propose the tungsten bur at low speed as the best technique. Conclusions: Randomized studies with control group, double-blind and a standardized technique of enamel analysis are required to generate a high level of evidence and give more accurate recommendations for clinicians.

BACKGROUND: Despite numerous trials assessing optimal antibiotic prophylaxis strategies for colorectal surgery, few studies have assessed real-world practice on a national scale with respect to risk of surgical site infections. OBJECTIVE: Using a large national claims database we aimed to describe current use of prophylactic antibiotics (type and duration) and associations with surgical site infection after open colectomies. DESIGN: This was a retrospective study using the Premier Perspective database. SETTINGS: Included were patient hospitalizations nationwide from January 2006 to December 2013. PATIENTS: A total of 90,725 patients who underwent an open colectomy in 445 different hospitals were included in the study. MAIN OUTCOME MEASURES: Multilevel, multivariable logistic regressions measured associations between surgical site infection and type of antibiotic used and duration (day of surgery only, day of surgery and the day after, and >1 day after surgery). RESULTS: Overall surgical site infection prevalence was 5.2% (n = 4750). Most patients (41.8%) received cefoxitin for prophylaxis; other choices were ertapenem (18.2%), cefotetan (10.3%), metronidazole with cefazolin (9.9%), and ampicillin with sulbactam (7.6%), whereas 12.2% received other antibiotics. Distribution of prophylaxis duration was 51.6%, 28.5%, and 19.9% for day of surgery only, day of surgery and the day after, and >1 day after surgery, respectively. Compared with cefoxitin, lower odds for surgical site infection were observed for ampicillin with sulbactam (OR = 0.71 (95% CI, 0.63–0.82)), ertapenem (OR = 0.65 (95% CI, 0.58–0.71)), metronidazole with cefazolin (OR = 0.56 (95% CI, 0.49–0.64)), and “other” (OR = 0.81 (95% CI, 0.73–0.90)); duration was not significantly associated with altered odds for surgical site infection. Sensitivity analyses supported the main findings. LIMITATIONS: The study was limited by its lack of detailed clinical information in the billing data set used. CONCLUSIONS: In this national study assessing real-world use of prophylactic antibiotics in open colectomies, the type of antibiotic used appeared to be associated with up to 44% decreased odds for surgical site infections. Although there are numerous trials on optimal prophylactic strategies, studies that particularly focus on factors that influence the choice of prophylactic antibiotic might provide insights into ways of reducing the burden of surgical site infections in colorectal surgeries.

3581 Background: Half of patients diagnosed with colorectal cancer (CRC) develop metastases and most are CRC liver metastasis (CRLM). A mere 20% of these patients undergo complete resection of their liver disease and 5-year overall survival (OS) is only 50%. We hypothesized that we could identify a specific molecular profile associated with extraordinary survivorship in CRLM patients that would more precisely inform underlying tumor biology beyond standard clinical and pathologic features. Methods: Tumor samples were identified from patients who underwent curative resection. Patients with disease-specific survival (DSS) ≥10 years following resection were compared to those with ≤2-year survival (10yr vs. 2yr). Evaluable DNA was obtained from 36 cases (2yr, n = 17; 10yr, n = 19) then sequenced and analyzed with MSK-IMPACT (MSK-I), a hybridization capture, next generation sequencing platform. Differentially altered genes in 10yr vs. 2yr cohorts were identified (Fisher’s exact). Findings in the extraordinary survivors group were validated using MSK-I in an independent cohort of 965 metastatic CRCs (metCRCs). Kaplan-Meier estimates and log-rank test were used. Results: In the 2yr group, we noted higher clinical risk scores and more complex chemotherapy regimens vs. the 10yr group. Molecularly, mutually exclusive KRAS and TP53 mutations were noted in the 10yr group, whereas significant co-occurrence of KRAS and TP53 mutations was seen in the 2yr group. Further, we noted significant enrichment of VEGF copy number gains in the 2yr group vs. the 10yr group. APC mutation was equally common. In the validation cohort, KRASmut/TP53wt and TP53mut/KRASwt patients (median OS of 10 and 15 years respectively) had significantly better OS than the co-occurring KRASmut / TP53mutpatients (median OS of 4.9 years; (P = 0.0001)). Conclusions: Single mutation of either KRAS or TP53 is associated with better outcomes than co-occurring KRAS/TP53 mutations in metCRC. These data demonstrate use of an extraordinary survivor cohort to identify a molecular profile associated with significant survival differences in an independent cohort of metCRC patients.

587 Background: Few markers reliably identify colorectal cancer (CRC) patients at risk of recurrence and death. SMAD4 loss occurs in 10-20% of cases and has shown promise in identifying high-risk stage II/III patients. We examined SMAD4 status and association with clinical/pathologic features in 446 stage I-IV CRC patients at Memorial Sloan Kettering (MSK). Methods: Patients undergoing curative resection were included (1981-2010). Familial polyposis syndrome patients and those with inadequate tissue were excluded. Tissue microarrays were constructed (n=364). Immunohistochemistry for SMAD4 and mismatch repair (MMR) proteins was completed. SMAD4 nuclear stain intensity was scored (scale=0-3; 0=loss). On whole sections, MMR proteins (present or absent), tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocyte aggregates (PLAs) were scored (scale=0-3). Associations between clinical/pathologic features and SMAD4 loss vs. retention were analyzed. Kaplan-Meier estimates and log-rank test were used for recurrence-free and overall survival analyses (RFS and OS). Results: SMAD4 loss was noted in 13%. Median age at diagnosis was 53 years, and 51% were male. The cohort consisted of 61% hindgut tumors and 62% stage II/III patients. With up to 33 years of follow-up, the mean was 6 years. SMAD4 loss correlated with higher tumor and nodal stage, adjuvant therapy use, and lower TIL and PLA scores (pmedian) were noted to have worse OS with SMAD4 loss (p