Purpose: Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. Patients and Methods: In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. Results: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%–44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and <1%, respectively; IHC staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15; P = 0.003, Fisher exact test) were observed for CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and <2.5, respectively, in tumor-infiltrating lymphocytes. Conclusions: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.

BACKGROUND: Intersphincteric resection has become a widely used treatment for patients with rectal cancer. However, the detailed anatomy of the anal canal related to this procedure has remained unclear. OBJECTIVE: The purpose of this study was to clarify the detailed anatomy of the anal canal. DESIGN: This is a descriptive study. SETTINGS: Histologic evaluations of paraffin-embedded tissue specimens were conducted at a tertiary referral hospital. PATIENTS: Tissue specimens were obtained from cadavers of 5 adults and from 13 patients who underwent abdominoperineal resection for rectal cancer. MAIN OUTCOME MEASURES: Sagittal sections from 9 circumferential portions of the cadaveric anal canal (histologic staining) and 3 circumferential portions from patients were studied (immunohistochemistry for smooth and skeletal muscle fibers). RESULTS: Longitudinal fibers between the internal and external anal sphincters consisted primarily of smooth muscle fibers that continued from the longitudinal muscle of the rectum. The levator ani muscle attached directly to the lateral surface of the longitudinal smooth muscle of the rectum. The length of the attachment was longer in the anterolateral portion and shorter in the posterior portion of the anal canal. In the lateral and posterior portions, the levator ani muscle partially overlapped the external anal sphincter; however, there was less overlap in the anterolateral portion. In the posterior portion, thick smooth muscle was present on the surface of the levator ani muscle and it continued to the longitudinal muscle of the rectum. LIMITATIONS: We observed only limited portions in some surgical specimens because of obstruction by tumors. CONCLUSIONS: The levator ani muscle attaches directly to the longitudinal muscle of the rectum. The spatial relationship between the smooth and skeletal muscles differed in different portions of the anal canal. For intersphincteric resection, dissection must be performed between the longitudinal muscle of the rectum and the levator ani muscle/external anal sphincter, and the appropriate surgical lines must be selected based on the specific structural characteristics of each portion.

Purpose: Posttreatment detection of ctDNA is strongly predictive of recurrence. Most minimal/molecular residual disease assays require prior tissue testing to guide ctDNA analysis, resulting in lengthy time to initial results and unevaluable patients. Experimental Design: We assessed a tissue-free assay (Guardant Reveal) that bioinformatically evaluates >20,000 epigenomic regions for ctDNA detection in 1,977 longitudinally collected postoperative plasma samples from 342 patients with resected colorectal cancer. Results: We observed sensitive and specific detection of minimal/molecular residual disease associated with clinically meaningful differences in recurrence-free intervals at each time point evaluated with a median lead time of 5.3 months. The longitudinal sensitivity in stage II or higher colon cancer was 81%. Sensitivity increased with serial measurement and varied by recurrence site: higher for liver (100%) versus lung (53%) and peritoneal (40%). Sensitivity among patients with rectal cancer was 60% owing to a high proportion of lung metastases. Specificity was 98.2% among 1,461 posttreatment samples (99.1% among those with follow-up longer than the upper IQR of the lead time observed in this study). Conclusions: Our data demonstrate the potential clinical utility of ctDNA as a tool to improve the management of stage II and higher colorectal cancer with a methodology that is noninvasive, accessible, and allows for rapid evaluation to inform clinical decisions.

The postoperative and survival outcomes of patients with primary advanced colorectal cancer who undergo partial versus total cystectomy have not been adequately compared, as studies of this topic are rare and comprise relatively small cohorts. This study aimed to investigate the short- and long-term outcomes of patients who underwent en bloc partial or total cystectomy for primary advanced colorectal cancer that was suspected of adhering to or invading the urinary bladder. The study included 90 patients who underwent various degrees of cystectomy between 1993 and 2013 to treat locally advanced primary colorectal cancer that was suspected of involving the urinary bladder. Patients in whom total cystectomy was performed solely because of prostate-invading lower rectal cancer were excluded. Data on patient characteristics and their short- and long-term outcomes were collected retrospectively to evaluate differences between partial cystectomy (the P group; n = 72) and total cystectomy (the T group; n = 18). Postoperative and oncologic outcomes were also analyzed. The T group had significantly greater operating times than the P group (median, 572 vs. 346 min); blood loss volume was also greater in the T group (median, 3092 vs. 1112 mL). The postoperative overall complication rate was significantly greater in the T group than in the P group (94.4% vs. 51.4%). With a median follow-up duration of 62 months, local recurrences were observed in 22.2 and 6.9% of patients in the T and P groups, respectively. On multivariate Cox regression analyses using partial cystectomy as the reference, total cystectomy was independently associated with poorer local recurrence-free survival (hazard ratio [HR], 4.0 95% confidence interval [CI], 1.1–15.0), relapse-free survival (HR, 2.9; 95% CI, 1.2–6.9), and overall survival (HR, 2.1; 95% CI, 1.0–4.3). Patients who undergo en bloc total cystectomy for locally advanced colorectal cancers have worse postoperative and oncologic outcomes than those who undergo partial cystectomy.