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4. Spatially organized multicellular immune hubs in human colorectal cancer.

Author

Pelka, Karin, Hofree, Matan, Chen, Jonathan, Sarkizova, Siranush, Pirl, Joshua, Jorgji, Vjola, Bejnood, Alborz, Dionne, Danielle, Ge, William, Xu, Katherine, Chao, Sherry, Zollinger, Daniel, Lieb, David, Reeves, Jason, Fuhrman, Christopher, Hoang, Margaret, Delorey, Toni, Nguyen, Lan, Waldman, Julia, Klapholz, Max, Wakiro, Isaac, Cohen, Ofir, Albers, Julian, Smillie, Christopher, Cuoco, Michael, Wu, Jingyi, Su, Mei-Ju, Yeung, Jason, Vijaykumar, Brinda, Magnuson, Angela, Asinovski, Natasha, Moll, Tabea, Goder-Reiser, Max, Applebaum, Anise, Brais, Lauren, DelloStritto, Laura, Denning, Sarah, Phillips, Susannah, Hill, Emma, Meehan, Julia, Frederick, Dennie, Sharova, Tatyana, Kanodia, Abhay, Todres, Ellen, Jané-Valbuena, Judit, Biton, Moshe, Izar, Benjamin, Lambden, Conner, Clancy, Thomas, Bleday, Ronald, Melnitchouk, Nelya, Irani, Jennifer, Kunitake, Hiroko, Berger, David, Srivastava, Amitabh, Hornick, Jason, Ogino, Shuji, Rotem, Asaf, Vigneau, Sébastien, Johnson, Bruce, Corcoran, Ryan, Sharpe, Arlene, Kuchroo, Vijay, Ng, Kimmie, Giannakis, Marios, Nieman, Linda, Boland, Genevieve, Aguirre, Andrew, Anderson, Ana, Rozenblatt-Rosen, Orit, Regev, Aviv, and Hacohen, Nir

Subjects
MSI, MSS, anti-tumor immunity, cell-cell interactions, colorectal cancer, mismatch repair-deficient, mismatch repair-proficient, scRNA-seq, spatial, tumor atlas, Bone Morphogenetic Proteins, Cancer-Associated Fibroblasts, Cell Compartmentation, Cell Line, Tumor, Chemokines, Cohort Studies, Colorectal Neoplasms, DNA Mismatch Repair, Endothelial Cells, Gene Expression Regulation, Neoplastic, Humans, Immunity, Inflammation, Monocytes, Myeloid Cells, Neutrophils, Stromal Cells, T-Lymphocytes, Transcription, Genetic
Abstract

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Published
2021

10. Long-term outcomes analysis of flap-based perineal reconstruction

Author

Rinkinen, Jacob R., primary, Fruge, Seth, additional, Welten, Vanessa M., additional, Kinsley, Sarah, additional, Bleday, Ronald, additional, Irani, Jennifer, additional, Yoo, James, additional, Goldberg, Joel E., additional, Melnitchouk, Nelya, additional, and Talbot, Simon G., additional

Published
2024
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16. Organ preservation for clinical T2N0 distal rectal cancer using neoadjuvant chemoradiotherapy and local excision (ACOSOG Z6041): results of an open-label, single-arm, multi-institutional, phase 2 trial

Author

Garcia-Aguilar, Julio, Renfro, Lindsay A, Chow, Oliver S, Shi, Qian, Carrero, Xiomara W, Lynn, Patricio B, Thomas, Charles R, Chan, Emily, Cataldo, Peter A, Marcet, Jorge E, Medich, David S, Johnson, Craig S, Oommen, Samuel C, Wolff, Bruce G, Pigazzi, Alessio, McNevin, Shane M, Pons, Roger K, and Bleday, Ronald

Subjects
Clinical Trials and Supportive Activities, Colo-Rectal Cancer, Biomedical Imaging, Clinical Research, Cancer, Digestive Diseases, Rare Diseases, Patient Safety, Evaluation of treatments and therapeutic interventions, 6.5 Radiotherapy and other non-invasive therapies, 6.1 Pharmaceuticals, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Chemoradiotherapy, Digestive System Surgical Procedures, Disease-Free Survival, Female, Humans, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Staging, Organ Sparing Treatments, Rectal Neoplasms, Time Factors, Treatment Outcome, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundLocal excision is an organ-preserving treatment alternative to transabdominal resection for patients with stage I rectal cancer. However, local excision alone is associated with a high risk of local recurrence and inferior survival compared with transabdominal rectal resection. We investigated the oncological and functional outcomes of neoadjuvant chemoradiotherapy and local excision for patients with stage T2N0 rectal cancer.MethodsWe did a multi-institutional, single-arm, open-label, non-randomised, phase 2 trial of patients with clinically staged T2N0 distal rectal cancer treated with neoadjuvant chemoradiotherapy at 26 American College of Surgeons Oncology Group institutions. Patients with clinical T2N0 rectal adenocarcinoma staged by endorectal ultrasound or endorectal coil MRI, measuring less than 4 cm in greatest diameter, involving less than 40% of the circumference of the rectum, located within 8 cm of the anal verge, and with an Eastern Cooperative Oncology Group performance status of at least 2 were included in the study. Neoadjuvant chemoradiotherapy consisted of capecitabine (original dose 825 mg/m(2) twice daily on days 1-14 and 22-35), oxaliplatin (50 mg/m(2) on weeks 1, 2, 4, and 5), and radiation (5 days a week at 1·8 Gy per day for 5 weeks to a dose of 45 Gy, followed by a boost of 9 Gy, for a total dose of 54 Gy) followed by local excision. Because of adverse events during chemoradiotherapy, the dose of capecitabine was reduced to 725 mg/m(2) twice-daily, 5 days per week, for 5 weeks, and the boost of radiation was reduced to 5·4 Gy, for a total dose of 50·4 Gy. The primary endpoint was 3-year disease-free survival for all eligible patients (intention-to-treat population) and for patients who completed chemotherapy and radiation, and had ypT0, ypT1, or ypT2 tumours, and negative resection margins (per-protocol group). This study is registered with ClinicalTrials.gov, number NCT00114231.FindingsBetween May 25, 2006, and Oct 22, 2009, 79 eligible patients were recruited to the trial and started neoadjuvant chemoradiotherapy. Two patients had no surgery and one had a total mesorectal excision. Four additional patients completed protocol treatment, but one had a positive margin and three had ypT3 tumours. Thus, the per-protocol population consisted of 72 patients. Median follow-up was 56 months (IQR 46-63) for all patients. The estimated 3-year disease-free survival for the intention-to-treat group was 88·2% (95% CI 81·3-95·8), and for the per-protocol group was 86·9% (79·3-95·3). Of 79 eligible patients, 23 (29%) had grade 3 gastrointestinal adverse events, 12 (15%) had grade 3-4 pain, and 12 (15%) had grade 3-4 haematological adverse events during chemoradiation. Of the 77 patients who had surgery, six (8%) had grade 3 pain, three (4%) had grade 3-4 haemorrhage, and three (4%) had gastrointestinal adverse events.InterpretationAlthough the observed 3-year disease free survival was not as high as anticipated, our data suggest that neoadjuvant chemoradiotherapy followed by local excision might be considered as an organ-preserving alternative in carefully selected patients with clinically staged T2N0 tumours who refuse, or are not candidates for, transabdominal resection.FundingNational Cancer Institute and Sanofi-Aventis.

Published
2015

28. Local Excision of Distal Rectal Cancer: An Update of Cancer and Leukemia Group B 8984

Author

Greenberg, Jacob, Shibata, David, Herndon, James, Steele, Glenn, Mayer, Robert, and Bleday, Ronald

Abstract

Abstract: Purpose: The efficacy of local excision in the treatment of some early-stage distal rectal cancers is still being debated, because few high-quality, long-term prospective data on outcomes are available. Methods: Fifty-nine patients with T1 lesions were treated with local excision alone, whereas 51 patients with T2 lesions received external beam irradiation (5,400 cGY) and 5-fluorouracil (500 mg/m2 intravenously Days 1–3, Days 29–31) after local excision. Kaplan-Meier curves were used to estimate the primary outcomes. The log-rank test and Cox’s proportional hazards model were used to compare subgroups relative to these outcomes. Results: With a median follow-up of 7.1 (range, 2.1–11.4) years, ten-year rates of overall survival were 84 percent for patients with T1 and 66 percent for T2 rectal cancer. Disease-free survival was 75 percent for T1 and 64 percent for T2 disease. Local recurrence rates for patients with T1 and T2 lesions were 8 and 18 percent, respectively, and rates of distant metastases were 5 percent for T1 and 12 percent for T2 lesions. T stage was a statistically significant predictor of overall survival (P = 0.04) and approached statistical significance as a predictor of disease-free survival (P = 0.07). Conclusions: Local excision alone for T1 rectal adenocarcinomas is associated with low recurrence and good survival rates that remain durable with long-term follow-up. T2 lesions treated via local excision and adjuvant therapy are associated with higher recurrence rates.

Published
2024
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38. Surgical Treatment of Rectal Cancer

Author

Bleday, Ronald, Melnitchouk, Nelya, Beck, David E., editor, Wexner, Steven D., editor, Hull, Tracy L., editor, Roberts, Patricia L., editor, Saclarides, Theodore J., editor, Senagore, Anthony J., editor, Stamos, Michael J., editor, and Steele, Scott R., editor

Published
2014
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45. Surgical Treatment of Rectal Cancer

Author

Bleday, Ronald, Brindzei, Nelya, Beck, David E., editor, Roberts, Patricia L., editor, Saclarides, Theodore J., editor, Senagore, Anthony J., editor, Stamos, Michael J., editor, and Wexner, Steven D., editor

Published
2011
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