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Sixteen patients with mismatch repair–deficient, locally advanced rectal cancer were enrolled in a pilot study in which 6 months of neoadjuvant anti–PD-1 therapy was to be followed by surgical resection. Twelve patients have completed treatment and have had at least 6 months of follow-up; all 12 had a clinical complete response. All imaging tests and biopsies have shown no viable tumor.

Importance Robotic colorectal resection continues to gain in popularity. However, limited data are available regarding how surgeons gain competency and institutions develop programs. Objective To determine the number of cases required for establishing a robotic colorectal cancer surgery program. Design Retrospective review. Setting Cancer center. Patients We reviewed 418 robotic-assisted resections for colorectal adenocarcinoma from January 1, 2009, to December 31, 2014, by surgeons at a single institution. The individual surgeon’s and institutional learning curve were examined. The earliest adopter, Surgeon 1, had the highest volume. Surgeons 2–4 were later adopters. Surgeon 5 joined the group with robotic experience. Interventions A cumulative summation technique (CUSUM) was used to construct learning curves and define the number of cases required for the initial learning phase. Perioperative variables were analyzed across learning phases. Main outcome measure Case numbers for each stage of the learning curve. Results The earliest adopter, Surgeon 1, performed 203 cases. CUSUM analysis of surgeons’ experience defined three learning phases, the first requiring 74 cases. Later adopters required 23–30 cases for their initial learning phase. For Surgeon 1, operative time decreased from 250 to 213.6 min from phase 1–3 ( P  = 0.008), with no significant changes in intraoperative complication or leak rate. For Surgeons 2–4, operative time decreased from 418 to 361.9 min across the two phases ( P  = 0.004). Their intraoperative complication rate decreased from 7.8 to 0 % ( P  = 0.03); the leak rate was not significantly different (9.1 vs. 1.5 %, P  = 0.07), though it may be underpowered given the small number of events. Conclusions Our data suggest that establishing a robotic colorectal cancer surgery program requires approximately 75 cases. Once a program is well established, the learning curve is shorter and surgeons require fewer cases (25–30) to reach proficiency. These data suggest that the institutional learning curve extends beyond a single surgeon’s learning experience.

Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Here, we define the clinical features, genomic landscape, and germline alterations in 174 patients with colitis-associated cancers and sequenced 29 synchronous or isolated dysplasia. TP53 alterations, an early and highly recurrent event in colitis-associated cancers, occur in half of dysplasia, largely as convergent evolution of independent events. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. Sequencing of multiple dysplasia/cancer lesions from mouse models and patients demonstrates rare shared alterations between lesions. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events. Colitis-associated cancers (CACs) develop in patients with inflammatory bowel disease and have distinct genomic features compared to sporadic colorectal cancers. Here, the authors characterize the genomic alterations of CAC tumors and dysplasia, finding decreased Wnt signaling and a lack of shared early genetic steps.

Background Data on the clinical value of second opinions in oncology are limited. We examined diagnostic and treatment changes resulting from second opinions and the expected impact on morbidity and prognosis. Methods This retrospective cohort study included patients presenting in 2018 to a high‐volume cancer center for second opinions about newly diagnosed colorectal, head and neck, lung, and myeloma cancers or abnormal results. Two sub‐specialty physicians from each cancer type reviewed 30 medical records (120 total) using a process and detailed data collection guide meant to mitigate institutional bias. The primary outcome measure was the rate of treatment changes that were “clinically meaningful”, i.e., expected to impact morbidity and/or prognosis. Among those with treatment changes, another outcome measure was the rate of clinically meaningful diagnostic changes that led to treatment change. Results Of 120 cases, forty‐two had clinically meaningful changes in treatment with positive expected outcomes (7 colorectal, 17 head and neck, 11 lung, 7 myeloma; 23–57%). Two patients had negative expected outcomes from having sought a second opinion, with worse short‐term morbidity and unchanged long‐term morbidity and prognosis. All those with positive expected outcomes had improved expected morbidity (short‐ and/or long‐term); 11 (0–23%) also had improved expected prognosis. Nine involved a shift from treatment to observation; 21 involved eliminating or reducing the extent of surgery, compared to 6 adding surgery or increasing its extent. Of the 42 with treatment changes, 13 were due to clinically meaningful diagnostic changes (1 colorectal, 5 head and neck, 3 lung, 4 myeloma; 3%–17%) . Conclusions Second‐opinion consultations sometimes add clinical value by improving expected prognoses; more often, they offer treatment de‐escalations, with corresponding reductions in expected short‐ and/or long‐term morbidity. Future research could identify subgroups of patients most likely to benefit from second opinions. In a retrospective review of the clinical value of second opinions in oncology, between 23% and 57% of patients across four disease types had significant changes in management from the second opinion expected to impact outcomes of morbidity and prognosis. De‐escalations in care, including some to no treatment needed, were common, with resulting expected reductions in morbidity.

Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown. We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated. A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients. Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).

Background The objective of this project was to achieve high, sustainable levels of net coverage in a village in rural Tanzania by combining free distribution of long-lasting insecticide-impregnated nets (LLINs) with community-tailored education. In Tanzania, malaria is the leading cause of morbidity and mortality. Although malaria bed nets have a well-established role in reducing disease burden, few rural households have access to nets, and effective use depends on personal practices and attitudes. Methods Five practices and attitudes inconsistent with effective LLIN use were identified from household interviews (n = 10). A randomized survey of villagers (n = 132) verified local prevalence of these practices and attitudes. Community leaders held an educational session for two members of every household addressing these practice and attitudes, demonstrating proper LLIN use, and emphasizing behaviour modification. Attendees received one or two LLINs per household. Surveys distributed three weeks (n = 104) and 15 months (n = 104) post-intervention assessed corrected practices and attitudes. Project efficacy was defined by correction of baseline practices and attitudes as well as high rates of reported daily net use, with statistical significance determined by chi-square test. Results Baseline interviews and surveys revealed incorrect practices and attitudes regarding 1) use of nets in dry season, 2) need to retreat LLINs, 3) children napping under nets, 4) need to repair nets, and 5) net procurement as a priority, with 53- 88.6% incorrect responses (11.4-47% correct responses). A three-week follow-up demonstrated 83-95% correct responses. Fifteen-month follow-up showed statistically significant (p < 0.01) corrections from baseline in all five practice and attitudes (39.4-93.3% correct answers). 89.4% of respondents reported using their nets every night, and 93.3% affirmed purchase of nets as a financial priority. Conclusions Results suggest that addressing community-specific practices and attitudes prior to LLIN distribution promotes consistent and correct use, and helps change attitudes towards bed nets as a preventative health measure. Future LLIN distributions can learn from the paradigm established in this project.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival. DNA and RNA sequencing in large cohorts of patients with rectal cancer treated with neoadjuvant therapies identifies biomarkers of response that could inform patient selection for non-operative treatment strategies.

Background Rectal tumors display varying degrees of response to total neoadjuvant therapy (TNT). We evaluated the performance of a convolutional neural network (CNN) in interpreting endoscopic images of either a non-complete response to TNT or local regrowth during watch-and-wait surveillance. Methods Endoscopic images from stage II/III rectal cancers treated with TNT from 2012 to 2020 at a single institution were retrospectively reviewed. Images were labelled as Tumor or No Tumor based on endoscopy timing (before, during, or after treatment) and the tumor’s endoluminal response. A CNN was trained using ResNet-50 architecture. The area under the curve (AUC) was analyzed during training and for two test sets. The main test set included images of tumors treated with TNT. The other contained images of local regrowth. The model’s performance was compared to sixteen surgeons and surgical trainees who evaluated 119 images for evidence of tumor. Fleiss’ kappa was calculated by respondent experience level. Results A total of 2717 images from 288 patients were included; 1407 (51.8%) contained tumor. The AUC was 0.99, 0.98, and 0.92 for training, main test, and local regrowth test sets. The model performed on par with surgeons of all experience levels for the main test set. Interobserver agreement was good ( k = 0.71–0.81). All groups outperformed the model in identifying tumor from images of local regrowth. Interobserver agreement was fair to moderate ( k = 0.24–0.52). Conclusions A highly accurate CNN matched the performance of colorectal surgeons in identifying a noncomplete response to TNT. However, the model demonstrated suboptimal accuracy when analyzing images of local regrowth.

Total mesorectal excision (TME) with intersphincteric resection and handsewn coloanal anastomosis (ISR-CAA) has been shown to be oncologically safe in patients with distal rectal cancer treated with preoperative chemoradiation. The introduction of the watch-and-wait (WW) strategy for rectal cancer patients with a clinical complete response to neoadjuvant therapy is changing the profile of patients undergoing TME surgery immediately following neoadjuvant treatment. The outcomes of ISR-CAA for patients with locally advanced rectal cancers not qualifying for WW have not been investigated. We conducted a retrospective analysis comparing the outcomes of ISR-CAA and abdominoperineal resection (APR) in patients with distal rectal cancer treated with neoadjuvant therapy and not qualifying for WW, at a comprehensive cancer center with an established WW program. The primary outcome was local recurrence-free survival. Sixty-seven patients had ISR-CAA and 79 had APR. Median follow-up was 61.1 months. The two groups were similar in sex, tumor stage, grade, and distance from the anal verge, but patients in the APR group were older on average. An R0 resection was achieved in 94% of ISR-CAA patients and 91% of APR patients. Patients in the ISR-CAA group had a lower 5-year rate of local recurrence-free survival (79% vs. 93%; p = 0.038) compared with the APR group; however, 5-year disease-free survival did not differ significantly between groups (67% for ISR-CAA and 64% for APR; p = 0.19). The local recurrence rate after ISR-CAA may be higher than after APR for patients without a clinical complete response to neoadjuvant therapy requiring TME surgery.