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The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for more personalized probabilistic predictions than those delivered by ordinal staging systems, particularly through the use of accurate risk models or calculators. However, judging the quality and acceptability of a risk model is complex. The AJCC Precision Medicine Core conducted a 2-day meeting to discuss characteristics necessary for a quality risk model in cancer patients. More specifically, the committee established inclusion and exclusion criteria necessary for a risk model to potentially be endorsed by the AJCC. This committee reviewed and discussed relevant literature before creating a checklist unique to this need of AJCC risk model endorsement. The committee identified 13 inclusion and 3 exclusion criteria for AJCC risk model endorsement in cancer. The emphasis centered on performance metrics, implementation clarity, and clinical relevance. The facilitation of personalized probabilistic predictions for cancer patients holds tremendous promise, and these criteria will hopefully greatly accelerate this process. Moreover, these criteria might be useful for a general audience when trying to judge the potential applicability of a published risk model in any clinical domain.

Immune checkpoint blockade targeting the programmed death-1 (PD-1) pathway has shown efficacy in several types of cancers including mismatch-repair-deficient colorectal carcinoma. In some tumor types, programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry has shown utility as a predictive marker for response to anti-PD-1 therapies. This utility, however, remains to be determined in colorectal carcinoma. In addition, although tumor-infiltrating lymphocytes have been associated with better prognosis in colorectal carcinoma, the prognostic value of PD-1 expression in these lymphocytes and its interaction with PD-L1 expression still await investigation. To address these questions, we performed a pilot study to evaluate the patterns of PD-L1 and PD-1 immunohistochemical expression on colorectal carcinoma cells and their tumor-infiltrating lymphocytes, respectively. Using tissue microarray, we found that 5% (19/394) of colorectal carcinomas exhibited high tumor PD-L1 expression, and 19% (76/392) had elevated numbers of PD-1-positive tumor-infiltrating lymphocytes. PD-L1 levels correlated with PD-1 levels (P<0.001), and mismatch-repair-deficient tumors had significantly higher rates of high PD-L1 and PD-1 expression when compared with mismatch-repair-proficient tumors (18% vs 2% and 50% vs 13%, respectively; P<0.001 for both). Staining intensity was also stronger for both markers in mismatch-repair-deficient tumors. Furthermore, we observed that among patients with mismatch-repair-deficient colorectal carcinoma, PD-1/PD-L1 expression stratified recurrence-free survival in an inter-dependent manner: an association between high PD-1-positive tumor-infiltrating lymphocytes and improved recurrence-free survival (P=0.041) was maintained only when the tumors had low-level PD-L1 expression (P=0.006); patients whose tumors had both high PD-1-positive tumor-infiltrating lymphocytes and high PD-L1 expression had a significantly worse recurrence-free survival (P<0.001). Thus, our results not only provide a foundation for further assessment of PD-L1 immunohistochemistry as a predictive marker for anti-PD-1 therapy in colorectal carcinoma, they also shed light on the prognostic impact of tumor-infiltrating lymphocytes in different subsets of mismatch-repair-deficient colorectal carcinomas.

PurposeTo predict microsatellite instability (MSI) status of colon cancer on preoperative CT imaging using radiomic analysis.MethodsThis retrospective study involved radiomic analysis of preoperative CT imaging of patients who underwent resection of stage II–III colon cancer from 2004 to 2012. A radiologist blinded to MSI status manually segmented the tumor region on CT images. 254 Intensity-based radiomic features were extracted from the tumor region. Three prediction models were developed with (1) only clinical features, (2) only radiomic features, and (3) “combined” clinical and radiomic features. Patients were randomly separated into training (n = 139) and test (n = 59) sets. The model was constructed from training data only; the test set was reserved for validation only. Model performance was evaluated using AUC, sensitivity, specificity, PPV, and NPV.ResultsOf the total 198 patients, 134 (68%) patients had microsatellite stable tumors and 64 (32%) patients had MSI tumors. The combined model performed slightly better than the other models, predicting MSI with an AUC of 0.80 for the training set and 0.79 for the test set (specificity = 96.8% and 92.5%, respectively), whereas the model with only clinical features achieved an AUC of 0.74 and the model with only radiomic features achieved an AUC of 0.76. The model with clinical features alone had the lowest specificity (70%) compared with the model with radiomic features alone (95%) and the combined model (92.5%).ConclusionsPreoperative prediction of MSI status via radiomic analysis of preoperative CT adds specificity to clinical assessment and could contribute to personalized treatment selection.

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.

The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between ‘microsatellite instability-high histology' and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology–molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.

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 Approximately 5% of gastrointestinal stromal tumors (GISTs) originate in the rectum, and historically, radical resection was commonly performed. Little is known about the outcome for rectal GIST in the era of imatinib. Methods Using a prospectively maintained database, this study retrospectively analyzed 47 localized primary rectal GISTs treated at our center from 1982 to 2016, stratified by when imatinib became available in 2000. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were analyzed by the Kaplan–Meier method. Results Rectal GISTs represented 7.1% of 663 primary GISTs. The findings showed 17 patients in the pre-imatinib era and 30 patients in the imatinib era. The two groups had similar follow-up evaluation, age, gender, Miettinen risk, and distance to the anal verge. In the imatinib era, tumors were smaller at diagnosis (median 4 vs. 5 cm; p  = 0.029), and 24 of the 30 patients received perioperative imatinib. In the high-risk patients, organ preservation and negative margins were more common among the 13 patients treated with neoadjuvant imatinib than among the 21 patients treated directly with surgery. High-risk patients who received perioperative imatinib ( n  = 15) had greater (or nearly significantly greater) 5-year OS, DSS, local RFS, and distant RFS than those who did not ( n  = 19) (91, 100, 100, and 71% vs. 47, 65, 74, and 41%; p  = 0.049, 0.052, 0.077, 0.051, respectively). In the imatinib era, no patient has had a local recurrence or death due to GIST. Conclusions The use of imatinib is associated with organ preservation and improved oncologic outcome for patients with rectal GIST.

Locally advanced rectal cancer requires multidisciplinary care. In the United States, most patients are treated with neoadjuvant chemoradiation delivered over 25‐28 days, total mesorectal excision, and 4 months of adjuvant chemotherapy. While effective, this trimodal approach is arduous. Alternative approaches have emerged to streamline treatment without sacrificing oncologic outcomes. These approaches include preoperative chemotherapy with selective use of radiation, short‐course radiotherapy delivered over 5 days, and total neoadjuvant therapy with attempted nonoperative organ‐preserving management (watch and wait). Ongoing trials are assessing the efficacies of these approaches in combination with various risk stratification strategies.