Preference Phenotypes in Thyroid Nodule Management: A Patient Segmentation Approach.

OBJECTIVE: Patient preferences regarding thyroid nodules are poorly understood. Our objective is to (1) employ a discrete choice experiment (DCE) to explore risk tradeoffs in thyroid nodule management, and (2) segment respondents into preference phenotypes. STUDY DESIGN: DCE. SETTING: Thyroid surgery clinic, online survey. METHODS: A DCE including 5 attributes (cancer risk, voice concerns, incision/scar, medication requirement, follow-up frequency) was refined with qualitative patient and physician input. A final DCE including 8 choice tasks, demographics, history, and risk tolerance was administered to participants with and without thyroid disease. Analysis was performed with multinomial logit modeling and latent class analysis (LCA) for preference phenotyping. RESULTS: A total of 1026 respondents were included; 480 had thyroid disease. Risk aversion was associated with increasing age (P < .001), female gender (P < .001), and limited education (P = .038), but not previous thyroid disease. Cancer risk most significantly impacted decision-making. Of the total possible utility change from thyroid nodule decision-making, 47.8% was attributable to variations in cancer risk; 20.0% from medication management; 14.9% from voice changes; 12.7% from incision/scar; and 4.6% from follow-up concerns. LCA demonstrated 3 classes with distinct preference phenotypes: the largest group (64.2%) made decisions primarily based on cancer risk; another group (18.2%) chose based on aversion to medication; the smallest group (17.7%) factored in medication and cancer risk evenly. CONCLUSION: Cancer risk and the need to take medication after thyroid surgery factor into patient decision-making most heavily when treating thyroid nodules. Distinct preference phenotypes were demonstrated, reinforcing the need for individual preference assessment before the treatment of thyroid disorders.

Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea in a Young Child With Down Syndrome.

Obstructive sleep apnea (OSA) is common in children with Down syndrome (DS). Adenoidectomy and/or tonsillectomy are the usual first interventions employed to treat OSA in children with DS but sometimes do not achieve adequate resolution of clinical signs. Positive airway pressure treatment is often used next, but this treatment is poorly tolerated by this population. Persistent OSA can adversely affect a child's health and cognitive development. Hypoglossal nerve stimulation (HGNS), previously shown to be safe and effective in adults with OSA, has been used in children as young as 10 years old with DS and has achieved measurable neurocognitive benefits. The US Food and Drug Administration recently lowered the age for HGNS implantation to 13 years for children with DS. However, questions remain regarding treatment of refractory OSA in younger children. Here, we report the case of a 4-year-old boy with DS and treatment-refractory OSA who underwent successful HGNS implantation. The decision to proceed with HGNS implantation in such a young child involved discussions about anatomic feasibility and potential neurocognitive benefits. The device was implanted without complication and with minimal postoperative bulk. This case suggests a possible treatment option that can be discussed in the course of shared decision-making between clinicians and families of young children with DS and treatment-refractory OSA.

Ear, Nose, and Throat Manifestations of Vasculitis and Other Systemic Autoimmune Diseases: Otologic, Sinus, and Airway.

Auricular, nasal, and laryngeal manifestations occur frequently in rheumatic diseases. Inflammatory ear, nose, and throat (ENT) processes often result in organ damage and have profound effects on quality of life. Herein, we review the otologic, nasal, and laryngeal involvement of rheumatic diseases, focusing on their clinical presentation and diagnosis. ENT manifestations generally respond to treatment of the systemic disease, which is outside the scope of this review; however, adjunctive topical and surgical treatment approaches, as well as treatment of idiopathic inflammatory ENT manifestations will be reviewed.

Pulmonary manifestations of chronic HPV infection in patients with recurrent respiratory papillomatosis.

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 Invasion by Thyroid Cancer: Laryngeal Function and Survival Outcomes.

BACKGROUND: Recurrent laryngeal nerve (RLN) invasion by thyroid carcinoma represents an advanced disease status with potentially significant co-morbidity. METHODS: 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. RESULTS: 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. CONCLUSION: 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. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2285-2292, 2022.

Type of recurrence is associated with disease-free survival after salvage surgery for locally recurrent rectal cancer.

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.

Pre-hospital antiplatelet medication use on COVID-19 disease severity.

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.

Redefining risk of contralateral cervical nodal disease in early stage oropharyngeal cancer in the human papillomavirus era.

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.

Simulation capacity building in rural Indian hospitals: a 1-year follow-up qualitative analysis.

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.

Oral and Maxillofacial Surgery: An Opportunity to Improve Surgical Care and Advance Sustainable Development Globally.

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.

Ambulatory tonsillectomy for children with severe obstructive sleep apnea without risk factors.

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 <80%. 69 (85%) patients with PSG-diagnosed severe OSA were admitted overnight. Of the entire cohort, 5 patients (0.44%) had hypoxemia requiring blow-by oxygen or repositioning. 4 (0.43%) patients without PSG experienced respiratory events and were converted to overnight stay. The timing of respiratory events for all children ranged from immediately following extubation in the operating room to 3 h postoperatively. 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.

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

BACKGROUND: A watch-and-wait strategy is a nonoperative alternative to sphincter-preserving surgery for patients with locally advanced rectal cancer who achieve a clinical complete response after neoadjuvant therapy. There are limited data about bowel function for patients undergoing this organ-preservation approach. OBJECTIVE: The purpose of this study was to compare bowel function in patients with rectal cancer managed with a watch-and-wait approach with bowel function in patients who underwent sphincter-preserving surgery (total mesorectal excision). DESIGN: This was a retrospective case-control study using patient-reported outcomes. SETTINGS: The study was conducted at a comprehensive cancer center. PATIENTS: Twenty-one patients underwent a watch-and-wait approach and were matched 1:1 with 21 patients from a pool of 190 patients who underwent sphincter-preserving surgery, based on age, sex, and tumor distance from the anal verge. MAIN OUTCOME MEASURES: Bowel function was measured using the Memorial Sloan Kettering Cancer Center Bowel Function Instrument. RESULTS: Patients in the watch-and-wait arm had better bowel function on the overall scale (median total score, 76 vs 55; p < 0.001) and on all of the subscales, with the greatest difference on the urgency/soilage subscale (median score, 20 vs 12; p < 0.001). LIMITATIONS: The study was limited by its retrospective design, small sample size, and temporal variability between surgery and time of questionnaire completion. CONCLUSIONS: A watch-and-wait strategy correlated with overall better bowel function when compared with sphincter-preserving surgery using a comprehensive validated bowel dysfunction tool. See Video Abstract at http://links.lww.com/DCR/B218. FUNCIÓN EVACUATORIA INFORMADA POR PACIENTES EN CÁNCER RECTAL MANEJADO CON UNA ESTRATEGIA DE OBSERVAR Y ESPERAR DESPUÉS DE LA TERAPIA NEOADYUVANTE: UN ESTUDIO DE CASOS Y CONTROLES: Observar y esperar es una alternativa no operativa a la cirugía de preservación del esfínter para pacientes con cáncer rectal localmente avanzado que logran una respuesta clínica completa después de la terapia neoadyuvante. Hay datos limitados sobre la función evacuatoria en pacientes sometidos a este abordaje para preservación de órganos.Evaluar la función evacuatoria en pacientes con cáncer rectal manejados con observar y esperar comparado a pacientes sometidos a cirugía de preservación de esfínteres (escisión mesorrectal total).Estudio retrospectivo de casos y controles utilizando resultados reportados por pacientes.Centro especializado oncológico.21 pacientes se sometieron a observar y esperar y se compararon con 21 pacientes de un grupo de 190 pacientes que se sometieron a cirugía de preservación de esfínteres controlando por edad, sexo y la distancia del tumor al borde anal.Función evacuatoria utilizando un instrumento de valoración del Centro de Cáncer Memorial Sloan Kettering.Los pacientes de observar y esperar demostraron mejor función evacuatoria en la escala general (puntuación total media, 76 versus 55; p <0,001) y en todas las subescalas, con la mayor diferencia en la subescala de urgencia / ensuciamiento fecal (puntuación media, 20 versus 12; p <0,001).Diseño retrospectivo, numero de muestra pequeño y variabilidad temporal entre la cirugía y el tiempo de finalización del cuestionario.Observar y esperar se correlacionó con mejor función evacuatoria en general en comparación con la cirugía de preservación del esfínter utilizando una herramienta integral validada para la disfunción evacuatoria. Consulte Video Resumen en http://links.lww.com/DCR/B218. (Traducción-Dr. Adrián Ortega).

Epigenetic preconditioning with decitabine sensitizes glioblastoma to temozolomide via induction of MLH1.

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.

Surgathon: a new model for creating a surgical innovation ecosystem in low-resource settings.

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.

Global Burden of Head and Neck Cancer: Economic Consequences, Health, and the Role of Surgery.

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.

Coaltered Ras/B-raf and TP53 Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer.

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.

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

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

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

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.

Correction to: Global surgery and the World Health Organization: indispensable partners to achieve triple billion goals.

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.