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Masaadeh AH, Eletrebi M, Parajuli B, De Jager N, Bosch DE. Human colitis-associated colorectal carcinoma progression is accompanied by dysbiosis with enriched pathobionts. Gut Microbes 2025; 17:2479774. [PMID: 40094201 PMCID: PMC11917176 DOI: 10.1080/19490976.2025.2479774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/14/2025] [Accepted: 03/10/2025] [Indexed: 03/19/2025] Open
Abstract
Dysbiosis and pathobionts contribute to inflammation and the risk of colitis-associated carcinoma (CAC) in animal models, but their roles in humans with this uncommon disease are unknown. We identified microbiome differences in human CAC compared with longstanding inflammatory bowel disease (IBD) and sporadic colorectal carcinoma (CRC). Twenty-four CAC resections were matched with CRC and IBD controls. Methods included histopathology, 16S rDNA metagenomics, and pathobiont-specific qPCR. Beta diversity differed by diagnosis (PERMANOVA p = 0.007). The distinguishing taxa included Akkermansia enriched in CRC, and Bacteroides spp. enriched in IBD. The non-neoplastic mucosae presented distinct beta diversity (p = 0.005), but the CAC/CRC tumor microbiomes were similar (p = 0.7). Within metastases and margins, Enterobacteriaceae were enriched in CAC, and Bacteroidales in CRC. Pathobiont-specific qPCR confirmed a greater frequency of pks+ E. coli and enterotoxigenic Bacteroides fragilis in CAC than IBD. High alpha diversity was associated with active inflammation, advanced cancer stage, and shorter overall survival (log-rank p = 0.008). Mucosal microbiomes distinguish CAC from longstanding IBD, implicating pathobionts as markers for disease progression. Integrating our findings with prior animal model research, pathobionts promote carcinogenesis in IBD patients through genotoxicity and host cell signaling.
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Affiliation(s)
- Amr H. Masaadeh
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Mohamed Eletrebi
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Bishal Parajuli
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Nicola De Jager
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Dustin E. Bosch
- Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, Iowa City, IA, USA
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Fu Z, Park E, Aydin HB, Shrestha N, Yang LM, Dabaghian A, Lee H. Acellular mucin in non-neoplastic inflammatory conditions of lower gastrointestinal tract. Ann Diagn Pathol 2025; 76:152449. [PMID: 39951910 DOI: 10.1016/j.anndiagpath.2025.152449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 02/03/2025] [Accepted: 02/05/2025] [Indexed: 02/17/2025]
Abstract
PURPOSE In the context of neoplasia, acellular mucin in lower gastrointestinal (GI) tract implies occult mucin-producing tumor and warrants additional workup. The clinical significance of acellular mucin in benign conditions remains unclear. METHODS Lower GI tract surgical specimens with acellular mucin without documented neoplastic conditions (colonic diverticulitis (n = 16), appendicitis (n = 14), and others (n = 8)) were retrieved. Low grade appendiceal mucinous neoplasm (LAMN) (n = 24) and diverticulitis without acellular mucin (n = 28) were used as controls for appendicitis and diverticulitis cases, respectively. Clinical data, histological findings, and additional workups performed due to acellular mucin were collected. RESULTS Patients with appendicitis with acellular mucin frequently presented with signs and symptoms of acute appendicitis (p = 0.016) compared to LAMN. 71 % were interval appendectomy, and 57 % had diverticula. In colonic diverticulitis cohort, no differences were found in terms of the duration of symptoms, age, gender and the degree of inflammation between the groups with and without acellular mucin. Seven of 8 patients with other conditions with acellular mucin had a history of abdominal surgery or fistula. Additional workup included levels (n = 7), consults (n = 11), and stains (n = 4). CONCLUSION Acellular mucin can be seen in a variety of benign conditions but this phenomenon is probably under-recognized and leads to additional investigations. Acellular mucin is likely translocated from the lumen through diverticulum or mural defect. Considering clinical context is crucial in providing accurate diagnosis while preserving laboratory resources.
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Affiliation(s)
- Zhiyan Fu
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Eundong Park
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, USA
| | - Hasan Basri Aydin
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, USA
| | - Neharika Shrestha
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, USA
| | - Liz M Yang
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Antranik Dabaghian
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, USA
| | - Hwajeong Lee
- Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY, USA.
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Abukhiran IM, Masaadeh AH, Byrne JD, Bosch DE. Mucosal Microbiome Markers of Complete Pathologic Response to Neoadjuvant Therapy in Rectal Carcinoma. CANCER RESEARCH COMMUNICATIONS 2025; 5:756-766. [PMID: 40259625 PMCID: PMC12051095 DOI: 10.1158/2767-9764.crc-25-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/10/2025] [Accepted: 04/16/2025] [Indexed: 04/23/2025]
Abstract
Abstract The intestinal microbiome contributes to colorectal carcinogenesis, disease progression, and response to therapy. Pathologic complete response is the therapeutic goal of neoadjuvant chemoradiation in rectal carcinoma. Nonoperative management has become an accepted strategy, and markers of complete treatment response are needed. Intestinal commensal bacteria contribute to treatment response and radiation colitis, and microbiome-targeted therapies have shown promise in clinical trials. We investigated the relationship among mucosa-associated bacteria, neoadjuvant therapy response, and radiation colitis symptoms in 57 patients who received neoadjuvant regimens with no therapy, chemotherapy only, or chemoradiation. The design was a retrospective cohort study. Microbiome profiling was performed by 16S rDNA sequencing of formalin-fixed, paraffin-embedded tissue at the proximal margin of resection. Global β diversity differed according to neoadjuvant therapy modality and was associated with radiation colitis. Taxonomic differences were detectable at phylum and lower classification levels, and radiation-induced colitis was associated with enrichment of the Bacillaceae family. Taxonomic features, including reduced Streptococcus, Lachnospiraceae, and Bacillaceae, were enriched in complete histopathologic responders to neoadjuvant therapy. Taxon-based prediction of metabolic pathways identified enrichment of prokaryotic NAD+ biosynthesis and salvage pathways in complete responders. Mucosal microbiome responses to multimodal neoadjuvant therapy reflect symptomatic radiation colitis, histopathologic evidence of radiation injury, and pathologic treatment response. Posttreatment microbiome β diversity markers of complete pathologic response may be useful in decisions to manage rectal carcinoma nonoperatively. Significance Posttreatment markers of the complete response of rectal carcinoma to neoadjuvant chemoradiation are needed to guide decisions about surgical resection. We found that mucosal microbiome β diversity, bacterial metabolic capacities, and specific taxonomic groups distinguished between complete and incomplete responders. The mucosal microbiome provides markers for complete pathologic response.
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Affiliation(s)
- Ibrahim M. Abukhiran
- Department of Pathology, Roy J. and Lucilla A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Amr H. Masaadeh
- Department of Pathology, Roy J. and Lucilla A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - James D. Byrne
- Department of Radiation Oncology, Roy J. and Lucilla A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Dustin E. Bosch
- Department of Pathology, Roy J. and Lucilla A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
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Lee SH, Pankaj A, Yilmaz O, Deshpande V, Yilmaz O. Beta-2-microglobulin positive tumor cells and CD8 positive lymphocytes are associated with outcome in post-neoadjuvant colorectal cancer resections. Hum Pathol 2025; 155:105737. [PMID: 39988058 DOI: 10.1016/j.humpath.2025.105737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 02/25/2025]
Abstract
Locally advanced colorectal cancers are treated with neoadjuvant therapy (NAT), which has been shown to alter the characteristics of the tumor including size, lymph node yield, and histologic grade. We seek to interrogate the effect of NAT on the immune microenvironment. We compared 190 patients with colorectal adenocarcinoma treated with NAT with those without NAT (n = 926). We evaluated clinicopathologic and molecular factors and performed immunohistochemistry and quantification on tissue microarrays for HLA class I/II proteins, beta-2-microglobulin (B2M), CD8, CD163, LAG3, PD-L1, and FoxP3. Patients in the NAT group were younger (60.9 vs 67.9, p < 0.001) and more often male (59.5 vs. 47.9, p = 0.004) than those in the non-NAT group. Tumors in the NAT group were smaller (3.5 vs 4.7 cm, p < 0.001), less often high grade (6.5% vs. 16.2%, p = 0.001), more frequently in the rectum (68.9% vs. 6.6%, p < 0.001) and associated with lower lymph node yields (p = 0.002); however, the incidence of extramural venous invasion, perineural invasion, and AJCC stage 3-4 disease were not different. Immune cells positive for CD8 (p = 0.011) were significantly lower in the NAT group. A high number of CD8+ cells and higher expression of B2M in tumor cells showed a significant survival benefit in both NAT and non-NAT group. NAT is associated with an immune-low tumor environment. CD8+ cells and tumor B2M expression may help identify a subset of immune high-tumors following NAT. This identification could aid in determining patients who may benefit from conservative management of colorectal carcinomas.
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Affiliation(s)
- Soo Hyun Lee
- Department of Pathology, Boston Medical Center, Boston, MA, USA
| | - Amaya Pankaj
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Omer Yilmaz
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Harvard Medical School, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Osman Yilmaz
- Harvard Medical School, Boston, MA, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
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Harada Y, Ikeda S, Kawabe Y, Oguri Y, Hashimura M, Yokoi A, Sida A, Fukagawa N, Hayashi M, Ono M, Kusano C, Takahashi H, Saegusa M. S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma. Sci Rep 2024; 14:31338. [PMID: 39732925 PMCID: PMC11682060 DOI: 10.1038/s41598-024-82814-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.
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Affiliation(s)
- Yohei Harada
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Sayako Ikeda
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Yuna Kawabe
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Akiko Sida
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Naomi Fukagawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Misato Hayashi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Mototsugu Ono
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
- Department of Pathology, Kitasato University School of Allied Health Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Chika Kusano
- Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, Kitasato University School of Allied Health Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374, Kanagawa, Japan.
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Cai Y, Chen M, Ye F, Liu Z, Luo S, Huang L, Kang L. The clinical relevance of adjuvant chemotherapy in locally advanced rectal cancer patients achieving near pathological complete response following neoadjuvant chemoradiotherapy: Insights from ypT stage. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108001. [PMID: 38364330 DOI: 10.1016/j.ejso.2024.108001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/20/2024] [Accepted: 02/01/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND Near-pathological complete response (Near-pCR) patients constitute a distinct subgroup with limited research attention. The clinical relevance of adjuvant chemotherapy (ACT) in this patient cohort remains uncertain. METHODS We conducted a retrospective analysis of 245 patients with locally advanced rectal cancer (LARC) who achieved near-pCR following neoadjuvant chemoradiotherapy (NCRT) between 2011 and 2018. Based on their receipt of ACT or not (non-ACT), patients were divided into two groups. We examined their characteristics, treatment modalities, and survival outcomes, particularly focusing on 5-year disease-free survival (DFS) and 5-year overall survival (OS). RESULTS Among the 245 near-pCR patients, 191 (77.96%) received ACT, and 42 (17.14%) experienced disease recurrence. All 54 (22.04%) Patients in the non-ACT group exhibited a lower 5-year DFS rate (72.2% vs. 85.9%, P = 0.014) and a similar 5-year OS rate (87.0% vs. 91.1%, P = 0.351). Interestingly, those with ypT3-T4 stage tumors demonstrated a worse DFS (76.8% vs. 89.9%, P = 0.010) and OS (87.5% vs. 97.0%, P = 0.004) compared to their counterparts with ypT1-T2 stage tumors. Patients with Non-Downstage tumors showed inferior DFS (76.9% vs. 88.3%, P = 0.025) and OS (87.2% vs. 93.0%, P = 0.166) in comparison to patients with Downstage tumors. The ACT subgroup in patients with Downstage demonstrated statistically better 5-year DFS (93.0% vs. 71.4%, P = 0.001) but analogous survival rates for 5-year OS (OS: 94.0% vs. 89.3%, P = 0.402). Pathological T stage 3-4, perineural invasion (PNI) (positive) and ACT were independent factors influencing 5-year DFS in multivariate analysis. Both univariate and multivariate analysis demonstrated a link between serum carcinoembryonic antigen (CEA) before treatment ≥5 ng/ml and shorter 5-year OS. Notably, near-pCR patients with positive lymph nodes experienced notably diminished 5-year DFS in the absence of ACT post-surgery (61.1% vs. 93.2%, P < 0.001). CONCLUSIONS ACT demonstrated a significant positive impact on the prognosis of select near-pCR patients, particularly those with ypT1-T2 stage tumors and positive lymph nodes. ypT staging may emerge as a valuable criterion for precise post-surgical ACT guidance in near-pCR patients.
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Affiliation(s)
- Yebing Cai
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China
| | - Mian Chen
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China
| | - Fujin Ye
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China
| | - Zhanzhen Liu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China
| | - Shuangling Luo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China
| | - Liang Huang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China.
| | - Liang Kang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, China.
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Shen Q, Liu D, Liu S. Response to Neoadjuvant Chemoradiotherapy as a Predictor of Long-Term Survival in Patients with Locally Advanced Rectosigmoid Junction Cancer: An Analysis Based On SEER Database. IRANIAN JOURNAL OF PUBLIC HEALTH 2023; 52:1935-1941. [PMID: 38033833 PMCID: PMC10682576 DOI: 10.18502/ijph.v52i9.13575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/06/2023] [Indexed: 12/02/2023]
Abstract
Background Neoadjuvant chemoradiotherapy is recommended to locally advanced rectal cancer, especially for the lower and middle ones. However, the role of neoadjuvant chemoradiotherapy in rectosigmoid junction cancer remains undetermined. We investigated whether patients with a good response to neoadjuvant chemoradiotherapy will have a relatively better long-term survival compared with those with no response. Methods Overall, 1325 patients diagnosed with locally advanced rectosigmoid junction cancer from Surveillance, Epidemiology, and End-Results (SEER) cancer registry database (2004-2014, America) were selected. All of them had received neoadjuvant chemoradiotherapy and were evaluated by Collaborative Stage Data Collection System. We performed Kaplan-Meier univariate analysis and Cox regression multivariate analysis models to estimate the potential prognostic factors of long-term survival outcomes. Response to neoadjuvant chemoradiotherapy and histological type of tumor were the two prognostic factors. Results The 5-year OS was 78.1% in responders, and 63.4% in nonresponders. In addition the 5-year DSS was 85.1% in responders, and 72.9% in nonresponders. Conclusion Based on SEER database in locally advanced rectosigmoid junction cancer, patients with a good response to neoadjuvant chemoradiotherapy could have a benefit of long-term survival.
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Affiliation(s)
- Qi Shen
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui,230001, China
| | - Dandan Liu
- Department of Geriatric Medicine, The Second People’s Hospital of Hefei (Hefei Hospital Affiliated to Anhui Medical University), Hefei, Anhui, 230001,China
| | - Shaojun Liu
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001,China
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Prognostic Impact of TP53 Mutations and Tumor Mutational Load in Colorectal Cancer. GASTROINTESTINAL DISORDERS 2022. [DOI: 10.3390/gidisord4030016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The DNA damage response (DDR) is critical for maintaining genome stability, and abnormal DDR—resulting from mutations in DNA damage-sensing and repair proteins—is a hallmark of cancer. Here, we aimed to investigate the predictive power of DDR gene mutations and the tumor mutational load (TML) for survival outcomes in a cohort of 22 rectal cancer patients who received pre-operative neoadjuvant therapy. Univariate analysis revealed that TML-high and TP53 mutations were significantly associated with worse overall survival (OS) with TML-high retaining significance in multivariate analyses. Kaplan–Meier survival analyses further showed TML-high was associated with worse disease-free (p = 0.036) and OS (p = 0.024) results in our patient cohort. A total of 53 somatic mutations were identified in 22 samples with eight (36%) containing mutations in DDR genes, including ATM, ATR, CHEK2, MRE11A, RAD50, NBN, ERCC2 and TP53. TP53 was the most frequently mutated gene, and TP53 mutations were significantly associated with worse OS (p = 0.023) in Kaplan–Meier survival analyses. Thus, our data indicate that TML and TP53 mutations have prognostic value for rectal cancer patients and may be important independent biomarkers for patient management. This suggests that prognostic determination for rectal cancer patients receiving pre-operative neoadjuvant therapy should include consideration of the initial TML and tumor genetic status.
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Takahashi H, Watanabe H, Hashimura M, Matsumoto T, Yokoi A, Nakagawa M, Ishibashi Y, Ito T, Ohhigata K, Saegusa M. A combination of stromal PD-L1 and tumoral nuclear β-catenin expression as an indicator of colorectal carcinoma progression and resistance to chemoradiotherapy in locally advanced rectal carcinoma. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2022; 8:458-469. [PMID: 35762092 PMCID: PMC9353658 DOI: 10.1002/cjp2.285] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/18/2022] [Accepted: 06/02/2022] [Indexed: 11/10/2022]
Abstract
Programmed cell death-1 (PD-1) and its ligand (PD-L1) are significant mediators of immune suppression in the tumor microenvironment. We focused on the immunological impact of PD-1/PD-L1 signaling during tumor progression in colorectal carcinoma (CRC) and its association with resistance to neoadjuvant chemoradiotherapy (NCRT) in locally advanced rectal carcinoma (LAd-RC). Histopathological and immunohistochemical analyses of 100 CRC cases (including 34 RC) without NCRT and 109 NCRT-treated LAd-RC cases were performed. Membranous tumoral PD-L1 expression was identified in 9 of 100 (9%) CRC cases, including 1 of 34 (2.9%) RC cases, but PD-L1 immunopositivity was not associated with any clinicopathological factors, with the exception of deficient mismatch repair (dMMR) status. In contrast, stromal PD-L1+ immune cells, which frequently exhibited coexpression of PD-1 and CD8 markers, were significantly correlated with tumor vessel invasion, nuclear β-catenin+ tumor budding cancer stem cell (CSC)-like features, and unfavorable prognosis. In the LAd-RC cases, stromal CD8+ (but not PD-L1+) immune cell infiltration in pretreatment-biopsied samples was significantly and positively associated with therapeutic efficacy. After NCRT, tumoral PD-L1 expression was observed in only 2 of 83 (2.4%) tumors, independent of dMMR status, whereas high stromal PD-L1+ and tumoral nuclear β-catenin positivity were significantly linked to a poor response to NCRT and high tumor budding features. In addition, high stromal PD-L1 immunoreactivity was significantly associated with poorer overall survival. In conclusion, a combination of stromal PD-L1+ immune cells and nuclear β-catenin+ tumor budding may contribute to tumor progression in CRC and resistance to NCRT in LAd-RC, through formation of niche-like lesions that exhibit immune resistance and CSC properties.
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Affiliation(s)
- Hiroyuki Takahashi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.,Department of Pathology, Kitasato University School of Allied Health Science, Sagamihara, Japan
| | - Hirono Watanabe
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Toshihide Matsumoto
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan.,Department of Pathology, Kitasato University School of Allied Health Science, Sagamihara, Japan
| | - Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Mayu Nakagawa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Yu Ishibashi
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takashi Ito
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kensuke Ohhigata
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
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10
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Li JY, Huang XZ, Gao P, Song YX, Chen XW, Lv XE, Fu Y, Xiao Q, Ye SY, Wang ZN. Survival landscape of different tumor regression grades and pathologic complete response in rectal cancer after neoadjuvant therapy based on reconstructed individual patient data. BMC Cancer 2021; 21:1214. [PMID: 34773999 PMCID: PMC8590217 DOI: 10.1186/s12885-021-08922-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/27/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Neoadjuvant therapy can lead to different tumor regression grades (TRG) in rectal cancer after neoadjuvant therapy. The purposes of this study are to investigate the relationships among TRG, pathologic complete response (pCR) and long-term survival, on the basis of reconstructed individual patient data (IPD). METHODS The PubMed, Embase, Ovid and Cochrane CENTRAL databases were searched. The primary endpoint was to evaluate the survival landscape of different TRGs after neoadjuvant therapy and the secondary endpoint was to evaluate the associations between pCR and survival. IPD were reconstructed with Kaplan-Meier curves. RESULTS The 10-year overall survival (OS) and 5-year disease-free survival (DFS) were clearly higher in the pCR group than in the non-pCR (npCR) group (80.5% vs. 48.3, 90.1% vs. 69.8%). Furthermore, the OS and DFS increased with improvement in tumor regression after neoadjuvant therapy. According to the IPD, the pCR group had longer OS (HR = 0.240, 95% CI = 0.177-0.325, p < 0.001) and DFS (HR = 0.274, 95% CI = 0.205-0.367, p < 0.001) than the npCR group. Better tumor regression was associated with better survival outcomes (p < 0.005). Direct calculation of published HR values yielded similar results. CONCLUSIONS Our results indicate a positive relationship between better tumor regressions and improved survival benefits among the npCR group and patients with rectal cancer achieving pCR had much longer OS and DFS than patients achieving npCR, presenting a survival landscape of different TRGs and pCR in rectal cancer after neoadjuvant therapy.
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Affiliation(s)
- Jia-Yi Li
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Yong-Xi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Xiao-Wan Chen
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Xing-Er Lv
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Yv Fu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Qiong Xiao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Shi-Yv Ye
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang City, 110001, China.
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11
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Duzova M, Basaran H, Inan G, Gul OV, Eren OO, Korez MK. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Outcomes of survival, toxicity, sphincter preserving and prognostic factors. Transpl Immunol 2021; 69:101489. [PMID: 34687908 DOI: 10.1016/j.trim.2021.101489] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 10/18/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND This study aimed to compare preoperative chemoradiotherapy (CRT) with postoperative CRT regarding survival, local control, disease control, sphincter preservation, toxicity and also prognostic factors for the treatment of locally advanced rectal cancer. METHODS Records of 140 patients with locally advanced rectal cancer who received preoperative or postoperative CRT were analyzed retrospectively. We compared the treatment groups (preoperative vs postoperative) according to baseline characteristics (demographic and rectal cancer disease characteristics), and also carried out the survival analyses. RESULTS From January 2010 to December 2019, 140 patients were included in the analysis, 65 received preoperative treatment and 75 postoperative treatment. There was no difference in survival, recurrence or distant metastasis rate in both treatment groups. The ratios of the failure to complete adjuvant chemotherapy (32% vs 4.6%) and acute grade 3-4 toxicity (32% vs 6.2%) were higher in the postoperative group (p < 0.001). In lower located tumors (≤5 cm from anal verge) the ratio of the sphincter preserving in the preoperative group was 60.7% (n = 17/28), and was 16.6% (n = 3/18) in the postoperative group (Yates χ2 = 5.829, p = 0.005). CONCLUSION This study showed no difference in recurrence and survival rate. Preoperative CRT is the preferred treatment for patients with locally advanced rectal cancer, given that it is associated with a superior overall treatment compliance rate, reduced toxicity, and an increased rate of sphincter preservation in low-lying tumors, but not for overall survival.
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Affiliation(s)
- Mursel Duzova
- Selcuk University, Faculty of Medicine, Department of Radiation Oncology, Konya, Turkey.
| | - Hamit Basaran
- Selcuk University, Faculty of Medicine, Department of Radiation Oncology, Konya, Turkey.
| | - Gokcen Inan
- Selcuk University, Faculty of Medicine, Department of Radiation Oncology, Konya, Turkey.
| | - Osman Vefa Gul
- Selcuk University, Faculty of Medicine, Department of Radiation Oncology, Konya, Turkey.
| | - Orhan Onder Eren
- Selcuk University, Faculty of Medicine, Department of Medical Oncology, Konya, Turkey
| | - Muslu Kazım Korez
- Selcuk University, Faculty of Medicine, Biostatistics Department, Konya, Turkey.
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12
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Flood M, Narasimhan V, Wilson K, Lim WM, Ramsay R, Michael M, Heriot A. Organoids as a Robust Preclinical Model for Precision Medicine in Colorectal Cancer: A Systematic Review. Ann Surg Oncol 2021; 29:47-59. [PMID: 34596795 DOI: 10.1245/s10434-021-10829-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/24/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Patients with locally advanced or metastatic colorectal cancer (CRC) display heterogeneous responses to standard-of-care therapy. Robust preclinical models of malignancy in the form of patient-derived tumor organoids (PDTOs) have recently come to the fore in tailoring patient care to a personalized medicine level. This study aimed to review the literature systematically regarding PTDOs and gauge their impact on precision medicine in the management of CRC. METHODS A PRISMA-compliant systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library databases was performed. The results were categorized based on the primary objective of the individual studies as follows: organoid use in predicting effective hyperthermic intraperitoneal chemotherapy (HIPEC), systemic chemotherapy in CRC, or neoadjuvant chemoradiotherapy in rectal cancer. RESULTS The literature search found 200 publications, 16 of which met the inclusion criteria. Organoid models of primary and metastatic CRC have been increasingly used to assess clinical responses to standard therapy. Marked heterogeneity exists, matching the responses observed in clinical practice with ex vivo drug and radiation screening. Repeated correlation between organoid and patient sensitivity to forms of HIPEC, systemic chemotherapy, and chemoradiotherapy has been observed. CONCLUSION Patient-derived tumor organoids are the latest tool in predictive translational research. Current organoid-based studies in precision medicine have shown their great potential for predicting the clinical response of patients to CRC therapy. Larger-scale, prospective data are required to fully support this exciting avenue in cancer care.
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Affiliation(s)
- Michael Flood
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
| | - Vignesh Narasimhan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Kasmira Wilson
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Wei Mou Lim
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Robert Ramsay
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Michael Michael
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Alexander Heriot
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
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13
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Khan S, Haider G, Abid Z, Bukhari N, Khan SZ, Abid M. Adequacy of Surgical Pathology Reports of Colorectal Carcinoma and Its Significance. Cureus 2021; 13:e16965. [PMID: 34540379 PMCID: PMC8423118 DOI: 10.7759/cureus.16965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 11/05/2022] Open
Abstract
Introduction Colorectal cancer is the fifth most common cancer in the world. For loco-regionally confined disease surgery is the definitive treatment. An adequate surgical pathology report is mandatory for the selection of adjuvant therapy. The objective of this study is to analyze whether adequate information is provided or not in the surgical pathology reports of colorectal carcinoma as according to College of American Pathologists (CAP) guidelines. Method This is a cross-sectional study carried out in the Department of Clinical Oncology, Jinnah Postgraduate Medical Center (JPMC) Karachi, tertiary care hospital in Pakistan. The duration of the study was from February 2020 to January 2021. A total of 153 surgical pathology reports issued by 11 different hospital-based laboratories after definitive surgery was assessed to look at its concordance rate with the checklist adapted from the CAP guidelines. Results Out of 153 surgical pathology reports, clinical information was provided in 72.5% of reports. Details of tumor extension were present in 88.2%, tumor margin in 75%, surgical procedure in 79%, and tumor deposits in 39.2% of reports. Macroscopic details including tumor perforation and evaluation of mesorectum were documented in 51.6% and 53.5% of the reports respectively. Details regarding perineural invasion along with lymphovascular invasion were present in 81.6% and 93% of the reports, respectively. The treatment effect was documented in only 25% of reports and regional lymph node status has been described in 85% of reports. Parameters described in all surgical pathology reports were: tumor site, tumor type, histologic type, and histologic grade. The pathological stage of the disease was documented in 91.5% of the reports. Conclusion This study concluded that surgical pathology reports of the majority of pathology laboratories were not fully adhered to the checklist provided by the CAP guidelines. This will affect post-operative management along with the prediction of disease prognosis.
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Affiliation(s)
- Salahuddin Khan
- Medical Oncology, Jinnah Postgraduate Medical Centre, Karachi, PAK
| | - Ghulam Haider
- Medical Oncology, Jinnah Postgraduate Medical Centre, Karachi, PAK
| | - Zain Abid
- Medical Oncology, Jinnah Postgraduate Medical Centre, Karachi, PAK
| | - Neelma Bukhari
- Medical Oncology, Jinnah Postgraduate Medical Centre, Karachi, PAK
| | - Shah Zeb Khan
- Clinical Oncology, Bannu Institute of Nuclear Medicine Oncology and Radiotherapy, Bannu, PAK
| | - Masooma Abid
- Medicine, Jinnah Medical and Dental College, Karachi, PAK
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14
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Wang X, Wang H, Wang H, Huang J, Wang X, Jiang Z, Tan L, Jiang D, Hou Y. Prognostic value of visual residual tumour cells (VRTC) for patients with esophageal squamous cell carcinomas after neoadjuvant therapy followed by surgery. BMC Cancer 2021; 21:111. [PMID: 33535987 PMCID: PMC7860028 DOI: 10.1186/s12885-020-07779-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Accepted: 12/29/2020] [Indexed: 01/03/2023] Open
Abstract
Background We assessed visual residual tumour cells (VRTC) with both Becker’s tumour regression grading (TRG) system and Japanese TRG system in esophageal squamous cell carcinoma (ESCC) patients treated with neoadjuvant therapy followed by surgery. Methods We compared Becker system and Japanese system in 175 ESCC patients treated between 2009 and 2015. Results According to Becker system, the 5-year DFS/DSS rates were 70.0%/89.3, 53.8%/56.7, 43.0%/49.0, and 42.4%/39.1% for TRG 1a (VRTC 0), TRG 1b (1–10%), TRG 2 (11–50%), and TRG 3 (> 50%). According to Japanese system, the rates were 38.8%/34.1, 49.5%/58.7, 50.2%/49.0 and 70.0%/89.3% for Grade 0-1a (VRTC> 66.6%), Grade 1b (33.3–66.6%), Grade 2 (1–33.3%) and Grade 3 (0). TRG according to two systems significantly discriminate the patients’ prognosis. TRG according to Becker system (HR 2.662, 95% CI 1.151–6.157), and lymph node metastasis (HR 2.567, 95% CI 1.442–4.570) were independent parameters of DSS. Conclusions Both Becker and Japanese system had their advantage in risk stratification of these ESCC patients. It was speculated that dividing 1–10% VRTC into a group might contribute to independently prognostic significance of Becker’s TRG system. Therefore, in addition to TRG of different systems, the percentage of VRTC might be recommended in the pathologic report, which could make the results more comparable among different researches, and more understandable for oncologists in the clinical practice.
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Affiliation(s)
- Xingxing Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Hao Wang
- Department of Thoracic surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Haixing Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Xin Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Zhengzeng Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Lijie Tan
- Department of Thoracic surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China. .,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai, 200032, People's Republic of China. .,Department of Pathology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, People's Republic of China.
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15
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Cienfuegos JA, Rodríguez J, Baixauli J, Chopitea Ortega A, García-Consuegra A, Abengózar M, Sánchez Justicia C, Hernández Lizoain JL. Neoadjuvant chemotherapy without radiotherapy for patients with locally advanced rectal cancer. Oncologic outcomes. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2021; 112:16-22. [PMID: 31729235 DOI: 10.17235/reed.2019.6454/2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND the standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy, surgery and adjuvant chemotherapy. Only 50% of patients receive the adjuvant treatment due to the surgical complications and toxicity of radiotherapy. Recently, neoadjuvant chemotherapy has been investigated in the locally advanced rectal cancer setting, with the aim of guaranteeing an uninterrupted systemic treatment. The objective of the present study was to assess the safety and efficacy of neoadjuvant chemotherapy in locally advanced rectal cancer. METHODS AND PATIENTS patients treated with neoadjuvant chemotherapy and surgery were identified from a prospective database of patients with rectal cancer (cII-III). The primary outcomes were the assessment of the number of R0 resections, the degree of pathologic response, patterns of recurrence and overall and disease-free survival. Treatment schedule: patients received 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy. RESULTS twenty-seven patients who received neoadjuvant chemotherapy were identified. Twenty-six anterior resections and one Hartmann intervention were performed. An R0 resection was performed in 27 (100%) patients and no involvement of the circumferential margin was observed. Complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients. The median follow-up was 35 months (range: 10-81) and four distant recurrences were recorded. Overall and disease-free survival at five years was 85% and 84.7%, respectively. Twenty-seven (100%) patients received all the cycles of chemotherapy, with a mean of six cycles (range 5-8) per patient. CONCLUSIONS neoadjuvant chemotherapy is a promising alternative in the locally advanced rectal cancer setting and further phase III clinical trials are clearly warranted.
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Affiliation(s)
- Javier A Cienfuegos
- Cirugía General / Apoyo Investigación, Clinica Universidad de Navarra, España
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16
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The impact of sarcopenia on pathologic complete response following neoadjuvant chemoradiation in rectal cancer. Langenbecks Arch Surg 2020; 405:1131-1138. [PMID: 32902708 DOI: 10.1007/s00423-020-01983-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/01/2020] [Indexed: 01/06/2023]
Abstract
PURPOSE The role of sarcopenia in pathologic complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) in non-metastatic locally advanced rectal cancer is currently unknown. The present study investigates the association between sarcopenia and post-nCRT pCR. METHODS The data of patients operated on following nCRT between January 2013 and January 2020 were collected retrospectively. Sarcopenia was diagnosed based on the calculation of the skeletal muscle index (SMI) from computed tomography carried out at the time of the initial diagnosis. A statistical analysis was then conducted for predictors of pCR. RESULTS The study included 61 patients with an average age of 57.3 years, 28 of whom formed the non-sarcopenic group (NSG) and 33 the sarcopenic group (SG). Of the patients, 32.7% were at clinical stage 2, and 67.3% were at clinical stage 3. Pathologic data following a mesorectal excision revealed a pCR rate of 21.4% in the NSG compared with 3% in the SG, which was a statistically significant difference (p = 0.025). The TNM downstaging rate was higher in the NSG than in the SG, although the difference was not statistically significant (50% vs. 33.3%, p = 0.28). A univariate analysis revealed the factors affecting pCR to be non-sarcopenia (p = 0.025), age < 61 years (p = 0.004), interval to surgery ≥ 8 weeks (p = 0.029), and serum CEA < 2.5 ng/ml (p = 0.035). CONCLUSION Sarcopenia was found to be a negative marker of pCR following nCRT in non-metastatic locally advanced rectal cancer.
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17
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Engel RM, Oliva K, Koulis C, Yap R, McMurrick PJ. Predictive factors of complete pathological response in patients with locally advanced rectal cancer. Int J Colorectal Dis 2020; 35:1759-1767. [PMID: 32474708 DOI: 10.1007/s00384-020-03633-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Patients with locally advanced rectal cancer who achieve pathologic complete response (pCR) following neoadjuvant therapy have better long-term outcomes and could be spared from the perioperative and long-term morbidity of rectal resection. The aim of this study was to identify factors that predict the ability to achieve pCR at completion of conventional neoadjuvant therapy, therefore determining their suitability for non-surgical management. METHODS A retrospective analysis was performed on data obtained from a prospectively maintained colorectal neoplasia database. Patients treated for biopsy-proven primary rectal adenocarcinoma between January 1, 2010, and February 28, 2018, who received neoadjuvant radiotherapy or chemoradiotherapy and had undergone surgical resection, were included in this study. Five-year oncologic outcome data was also obtained for 144 patients. Clinicopathological tumour characteristics and treatment regimens were analysed for correlation to clinical outcome. RESULTS Three hundred fifty-four patients met inclusion criteria for this study. We identified significant differences between patients achieving a pCR and those that did not for tumour type (adenocarcinoma vs. mucinous/signet ring; p = 0.008), pre-treatment serum CEA level (</≥ 2.5 μg/L; p = 0.003), neoadjuvant therapy type (short-course radiotherapy and long-course chemoradiotherapy; p = 0.008) and preoperative lymph node status (node-negative versus node-positive disease; p = 0.031). Additionally, this is the first report to our knowledge to identify a significant correlation with pCR and the degree of tumour fixity (mobile vs. fixed/tethered; p = 0.038). CONCLUSIONS This retrospective analysis identified factors that significantly impact a patients' ability to achieve a pCR, which may prove useful for prospectively selecting patients suitable for non-surgical management of disease.
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Affiliation(s)
- Rebekah M Engel
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern, VIC, 3144, Australia.
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
- Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, VIC, 3800, Australia.
| | - Karen Oliva
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern, VIC, 3144, Australia
| | - Christine Koulis
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern, VIC, 3144, Australia
| | - Raymond Yap
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern, VIC, 3144, Australia
| | - Paul J McMurrick
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern, VIC, 3144, Australia
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18
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Johncilla M, Yantiss RK. Histology of Colorectal Carcinoma: Proven and Purported Prognostic Factors. Surg Pathol Clin 2020; 13:503-520. [PMID: 32773197 DOI: 10.1016/j.path.2020.05.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Although tumor stage has a profound influence on prognosis, several histologic features are also important. These parameters predict biological behavior and can be used by clinicians to determine whether patients are at high risk for disease progression and, thus, are candidates for adjuvant therapy, particularly when they have localized (ie, stage II) disease. This article summarizes the evidence supporting the prognostic values of various histologic parameters evaluated by pathologists who assign pathologic stage to colorectal cancers. Criteria to be discussed include histologic subtype, tumor grade, lymphatic and perineural invasion, tumor budding, and host immune responses.
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Affiliation(s)
- Melanie Johncilla
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA
| | - Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA.
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19
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Ho V, Chung L, Singh A, Lea V, Abubakar A, Lim SH, Chua W, Ng W, Lee M, Roberts TL, de Souza P, Lee CS. Aberrant Expression of RAD52, Its Prognostic Impact in Rectal Cancer and Association with Poor Survival of Patients. Int J Mol Sci 2020; 21:ijms21051768. [PMID: 32143539 PMCID: PMC7084626 DOI: 10.3390/ijms21051768] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 02/29/2020] [Accepted: 03/01/2020] [Indexed: 12/18/2022] Open
Abstract
The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and cancer survival and response to preoperative radiotherapy. RAD52 expression was examined in tumour samples from 179 patients who underwent surgery for rectal cancer, including a sub-cohort of 40 patients who were treated with neoadjuvant therapy. A high score for RAD52 expression in the tumour centre was significantly associated with worse disease-free survival (DFS; p = 0.045). In contrast, reduced RAD52 expression in tumour centre samples from patients treated with neoadjuvant therapy (n = 40) significantly correlated with poor DFS (p = 0.025) and overall survival (OS; p = 0.048). Our results suggested that RAD52 may have clinical value as a prognostic marker of tumour response to neoadjuvant radiation and both disease-free status and overall survival in patients with rectal cancer.
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Affiliation(s)
- Vincent Ho
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Correspondence: ; Tel.: +61-2-4620-3845; Fax: +61-2-4520-3116
| | - Liping Chung
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
| | - Amandeep Singh
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia; (A.S.); (V.L.)
| | - Vivienne Lea
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia; (A.S.); (V.L.)
| | - Askar Abubakar
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
| | - Stephanie H. Lim
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
- Macarthur Cancer Therapy Centre, Campbelltown Hospital, NSW 2560, Australia
- Discipline of Medical Oncology, School of Medicine, Western Sydney University, Liverpool, NSW 2170, Australia
| | - Wei Chua
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Weng Ng
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Mark Lee
- Department of Radiation Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Tara L. Roberts
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
- South Western Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
| | - Paul de Souza
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Discipline of Medical Oncology, School of Medicine, Western Sydney University, Liverpool, NSW 2170, Australia
- Department of Medical Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
| | - Cheok Soon Lee
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; (L.C.); (A.A.); (T.L.R.); (P.d.S.); (C.S.L.)
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia; (S.H.L.); (W.C.)
- Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW 2170, Australia; (A.S.); (V.L.)
- Department of Radiation Oncology, Liverpool Hospital, Liverpool, NSW 2170, Australia;
- Discipline of Pathology, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia
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20
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Sun XY, Cai SH, Xu L, Luo D, Qiu HZ, Wu B, Lin GL, Lu JY, Zhang GN, Xiao Y. Neoadjuvant chemoradiotherapy might provide survival benefit in patients with stage IIIb/IIIc locally advanced rectal cancer: A retrospective single-institution study with propensity score-matched comparative analysis. Asia Pac J Clin Oncol 2020; 16:142-149. [PMID: 32031326 DOI: 10.1111/ajco.13306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 01/04/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND Neoadjuvant chemoradiotherapy (NACRT) and total mesorectal excision (TME) are standard treatments of stage II/III locally advanced rectal cancer (LARC), currently. Here, we evaluated the oncological outcomes in LARC patients treated with NACRT compared to TME alone, and determined whether tumor regression grade (TRG) and pathologic response after NACRT was related to prognosis. METHODS This is a retrospective comparison of 358 LARC patients treated with either TME alone (non-NACRT group, n = 173) or NACRT plus TME (NACRT group, n = 185) during 2003-2013. Perioperative and oncologic outcomes, like overall survival (OS), disease-free survival (DFS) and recurrence were compared using 1:1 propensity score matching analysis. RESULTS A total of 133 patients were matched for the analysis. After a median follow-up of 45 months (8-97 months), the 5-year OS (NACRT vs non-NACRT: 75.42% vs 72.76%; P = 0.594) and 5-year DFS (NACRT vs non-NACRT: 74.25% vs 70.13%; P = 0.224) were comparable between NACRT and non-NACRT, whereas the 5-year DFS rate was higher in the NACRT group when only stage IIIb/IIIc patients were considered (NACRT vs. non-NACRT: 74.79% vs. 62.29%; P = 0.056). In the NACRT group of 185 patients, those with pCR/stage I (vs stage II/stage III disease) or TRG3/TRG4 disease (vs TRG0/TRG1/TRG2) had significantly better prognosis. CONCLUSION NACRT might provide survival benefit in patients with stage IIIb/IIIc locally advanced rectal cancer.
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Affiliation(s)
- Xi-Yu Sun
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Song-Hua Cai
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lai Xu
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dan Luo
- National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui-Zhong Qiu
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Wu
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guo-le Lin
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun-Yang Lu
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guan-Nan Zhang
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Xiao
- Department of General Surgery Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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21
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Stein JE, Lipson EJ, Cottrell TR, Forde PM, Anders RA, Cimino-Mathews A, Thompson ED, Allaf ME, Yarchoan M, Feliciano J, Wang H, Jaffee EM, Pardoll DM, Topalian SL, Taube JM. Pan-Tumor Pathologic Scoring of Response to PD-(L)1 Blockade. Clin Cancer Res 2020; 26:545-551. [PMID: 31672770 PMCID: PMC7002263 DOI: 10.1158/1078-0432.ccr-19-2379] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/11/2019] [Accepted: 10/24/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed. EXPERIMENTAL DESIGN Hematoxylin and eosin-stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types. RESULTS Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non-small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features. CONCLUSIONS irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.
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Affiliation(s)
- Julie E Stein
- Department of Dermatology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Evan J Lipson
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Tricia R Cottrell
- Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Patrick M Forde
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Robert A Anders
- Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ashley Cimino-Mathews
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
- Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elizabeth D Thompson
- Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mohamad E Allaf
- Department of Urology at Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark Yarchoan
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Josephine Feliciano
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Hao Wang
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Elizabeth M Jaffee
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Drew M Pardoll
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Suzanne L Topalian
- Department of Surgery at Johns Hopkins University School of Medicine, Baltimore, Maryland and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
| | - Janis M Taube
- Department of Dermatology at Johns Hopkins University School of Medicine, Baltimore, Maryland.
- Department of Oncology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, and The Bloomberg∼Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, Maryland
- Department of Pathology at Johns Hopkins University School of Medicine, Baltimore, Maryland
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22
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Fanelli GN, Loupakis F, Smyth E, Scarpa M, Lonardi S, Pucciarelli S, Munari G, Rugge M, Valeri N, Fassan M. Pathological Tumor Regression Grade Classifications in Gastrointestinal Cancers: Role on Patients' Prognosis. Int J Surg Pathol 2019; 27:816-835. [PMID: 31416371 DOI: 10.1177/1066896919869477] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Preoperative chemotherapy or combined radiotherapy and chemotherapy (CRT), followed by surgery, represents the standard approach for locally advanced esophageal, gastric, and rectal carcinomas. To adequately evaluate the effects of neoadjuvant CRT in the resection specimens, several histopathologic tumor regression grade (TRG) scoring systems have been introduced into clinical practice. The primary goal of these TRG systems relies on a correct prognostic stratification of patients in the attempt to help clinical decision-making and influence surgical strategies, postoperative adjuvant therapies, and surveillance intensity. However, most TRG systems suffer from poor reproducibility and low interobserver concordance rates. Many efforts have been made in the identification of alternative, robust, simple, and universally accepted TRG scoring systems, which would help in the comparison of different treatment strategies and in the standardization of multimodal therapies. The aim of this review is to analyze the most commonly used TRG systems in gastrointestinal cancers highlighting their pitfalls and usefulness, depending on the tumor type.
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Affiliation(s)
| | | | | | - Marco Scarpa
- Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy
| | - Sara Lonardi
- Istituto Oncologico Veneto, IOV-IRCCS, Padua, Italy
| | | | | | | | - Nicola Valeri
- Royal Marsden Hospital, London and Sutton, UK
- The Institute of Cancer Research, London and Sutton, UK
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23
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Bottarelli L, De' Angelis GL, Azzoni C, Di Mario F, De' Angelis N, Leandro G, Fornaroli F, Gaiani F, Negri F. Potential predictive biomarkers in locally advanced rectal cancer treated with preoperative chemo-radiotherapy. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:102-106. [PMID: 30561402 PMCID: PMC6502185 DOI: 10.23750/abm.v89i9-s.7881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Indexed: 02/08/2023]
Abstract
Fluorouracil-based preoperative chemoradiotherapy represents a standard option for the treatment of locally advanced rectal cancer. Randomized clinical trials have shown that fluorouracil concomitant to preoperative radiation enhances tumor shrinkage (with 10% to 15% of the patients showing a complete pathological tumor response) compared with preoperative radiation alone. A high response rate is of clinical importance in rectal cancer, since patients who achieve a complete pathological response may experience improved long-term survival. Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy has no effect on response of the primary rectal tumor and single-agent fluoropyrimidine remains the standard chemotherapy in this setting. Despite novel biological insights and therapeutic advances, little is known about potential biological markers able to predict pathological tumor response before treatment and to subsequently impact patients' prognosis. This review focuses on the current available data on main molecular markers and molecular subtypes and the possible upcoming introduction of such analyses in the clinical setting.
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Affiliation(s)
- Lorena Bottarelli
- Department of Medicine and Surgery, Unit of Pathological Anatomy, University Hospital of Parma, Parma, Italy.
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24
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Kong JCH, Guerra GR, Millen RM, Roth S, Xu H, Neeson PJ, Darcy PK, Kershaw MH, Sampurno S, Malaterre J, Liu DSH, Pham TD, Narasimhan V, Wang M, Huang YK, Visvanathan K, McCormick J, Lynch AC, Warrier S, Michael M, Desai J, Murray W, Mitchell C, Ngan S, Phillips WA, Heriot AG, Ramsay RG. Tumor-Infiltrating Lymphocyte Function Predicts Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer. JCO Precis Oncol 2018; 2:1-15. [DOI: 10.1200/po.18.00075] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Purpose The presence of tumor-infiltrating lymphocytes (TILs) in tumors is superior to conventional pathologic staging in predicting patient outcome. However, their presence does not define TIL functionality. Here we developed an assay that tests TIL cytotoxicity in patients with locally advanced rectal cancer before definitive treatment, identifying those who will obtain a pathologic complete response (pCR). We also used the assay to demonstrate the rescue of TIL function after checkpoint inhibition blockade (CIB). Patients and Methods Thirty-four consecutive patients were identified initially, with successful completion of the assay before surgery in those 17 patients who underwent full treatment. An in vitro cytotoxic assay of rectal cancer tumoroids cocultured with patient-matched TILs was established and validated. Newly diagnosed patients were recruited with pretreatment biopsy specimens processed within 1 month. Evaluation of TIL-mediated tumoroid lysis was performed by measuring the mean fluorescence intensity of cell death marker, propidium iodide. CIB (anti–programmed cell death protein 1 [anti–PD-1] antibody) response was also assessed in a subset of patient specimens. Results Six of the 17 patients achieved an objective pCR on final evaluation of the resected specimen after neoadjuvant chemoradiotherapy. Cytotoxic killing identified the pCR group with a higher mean fluorescence intensity (27,982 [95% CI, 25,340 to 30,625]) compared with the non-pCR cohort (12,428 [95% CI, 9,434 to 15,423]; p < .001). Assessment of the effectiveness of CIB revealed partial restoration of cytotoxicity in TILs with increased PD-1 expression with anti–PD-1 antibody exposure. Conclusion Evaluating TIL function can be undertaken within weeks of the diagnostic biopsy, affording the potential to alter patient management decisions and refine selection for a watch-and-wait protocol. This cytotoxic assay also has the potential to serve as a platform to assist in the additional development of CIB.
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Affiliation(s)
- Joseph Cherng Huei Kong
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Glen Robert Guerra
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Rosemary Magdalena Millen
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Sara Roth
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Huiling Xu
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Paul Joseph Neeson
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Phillip Kevin Darcy
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Michael Henry Kershaw
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Shienny Sampurno
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Jordane Malaterre
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - David Shi Hao Liu
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Toan Duc Pham
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Vignesh Narasimhan
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Minyu Wang
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Yu-Kuan Huang
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Kumar Visvanathan
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Jacob McCormick
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Andrew Craig Lynch
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Satish Warrier
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Michael Michael
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Jayesh Desai
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - William Murray
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Catherine Mitchell
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Samuel Ngan
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Wayne Allen Phillips
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Alexander Graham Heriot
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
| | - Robert George Ramsay
- Joseph Cherng Huei Kong, Glen Robert Guerra, Rosemary Magdalena Millen, Sara Roth, Huiling Xu, Paul Joseph Neeson, Phillip Kevin Darcy, Michael Henry Kershaw, Shienny Sampurno, Jordane Malaterre, David Shi Hao Liu, Toan Duc Pham, Vignesh Narasimhan, Minyu Wang, Yu-Kuan Huang, Jacob McCormick, Andrew Craig Lynch, Satish Warrier, Michael Michael, Jayesh Desai, William Murray, Catherine Mitchell, Samuel Ngan, Wayne Allen Phillips, Alexander Graham Heriot, and Robert George Ramsay, Peter MacCallum Cancer
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25
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Dinaux A, Leijssen L, Bordeianou L, Kunitake H, Amri R, Berger D. The negative impact of understaging rectal cancer patients. Am J Surg 2018; 216:93-98. [DOI: 10.1016/j.amjsurg.2017.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/11/2017] [Accepted: 11/02/2017] [Indexed: 01/09/2023]
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26
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Kong JC, Guerra GR, Warrier SK, Lynch AC, Michael M, Ngan SY, Phillips W, Ramsay G, Heriot AG. Prognostic value of tumour regression grade in locally advanced rectal cancer: a systematic review and meta-analysis. Colorectal Dis 2018; 20:574-585. [PMID: 29582537 DOI: 10.1111/codi.14106] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 03/01/2018] [Indexed: 02/08/2023]
Abstract
AIM The current standard of care for locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. There is a spectrum of response to neoadjuvant therapy; however, the prognostic value of tumour regression grade (TRG) in predicting disease-free survival (DFS) or overall survival (OS) is inconsistent in the literature. METHOD This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was undertaken using Ovid MEDLINE, Embase and Google Scholar. Inclusion criteria were Stage II and III locally advanced rectal cancer treated with long-course CRT followed by radical surgery. The aim of the meta-analysis was to assess the prognostic implication of each TRG for rectal cancer following neoadjuvant CRT. Long-term prognosis was assessed. The main outcome measures were DFS and OS. A random effects model was performed to pool the hazard ratio (HR) from all included studies. RESULTS There were 4875 patients from 17 studies, with 775 (15.9%) attaining a pathological complete response (pCR) and 719 (29.9%) with no response. A significant association with OS was identified from a pooled-estimated HR for pCR (HR = 0.47, P = 0.002) and nonresponding tumours (HR = 2.97; P < 0.001). Previously known tumour characteristics, such as ypN, lymphovascular invasion and perineural invasion, were also significantly associated with DFS and OS, with estimated pooled HRs of 2.2, 1.4 and 2.3, respectively. CONCLUSION In conclusion, the degree of TRG was of prognostic value in predicting long-term outcomes. The current challenge is the development of a high-validity tests to predict pCR.
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Affiliation(s)
- J C Kong
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - G R Guerra
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - S K Warrier
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A Craig Lynch
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - M Michael
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.,Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - S Y Ngan
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.,Division of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - W Phillips
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - G Ramsay
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
| | - A G Heriot
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
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27
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Abstract
Tumor stage, as determined by the Tumor, Node, Metastasis (TNM) staging system, is the single most influential factor determining treatment decisions and outcome among patients with colorectal cancer. Several stage-related elements in pathology reports consistently pose diagnostic challenges: recognition of serosal penetration by tumor (ie, pT3 vs pT4a), evaluation of regional lymph nodes, distinction between tumor deposits and effaced lymph nodes, and assessment of tumor stage in the neoadjuvant setting. This article discusses each of these issues in detail and provides practical tips regarding colorectal cancer staging.
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Affiliation(s)
- Rhonda K Yantiss
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, New York, NY 10065, USA.
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28
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Cui J, Yang L, Guo L, Shao Y, Tan D, Li N, Zhang H. The combination of early treatment response and ypT stage is a novel metric to stage rectal cancer patients treated with neoadjuvant chemoradiotherapy. Oncotarget 2018; 8:37845-37854. [PMID: 28103579 PMCID: PMC5514955 DOI: 10.18632/oncotarget.14708] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 12/01/2016] [Indexed: 01/08/2023] Open
Abstract
Rectal cancer patients receiving neoadjuvant chemoradiotherapy (NCRT) are currently classified using the same Tumor-Node-Metastasis staging system as those patients without NCRT. We determined whether the combination of tumor treatment response (TRG) and ypT stage more accurately assesses primary tumors in rectal cancer after NCRT. We analyzed data from 329 rectal cancer patients treated with NCRT followed by radical resection. Cox proportional hazards models were used to evaluate the effects of different staging parameters on disease-free survival (DFS). ypN stage and TRG were independently associated with 3-year DFS, but ypT stage was not. We developed a new modified T stage classification metric (M-TTRG) that categorized patients into 5 subgroups based on ypT stage and TRG, with weighting by β-coefficients from multivariate analyses. The incidence of patients developing local or distant recurrence increased with increasing M-TTRG level. All five M-TTRG classes correlated with 3-year DFS. Improvement was seen in the model with M-TTRG classification compared with ypT stage, based on area under the curve after computing receiver operating characteristic curves. Our modified ypTNM staging system significantly improved prediction of 3-year DFS. This suggests TRG could complement ypT stage, and we propose the new M-TTRG metric could be used to better classify NCRT-treated patients, thereby improving treatment and assessing prognosis. The M-TTRG metric might be applicable to other types of cancer.
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Affiliation(s)
- Jian Cui
- Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Lin Yang
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lei Guo
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongfu Shao
- Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Dongfeng Tan
- Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Ni Li
- National Office for Cancer Prevention and Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Haizeng Zhang
- Department of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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29
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Abstract
Examination of the rectum by pathologists is instrumental in the management of patients affected by rectal carcinoma. That role includes evaluation of multiple gross and microscopic features that convey prognostic implications. The analysis is based on the authors' experience handling rectal specimens along with review of the pertinent literature in these areas: margins of excision, quality of the mesorectum, diligence and techniques to sample lymph nodes, tumor budding, grading of residual amount of carcinoma after preoperative therapy, vascular/perineural invasion, and staging the tumor. Pathologists must communicate the findings in a clear manner. Evaluation of margins and completeness of mesorectum are markers of the quality of surgical excision. The number of lymph nodes obtained and examined is dependent in great part on the diligence of the pathologist finding them in the mesenteric adipose tissue. There are grades for budding and response to prior chemoradiation therapy. The location of vascular invasion (extramural vs. intramural) may predict aggressive behavior. Pathologists proactively are to choose sections of tumor for molecular testing. Meticulous macro- and microscopic evaluation of specimens for rectal carcinoma by pathologist is needed to determine an accurate assessment of staging and other prognostic factors. The modern pathologists play a pivotal part in the care and management of patients suffering from rectal adenocarcinoma. That role goes from the initial histological diagnosis to the gross and microscopic examination of the excised specimens. Based on that examination pathologists issue statements that not only evaluate the quality of the surgical procedure, but also through the application of molecular tests they give light on prognostic factors and information for therapeutic purposes.
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Affiliation(s)
- Mariana Berho
- Department of Pathology, Cleveland Clinic Florida, Weston, FL, USA -
| | - Pablo A Bejarano
- Department of Pathology, Cleveland Clinic Florida, Weston, FL, USA
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30
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Liu J, Su M, Wang J, Zhang G, Zhou J, Zhang A, Ren Z, Zheng X, Hong S, Wang S, Zhang R. A novel grade-lymph node ratio model predicts the prognosis of the advanced gastric cancer patients after neoadjuvant radiotherapy. Oncotarget 2017; 8:14058-14067. [PMID: 27740935 PMCID: PMC5355162 DOI: 10.18632/oncotarget.12573] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 10/05/2016] [Indexed: 12/12/2022] Open
Abstract
Although local advanced gastric cancer (AGC) could benefit from neoadjuvant radiotherapy (NRT), there are few studies evaluating patients survival after NRT. In current study, we aimed to investigate the value of prognostic factors in AGC patients after NRT and to evaluate whether post-therapy pathological characteristics were predictive factors in these patients. We retrospectively analyzed AGC patients who underwent NRT from Surveillance, Epidemiology, and End Results (SEER) Database. The patients clinical and post-therapy pathological characteristics were analyzed. The best cutoff points for continuous variables were identified by X-tile. The discrimination of risk factors were compared by receiver operating characteristic (ROC) curve. As a result, 1,429 AGC patients were included into this study. In the multivariate analysis, the lymph nodes status and histology grade were significant risk factors for DSS (disease special survival). Then, we propose a novel Grade-lymph node Ratio (G-R) staging system for the AGC patients survival prognosis. Clearly, the new G-R staging system has a more-accurate 3-year and 5-year DSS prediction than the AJCC staging system (p = 0.001, 0.007, respectively). In conclusions, the current large, general population-based study demonstrated that the G-R staging system resulting in more-accurate DSS prediction. It could be regarded as a reliable classification for AGC patients after NRT in future.
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Affiliation(s)
- Jianjun Liu
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Mingxue Su
- Department of Infectious Disease Epidemiology, Lu'an People's Hospital, Lu'an, China
| | - Jing Wang
- Department of Urologic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Gan Zhang
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Jing Zhou
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Anqing Zhang
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Zixue Ren
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Xucai Zheng
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Shikai Hong
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Shengying Wang
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
| | - Rongxin Zhang
- Department of Head - Neck and Thoracic Surgery, Anhui Provincial Cancer Hospital, West branch of Anhui Province Hospital, Hefei, China
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Applicability of American Joint Committee on Cancer and College of American Pathologists Regression Grading System in Rectal Cancer. Dis Colon Rectum 2017; 60:815-826. [PMID: 28682967 DOI: 10.1097/dcr.0000000000000806] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Different tumor grading systems have been proposed to predict the association between tumor response and clinical outcome after preoperative chemoradiotherapy in patients with rectal cancer. The American Joint Committee on Cancer and College of American Pathologists regression grading system was recommended as the standard tumor regression grading system for rectal adenocarcinoma. OBJECTIVE This study evaluated the clinical applicability of the American Joint Committee on Cancer and College of American Pathologists regression grading system in neoadjuvant-treated patients with rectal cancer. DESIGN This is a retrospective cohort study based on clinical data from a prospectively maintained colorectal cancer database. SETTINGS This study was performed at a single tertiary referral center. PATIENTS A total of 144 patients with primary locally advanced mid-to-low rectal adenocarcinoma who underwent preoperative long-course chemoradiotherapy and total mesorectal excision between 2003 and 2012 were included. MAIN OUTCOMES MEASURES The primary outcome measures were the 5-year overall survival rate, the relapse-free survival rate, the cancer-specific survival rate, and cumulative recurrence rates. RESULTS Of the 144 patients, 16 (11%) were diagnosed as American Joint Committee on Cancer and College of American Pathologists regression grade 0, 43 patients (30%) as grade 1, 61 patients (42%) as grade 2, and 25 patients (17%) as grade 3.After a median follow-up time of 83 months (range, 3 to 147 mo), 5-year survival estimates for grades 0, 1, 2, and 3, were 93%, 77%, 81%, and 54% for overall survival (p = 0.006); 93%, 82%, 75%, and 55% for relapse-free survival (p = 0.03); and 100%, 86%, 89%, and 63% for cancer-specific survival (p = 0.006). The multivariate Cox regression analyses confirmed the American Joint Committee on Cancer and College of American Pathologists regression grading system as a prognostic factor for overall (p = 0.04), relapse-free (p = 0.02), and cancer-specific survival (p = 0.04). LIMITATIONS This was a retrospective study. CONCLUSIONS Our study findings confirm the clinical relevance and applicability of the American Joint Committee on Cancer and College of American Pathologists regression grade system as a predictive factor for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/A320.
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32
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Lee JH, Chie EK, Jeong SY, Kim TY, Kim DY, Kim TH, Kim SY, Baek JY, Chang HJ, Kim MJ, Park SC, Oh JH, Kim SH, Lee JH, Choi DH, Park HC, Kang SB, Kim JS. Redefining the Positive Circumferential Resection Margin by Incorporating Preoperative Chemoradiotherapy Treatment Response in Locally Advanced Rectal Cancer: A Multicenter Validation Study. Cancer Res Treat 2017; 50:506-517. [PMID: 28546522 PMCID: PMC5912136 DOI: 10.4143/crt.2016.607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 05/17/2017] [Indexed: 12/31/2022] Open
Abstract
Purpose This study was conducted to validate the prognostic influence of treatment response among patients with positive circumferential resection margin for locally advanced rectal cancer. Materials and Methods Clinical data of 197 patientswith positive circumferentialresection margin defined as ≤ 2 mm after preoperative chemoradiotherapy followed by total mesorectal excision between 2004 and 2009were collected forthis multicenter validation study. All patients underwent median 50.4Gy radiationwith concurrentfluoropyrimidine based chemotherapy. Treatmentresponse was dichotomized to good response, including treatmentresponse of grade 2 or 3, and poor response, including grade 0 or 1. Results After 52 months median follow-up, 5-year overall survival (OS) for good responders and poor responders was 79.1% and 48.4%, respectively (p < 0.001). In multivariate analysis, circumferential resection margin involvement and treatment response were a prognosticator for OS and locoregional recurrence-free survival. In subgroup analysis, good responders with close margin showed significantly better survival outcomes for survival. Good responders with involved margin and poor responders with close margin shared similar results, whereas poorresponderswith involved margin hadworst survival (5-year OS, 81.2%, 57.0%, 50.0%, and 32.4%, respectively; p < 0.001). Conclusion Among patients with positive circumferential resection margin after preoperative chemoradiotherapy, survival of the good responders was significantly better than poor responders. Subgroup analysis revealed that definition of positive circumferential resection margin may be individualized as involvement for good responders, whereas ≤ 2 mm for poor responders.
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Affiliation(s)
- Joo Ho Lee
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Eui Kyu Chie
- Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Yong Jeong
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Yong Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Tae Hyun Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Sun Young Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Ji Yeon Baek
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Hee Jin Chang
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Min Ju Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Sung Chan Park
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Jae Hwan Oh
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Sung Hwan Kim
- Department of Radiation Oncology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Jong Hoon Lee
- Department of Radiation Oncology, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Doo Ho Choi
- Department of Radiation Oncology, Samsung Medical Center, Sung-kyunkwan University School of Medicine, Seoul, Korea
| | - Hee Chul Park
- Department of Radiation Oncology, Samsung Medical Center, Sung-kyunkwan University School of Medicine, Seoul, Korea
| | - Sung-Bum Kang
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae-Sung Kim
- Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Korea
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Takahashi H, Nakamura K, Usami A, Tsuruta T, Hashimura M, Matsumoto T, Saegusa M. Possible role of nuclear β-catenin in resistance to preoperative chemoradiotherapy in locally advanced rectal cancer. Histopathology 2017; 71:227-237. [DOI: 10.1111/his.13227] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 03/23/2017] [Indexed: 01/12/2023]
Affiliation(s)
- Hiroyuki Takahashi
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Kie Nakamura
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Akane Usami
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Tomoko Tsuruta
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Miki Hashimura
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Toshihide Matsumoto
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
| | - Makoto Saegusa
- Department of Pathology; Kitasato University School of Medicine; Sagamihara Kanagawa Japan
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Ozyurt H, Ozden AS, Ozgen Z, Gemici C, Yaprak G. Pre- and post-surgery treatments in rectal cancer: a long-term single-centre experience. ACTA ACUST UNITED AC 2017; 24:e24-e34. [PMID: 28270729 DOI: 10.3747/co.24.3229] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Our study evaluated long-term survival outcomes in rectal cancer patients treated with preoperative radiotherapy, and the impact on survival of concomitant and postoperative adjuvant chemotherapy (ctx), among other prognostic factors. METHODS The study included 196 patients [median age: 58 years (range: 20-86 years); 63.0% men] with locally advanced rectal carcinoma and, in some cases, resectable liver metastasis. Rates of distant metastasis and local recurrence and of 5-year distant metastasis-free survival (dmfs) and overall survival (os) were determined. RESULTS The 5-year os rate was 57.0%, with a median duration of 81.5 months (95% confidence interval: 73.7 months to 89.4 months), and the 5-year dmfs rate was 54.1%, with a median duration of 68.4 months (95% confidence interval: 40.4 months to 96.4 months). Prognostic factors for higher os and dmfs rates were downstaging (p = 0.013 and p = 0.005 respectively), radiotherapy dose (50 Gy vs. 56 Gy or 45-46 Gy, both p = 0.002), and concomitant ctx use (p = 0.004 and p = 0.001) and type (5-fluorouracil-leucovorin-folinic acid vs. tegafur-folinic acid, p = 0.034 and p = 0.043). Adjuvant ctx after neoadjuvant long-term concomitant chemoradiotherapy (ccrt) and surgery was associated with better 5-year os rates for postoperative T0-T3 disease (p = 0.003) and disease at all lymph node stages (p = 0.001). CONCLUSIONS Our findings revealed a favourable survival outcome with long-term fractionated irradiation and concomitant 5-fluorouracil-based ctx, achieving 5-year os and dmfs rates of 57.0% and 54.1% respectively. Preoperative administration of radiotherapy (50 Gy) and postoperative adjuvant ctx were associated with a significant survival benefit. Radiation doses above 50 Gy and the interval between ccrt and surgery had no significant effect on survival.
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Affiliation(s)
- H Ozyurt
- Department of Radiation Oncology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, and
| | - A S Ozden
- Department of Radiation Oncology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, and
| | - Z Ozgen
- Department of Radiation Oncology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - C Gemici
- Department of Radiation Oncology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, and
| | - G Yaprak
- Department of Radiation Oncology, Dr. Lutfi Kirdar Kartal Training and Research Hospital, and
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Siddiqui MRS, Bhoday J, Battersby NJ, Chand M, West NP, Abulafi AM, Tekkis PP, Brown G. Defining response to radiotherapy in rectal cancer using magnetic resonance imaging and histopathological scales. World J Gastroenterol 2016; 22:8414-8434. [PMID: 27729748 PMCID: PMC5055872 DOI: 10.3748/wjg.v22.i37.8414] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 07/04/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To define good and poor regression using pathology and magnetic resonance imaging (MRI) regression scales after neo-adjuvant chemotherapy for rectal cancer.
METHODS A systematic review was performed on all studies up to December 2015, without language restriction, that were identified from MEDLINE, Cochrane Controlled Trials Register (1960-2015), and EMBASE (1991-2015). Searches were performed of article bibliographies and conference abstracts. MeSH and text words used included “tumour regression”, “mrTRG”, “poor response” and “colorectal cancers”. Clinical studies using either MRI or histopathological tumour regression grade (TRG) scales to define good and poor responders were included in relation to outcomes [local recurrence (LR), distant recurrence (DR), disease-free survival (DFS), and overall survival (OS)]. There was no age restriction or stage of cancer restriction for patient inclusion. Data were extracted by two authors working independently and using pre-defined outcome measures.
RESULTS Quantitative data (prevalence) were extracted and analysed according to meta-analytical techniques using comprehensive meta-analysis. Qualitative data (LR, DR, DFS and OS) were presented as ranges. The overall proportion of poor responders after neo-adjuvant chemo-radiotherapy (CRT) was 37.7% (95%CI: 30.1-45.8). There were 19 different reported histopathological scales and one MRI regression scale (mrTRG). Clinical studies used nine and six histopathological scales for poor and good responders, respectively. All studies using MRI to define good and poor response used one scale. The most common histopathological definition for good response was the Mandard grades 1 and 2 or Dworak grades 3 and 4; Mandard 3, 4 and 5 and Dworak 0, 1 and 2 were used for poor response. For histopathological grades, the 5-year outcomes for poor responders were LR 3.4%-4.3%, DR 14.3%-20.3%, DFS 61.7%-68.1% and OS 60.7-69.1. Good pathological response 5-year outcomes were LR 0%-1.8%, DR 0%-11.6%, DFS 78.4%-86.7%, and OS 77.4%-88.2%. A poor response on MRI (mrTRG 4,5) resulted in 5-year LR 4%-29%, DR 9%, DFS 31%-59% and OS 27%-68%. The 5-year outcomes with a good response on MRI (mrTRG 1,2 and 3) were LR 1%-14%, DR 3%, DFS 64%-83% and OS 72%-90%.
CONCLUSION For histopathology regression assessment, Mandard 1, 2/Dworak 3, 4 should be used for good response and Mandard 3, 4, 5/Dworak 0, 1, 2 for poor response. MRI indicates good and poor response by mrTRG1-3 and mrTRG4-5, respectively.
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Jalilian M, Davis S, Mohebbi M, Sugamaran B, Porter IW, Bell S, Warrier SK, Wale R. Pathologic response to neoadjuvant treatment in locally advanced rectal cancer and impact on outcome. J Gastrointest Oncol 2016; 7:603-8. [PMID: 27563451 DOI: 10.21037/jgo.2016.05.03] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Downstaging and pathologic complete response (pCR) after chemoradiotherapy (CRT) may improve progression-free survival and overall survival (OS) after curative therapy of locally advanced adenocarcinoma of rectum. The purpose of this study is to evaluate the pathologic response subsequent to neoadjuvant chemoradiation in locally advanced rectal adenocarcinoma and any impact of response on oncological outcome [disease-free survival (DFS), OS]. METHODS A total of 127 patients with histologically-proven rectal adenocarcinoma, locally advanced, were treated with preoperative radiotherapy and concurrent 5-fluorouracil (5 FU), and followed by curative surgery. Pathologic response to neoadjuvant treatment was evaluated by comparing pathologic TN (tumour and nodal) staging (yp) with pre-treatment clinical staging. DFS and OS were compared in patients with: pCR, partial pathologic response and no response to neoadjuvant therapy. RESULTS 14.96% (19 patients) had a pCR, 58.27% [74] showed downstaging and 26.77% [34] had no change in staging. At follow-up (range, 4-9 years, median 6 years 2 months or 74 months), 17.32% [22] showed recurrence: 15.74% [20] distant metastasis, 1.57% [2] pelvic failure. 10.5% [2] of the patients with pCR showed distant metastasis, none showed local recurrence. In the downstaged group, nine developed distant failure and two had local recurrence (14.86%). Distant failure was seen in 26.47% [9] of those with no response to neoadjuvant treatment. DFS and OS rates for all groups were 82.67% and 88.97% respectively. Patients with pCR showed 89.47% DFS and 94.7% OS. In partial responders, DFS was 85.1% and OS was 90.5%. In non-responders, DFS and OS were 73.5% and 82.3% respectively. Patients with pCR had a significantly greater probability of DFS and OS than non-responders. Rectal cancer-related death was 11.02% [14]: one patient (5.26%) with pCR, 9.47% [7] in the downstaged group and 17.64% [6] of non-responders. CONCLUSIONS The majority of patients showed some response to neoadjuvant treatment. Findings of this study indicate tumour response to neoadjuvant CRT improves the long-term outcome, with a better result in patients with pCR.
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Affiliation(s)
- Mahshid Jalilian
- William Buckland Radiotherapy Centre, Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Sidney Davis
- William Buckland Radiotherapy Centre, Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Mohammadreza Mohebbi
- Biostatistics Unit, Faculty of Health, Deakin University, Burwood Highway, Burwood, Victoria 3125, Australia
| | - Bhuvana Sugamaran
- William Buckland Radiotherapy Centre, Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Ian W Porter
- William Buckland Radiotherapy Centre, Alfred Hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Stephen Bell
- Department of Colorectal Surgery, Alfred hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Satish K Warrier
- Department of Colorectal Surgery, Alfred hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
| | - Roger Wale
- Department of Colorectal Surgery, Alfred hospital, 55 Commercial Road, Melbourne, Victoria 3004, Australia
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Prognostic Significance of the Histologic Response of Perihilar Cholangiocarcinoma to Preoperative Neoadjuvant Chemoradiation in Liver Explants. Am J Surg Pathol 2016; 40:510-8. [PMID: 26752544 DOI: 10.1097/pas.0000000000000588] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Perihilar cholangiocarcinoma (pCCA) has a dismal prognosis. Protocols incorporating chemotherapy, radiotherapy, and liver transplantation (LT) have emerged as curative options for unresectable tumors with 70% 5-year survival rates. We aimed to assess the value of extent of residual tumor (ERT) and other pathologic factors following chemoradiation in predicting outcome; 152 liver explants with pCCA treated with neoadjuvant chemoradiation and LT between 1993 and 2013 were reviewed for ERT, pathologic stage, histologic grade, and perineural and lymphovascular invasion. ERT was quantified as the percentage of viable carcinoma in the tumor bed. Tumors were classified into 4 ERT categories: (1) complete/near-complete response (≤1% ERT); (2) marked response (>1 to <10% ERT); (3) moderate response (10 to <30% ERT); and (4) minimal response (≥30% ERT). Overall 5-year survival rate was 69%. 5-year disease-free estimate was 74%. 57%, 16%, 18%, and 9% of explants were placed in ERT categories 1, 2, 3, and 4, respectively. ERT correlated significantly with the overall 5-year survival rate and 5-year, disease-free estimate by univariate (P<0.0001) and multivariate analysis (P=0.004 and 0.009, respectively). By multivariate analysis, pathologic stage was also an independent predictor of recurrence (P=0.003). Other variables that correlated with risk of death and recurrence by univariate analysis included perineural (P<0.0001) and lymphovascular invasion (P<0.0001), absence of primary sclerosing cholangitis (P=0.006 and P<0.0001, respectively), and pretreatment CA19-9 level (P=0.001 and 0.02, respectively). Histologic grade did not predict outcome. In summary, ERT independently predicts outcome in pCCA patients following neoadjuvant chemoradiation and LT and can stratify patient prognosis.
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Wang X, Zhao L, Liu H, Zhong D, Liu W, Shan G, Dong F, Gao W, Bai C, Li X. A phase II study of a modified FOLFOX6 regimen as neoadjuvant chemotherapy for locally advanced gastric cancer. Br J Cancer 2016; 114:1326-33. [PMID: 27172250 PMCID: PMC4984457 DOI: 10.1038/bjc.2016.126] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 03/11/2016] [Accepted: 04/18/2016] [Indexed: 02/07/2023] Open
Abstract
Background: We evaluated the efficacy and safety of the modified FOLFOX6 (mFOLFOX6) regimen as
a neoadjuvant chemotherapy in gastric cancer patients. Methods: Seventy-three patients with T2–T4 or N+ were enroled. Preoperative
chemotherapy consisted of three cycles of mFOLFOX6. The primary end points were
the response rate and the R0 resection rate. Prognostic factors for overall
survival (OS) were investigated using univariate and multivariate analyses. Results: Sixty-seven (91.8%) patients completed 3 cycles, with grade 3–4
toxicity arising in 33.0%. The radiology response rate was 45.8%.
Sixty-seven (91.8%) patients receiving radical surgery showed different
levels of histological regression of the primary tumour, with a ⩾50%
regression rate of 49.2%. ypTNM stage (HR 4.045, 95% CI
1.429–11.446) and tumours of diffuse and mixed type (HR 9.963, 95% CI
1.937–51.235; HR 8.890, 95% CI 1.157–68.323, respectively) were
significantly associated with OS. The pathologic regression rate (GHR;
⩾2/3/<2/3, ⩾50%/<50%) was
statistically significantly associated with OS according to a univariate
analysis. Conclusions: Perioperative mFOLFOX6 was a tolerable and effective regimen for gastric cancer.
The ypTNM stage was an independent predictor of survival. GHR
⩾50%/<50% could be used as a surrogate marker for
selecting a postoperative chemotherapy regimen.
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Affiliation(s)
- Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100032, China
| | - Lin Zhao
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100032, China
| | - Hongfeng Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Dingrong Zhong
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Wei Liu
- Department of Radiation, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Guangliang Shan
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Fen Dong
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of basic Medicine, Peking Union Medical College, Beijing 100005, China
| | - Weisheng Gao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100032, China
| | - Xiaoyi Li
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
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Complete Pathological Response After Neoadjuvant Long-Course Chemoradiotherapy for Rectal Cancer and Its Relationship to the Degree of T3 Mesorectal Invasion. Dis Colon Rectum 2016; 59:361-8. [PMID: 27050597 DOI: 10.1097/dcr.0000000000000564] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Many studies have shown significantly improved outcomes (reduced local recurrence and improved overall survival) for patients achieving a complete pathological response from neoadjuvant chemoradiotherapy. OBJECTIVE This study aimed to document the complete pathological response rate and outcomes in patients receiving preoperative long-course chemoradiotherapy stratified for the extent of T3 mesorectal invasion measured on preoperative imaging. DESIGN This is a retrospective study of prospectively collected data, of patients with rectal cancer in the Cabrini Monash University Department of Surgery colorectal neoplasia database, incorporating data from Cabrini Hospital and The Alfred Hospital, identifying patients entered between January 2010 and June 2014. PATIENTS AND SETTINGS One hundred eighteen patients with T3 rectal cancer met the selection criteria for the study; 26 achieved complete pathological response (22%). MAIN OUTCOME MEASURES Outcomes in terms of complete pathological response and oncological outcomes such as disease-free and overall survival were analyzed. RESULTS Patients with complete pathological response had significantly less preoperative invasion than those with no complete pathological response (p < 0.001). Depth of invasion was the only variable associated with complete pathological response (p < 0.002), and the likelihood of complete pathological response decreased by 35% for every millimeter of invasion. Complete pathological response was associated with increased disease-free survival (p = 0.018) and a lower risk of cancer progression (p = 0.046). Depth of invasion was associated with an increased risk of death after surgery; HR increased by 1.07 (95% CI, 1.00-1.15) for each 1-mm increase in invasion. LIMITATIONS This was a retrospective study with the usual limitations, although these were minimized through the use of a clinician-driven prospective database. CONCLUSIONS The smaller the degree of T3 invasion, the higher the chance of achieving complete pathological response (up to 35%), which is associated with improved disease-free and overall survival. A higher complete pathological response rate is observed in early T3 disease in comparison with more extensive T3 invasion.
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Wang HJ, Solanki S, Traboulsi S, Kassouf W, Brimo F. Neoadjuvant chemotherapy-related histologic changes in radical cystectomy: assessment accuracy and prediction of response. Hum Pathol 2016; 53:35-40. [PMID: 27321168 DOI: 10.1016/j.humpath.2016.02.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/26/2016] [Accepted: 02/10/2016] [Indexed: 12/28/2022]
Abstract
We evaluated the spectrum of histologic changes associated with neoadjuvant chemotherapy (NAC) and compared them with those resulting from transurethral resection (TUR). Twenty-five patients who received NAC were divided based on both their preoperative clinical/radiographic findings (clinical stage, hydronephrosis, palpable mass) and the cystectomy (RC) findings into NAC respondents (advanced clinical stage and <pT2+pN0), possible NAC respondents (non-advanced clinical stage and <pT2+pN0), and NAC nonrespondents (≥pT2and/or ≥pN1). In addition, 14 patients who received TUR alone and had <pT2+pN0 on RC were included. Presence/absence of the following histologic features was assessed: fibrosis/myofibroblastic reaction, hyalinization in the bladder wall, inflammatory reaction, calcification, foreign-body giant cells, necrosis, sheets of foamy macrophages, and fibrosis/hyalinization/necrosis in the lymph nodes (LNs). Overall, there was a significant histologic overlap between all groups. However, patients who received NAC had a significantly higher likelihood of showing hyalinization and less giant cells and inflammatory reaction than did those who received TUR only. Moreover, the only significantly different histologic features in NAC respondents versus TUR respondents were hyalinization and LN changes, with those 2 features in 25% and 0% of the possible NAC respondents group, respectively. Lastly, there was no significant difference in the possible NAC respondent group in comparison to the TUR-only arm. It appears that TUR and NAC result in overlapping histologic changes. In cases with no/minimal residual disease on RC, it is difficult to attribute the changes to NAC effect only, except if (1) hyalinization of the bladder wall or LN changes are present, or (2) if the preoperative clinical stage was beyond what could be resected by TUR.
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Affiliation(s)
- Hui Jun Wang
- Department of Pathology, McGill University Health Center and McGill University, Montreal, Québec, Canada H4A 3J1
| | - Shraddha Solanki
- Department of Pathology, McGill University Health Center and McGill University, Montreal, Québec, Canada H4A 3J1
| | - Samer Traboulsi
- Department of Urology, McGill University Health Center and McGill University, Montreal, Québec, Canada H4A 3J1
| | - Wassim Kassouf
- Department of Urology, McGill University Health Center and McGill University, Montreal, Québec, Canada H4A 3J1
| | - Fadi Brimo
- Department of Pathology, McGill University Health Center and McGill University, Montreal, Québec, Canada H4A 3J1.
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Peponi E, Skloupiotis V, Tsironis D, Tasiou I, Capizzello A, Tsironis C, Tsimoyiannis KE, Pitouli E, Tsimoyiannis E, Tsekeris P. Preoperative Chemoradiation in Locally Advanced Rectal Cancer: Efficacy and Safety. Gastroenterology Res 2015; 8:303-308. [PMID: 27785313 PMCID: PMC5051030 DOI: 10.14740/gr681w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/24/2015] [Indexed: 12/18/2022] Open
Abstract
Background Preoperative chemoradiation (CRT) is considered the standard of care in the management of stage II/III rectal cancer. The aim of this retrospective study was to assess the efficacy and safety of preoperative CRT in our patient cohort with locally advanced rectal adenocarcinoma. Methods Forty patients with cT3-4N0-2M0 adenocarcinoma of the lower (n = 26) and mid/upper (n = 14) rectum were enrolled in this study between 2001 and 2012. Radiotherapy (RT) was given to the pelvis. The median prescribed dose was 45 Gy (daily dose, 1.8 - 2.0 Gy). All patients received chemotherapy concurrently with RT and underwent surgery 6 - 8 weeks after CRT. Low anterior resection (LAR) was achieved in 21 patients. Total mesorectal excision (TME) was performed in 24 patients. Results Tumor downstaging (expressed as TN downstaging) was observed in 15 patients (38%); a pathological complete response (pCR) was pathologically confirmed in six of them. In nine out of the 26 (23%) patients with low lying tumors, sphincter preservation (SP) was possible. SP was also possible in all but one patient (13%) who achieved a pCR. In three out of 15 patients (8%) with preoperative sphincter infiltration, SP was achieved. With a median follow-up of 58 months, the 4-year local control (LC), distant metastases-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) rates were 89.7%, 86.9%, 79.5% and 81.2%, respectively. The pretreatment tumor size was predictive of response to preoperative CRT. The response to preoperative CRT did show a significant impact on DFS and on OS. TME resulted in a statistically significant increased DFS rate. No grade 3/4 acute toxicity was reported. Three patients developed grade 3 late side effects. Conclusion Preoperative CRT demonstrates encouraging rates of disease control and facilitates complete resection and SP in advanced rectal cancer with acceptable late toxicity.
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Affiliation(s)
- Evangelia Peponi
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Vlassios Skloupiotis
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Dimitris Tsironis
- Department of Surgery, "Hatzikosta" Community Hospital, Ioannina, Greece
| | - Ifigenia Tasiou
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Antonio Capizzello
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Chris Tsironis
- Department of Surgery, "Hatzikosta" Community Hospital, Ioannina, Greece
| | | | - Evita Pitouli
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
| | | | - Pericles Tsekeris
- Department of Radiation Oncology, University Hospital of Ioannina, Ioannina, Greece
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Arredondo J, Baixauli J, Rodríguez J, Beorlegui C, Arbea L, Zozaya G, Torre W, -Cienfuegos JA, Hernández-Lizoáin JL. Patterns and management of distant failure in locally advanced rectal cancer: a cohort study. Clin Transl Oncol 2015; 18:909-14. [PMID: 26666769 DOI: 10.1007/s12094-015-1462-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 11/23/2015] [Indexed: 01/03/2023]
Abstract
PURPOSE To determine the long-term outcomes of locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (CRT) and surgery, and to analyze the management and survival once distant failure has developed. METHODS Data from LARC patients treated from 2000 to 2010 were retrospectively reviewed. CRT protocols were based on fluoropirimidines ± oxaliplatin. Follow-up consisted of physical examination, carcinoembryonic antigen levels, and chest-abdominal-pelvic CT scan. RESULTS The study included 228 patients with a mean age of 59 years. Forty-eight (21.1 %) patients had distant recurrence and 6 patients (2.6 %) had local recurrence. Median follow-up was 49 months. The 5- and 10-year actuarial disease free survival was 75.3 and 65.0 %, respectively. The 5- and 10-year actuarial overall survival (OS) was 89.6 and 71.2 %, respectively. Patients were classified as having liver (14 patients) or lung (27 patients) relapse according to the organ firstly metastasized. The variables significantly associated by univariate Cox analysis to survival were the achievement of an R0 metastases resection and the Köhne risk index, while the metastatic site showed a statistical trend. By multivariate Cox analysis, the only variable associated with survival was a R0 resection (HR = 16.3, p < 0.001). Median OS for patients undergoing a R0 resection was 73 months (95 % CI 67.8-78.2) compared to 25 months (95 % CI 5.47-44.5) in those non-operated patients (p < 0.001). CONCLUSIONS Combined treatment for LARC obtains a 5-year OS rounding 90 %. Follow-up based on thoracic-abdominal CT scan allows an early diagnosis of metastatic lesions. Surgical resection of metastases, regardless of their location, greatly increases the patient's survival rate.
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Affiliation(s)
- J Arredondo
- Department of General Surgery, Complejo Asistencial Universitario de León, c/Altos de Nava s/n, 24008, León, Spain.
| | - J Baixauli
- Department of General Surgery, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - J Rodríguez
- Department of Medical Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - C Beorlegui
- Department of Pathology, School of Medicine, Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - L Arbea
- Department of Radiation Oncology, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - G Zozaya
- Department of General Surgery, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - W Torre
- Department of Thoracic Surgery, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - J A -Cienfuegos
- Department of General Surgery, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
| | - J L Hernández-Lizoáin
- Department of General Surgery, Clínica Universidad de Navarra, Avenida Pío XII 36, 31008, Pamplona, Spain
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Clinical significance of cellular and acellular mucin pools in rectal carcinoma following preoperative chemoradiotherapy. Clin Transl Oncol 2015; 18:714-21. [PMID: 26474872 DOI: 10.1007/s12094-015-1422-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 09/26/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVES The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Pathological findings remain the most significant prognostic factor. The presence of mucin pools and their prognostic significance is a controversial issue. The aim of this study was to analyze the incidence of cellular and acellular mucin pools and their clinical significance. METHODS Four-hundred and forty-six consecutive prospectively collected specimens from patients with LARC treated with long-course preoperative CRT and surgery were analyzed. Kaplan-Meier analysis was performed. RESULTS Mucin pools were present in 182 specimens (40.8 %); 66 (14.7 %) were acellular, and viable tumor cells were identified in 116 (26 %). The complete pathological response rate was 13.5 % (60 of 446). With a median follow-up of 79.0 months, the 5- and 10-year disease-free survivals for patients with acellular and cellular mucin pools were 81.5, 78.1, 63.7 and 61.2 %, respectively (p ≤ 0.026). The presence of cells in the colloid response to treatment was associated with a 17.8 and 16.9 % decrease in 5- and 10-year disease survival vs. acellular colloid response. CONCLUSIONS Our results suggest that cellular mucin pools are an indicator of an aggressive phenotype and harbingers of a worse prognosis.
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McCluggage WG, Judge MJ, Clarke BA, Davidson B, Gilks CB, Hollema H, Ledermann JA, Matias-Guiu X, Mikami Y, Stewart CJR, Vang R, Hirschowitz L. Data set for reporting of ovary, fallopian tube and primary peritoneal carcinoma: recommendations from the International Collaboration on Cancer Reporting (ICCR). Mod Pathol 2015; 28:1101-22. [PMID: 26089092 DOI: 10.1038/modpathol.2015.77] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/24/2015] [Accepted: 02/25/2015] [Indexed: 12/20/2022]
Abstract
A comprehensive pathological report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but these vary in their content. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, with the aim of developing an evidence-based reporting data set for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of primary ovarian, fallopian tube and peritoneal carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set encompasses the recent International Federation of Obstetricians and Gynaecologists staging system for these neoplasms and the updated World Health Organisation Classification of Tumours of the Female Reproductive Organs. The data set also addresses issues about site assignment of the primary tumour in high-grade serous carcinomas and proposes a scoring system for the assessment of tumour response to neoadjuvant chemotherapy. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and hopefully will result in improved patient management.
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Affiliation(s)
- W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | - Meagan J Judge
- Royal College of Pathologists of Australasia, Sydney, NSW, Australia
| | - Blaise A Clarke
- Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Ben Davidson
- 1] Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway [2] Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - C Blake Gilks
- Department of Pathology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Harry Hollema
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLleida, Lleida, Spain
| | - Yoshiki Mikami
- Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan
| | - Colin J R Stewart
- 1] Department of Histopathology, King Edward Memorial Hospital, Perth, WA, Australia [2] School for Women's and Infant's Health, University of Western Australia, Crawley, WA, Australia
| | - Russell Vang
- Department of Pathology (Division of Gynecologic Pathology), The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lynn Hirschowitz
- Department of Cellular Pathology, Birmingham Women's Hospital, Birmingham, UK
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Transanal endoscopic microsurgery in treatment of small rectal T1 high-risk, T2 and T3 carcinomas combined with radiochemotherapy. Eur Surg 2015. [DOI: 10.1007/s10353-015-0330-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Identification of a DNA methylation signature to predict disease-free survival in locally advanced rectal cancer. Oncotarget 2015; 5:8123-35. [PMID: 25261372 PMCID: PMC4226671 DOI: 10.18632/oncotarget.2347] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In locally advanced rectal cancer a preoperative predictive biomarker is necessary to adjust treatment specifically for those patients expected to suffer relapse. We applied whole genome methylation CpG island array analyses to an initial set of patients (n=11) to identify differentially methylated regions (DMRs) that separate a good from a bad prognosis group. Using a quantitative high-resolution approach, candidate DMRs were first validated in a set of 61 patients (test set) and then confirmed DMRs were further validated in additional independent patient cohorts (n=71, n=42). We identified twenty highly discriminative DMRs and validated them in the test set using the MassARRAY technique. Ten DMRs could be confirmed which allowed separation into prognosis groups (p=0.0207, HR=4.09). The classifier was validated in two additional cohorts (n=71, p=0.0345, HR=3.57 and n=42, p=0.0113, HR=3.78). Interestingly, six of the ten DMRs represented regions close to the transcriptional start sites of genes which are also marked by the Polycomb Repressor Complex component EZH2. In conclusion we present a classifier comprising 10 DMRs which predicts patient prognosis with a high degree of accuracy. These data may now help to discriminate between patients that may respond better to standard treatments from those that may require alternative modalities.
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Flanagan L, Kehoe J, Fay J, Bacon O, Lindner AU, Kay EW, Deasy J, McNamara DA, Prehn JHM. High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer. Radiat Oncol 2015; 10:131. [PMID: 26071313 PMCID: PMC4480907 DOI: 10.1186/s13014-015-0437-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 06/05/2015] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance. METHODS We obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined. RESULTS We found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins. CONCLUSION These data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.
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Affiliation(s)
- L Flanagan
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. .,Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
| | - J Kehoe
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. .,Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland. .,Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland.
| | - J Fay
- Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland.
| | - O Bacon
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
| | - A U Lindner
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. .,Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
| | - E W Kay
- Departments of Pathology, Beaumont Hospital, Dublin 9, Ireland.
| | - J Deasy
- Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland.
| | - D A McNamara
- Departments of Surgery, Beaumont Hospital, Dublin 9, Ireland.
| | - J H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. .,Centre for Systems Medicine, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
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Hav M, Libbrecht L, Geboes K, Ferdinande L, Boterberg T, Ceelen W, Pattyn P, Cuvelier C. Prognostic value of tumor shrinkage versus fragmentation following radiochemotherapy and surgery for rectal cancer. Virchows Arch 2015; 466:517-23. [PMID: 25693669 DOI: 10.1007/s00428-015-1723-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 01/04/2015] [Accepted: 01/20/2015] [Indexed: 12/19/2022]
Abstract
Most patients with rectal cancer receive neoadjuvant radiochemotherapy (RCT), causing a variable decrease in tumor mass. We evaluated the prognostic impact of pathologic parameters reflecting tumor response to RCT, either directly or indirectly. Seventy-six rectal cancer patients receiving neoadjuvant RCT between 2006 and 2009 were included. We studied the association between disease-free survival (DFS) and the "classical" clinicopathologic features as well as tumor deposits, circumferential resection margin (CRM), Dworak regression grade, and tumor and nodal downstaging. Patients with tumor downstaging had a longer DFS (p = 0.05), indicating a more favorable prognosis when regression was accompanied by a decrease in tumor infiltrative depth, referred to as tumor shrinkage. Moreover, tumor downstaging was significantly associated with larger CRM and nodal downstaging (p = 0.02), suggesting that shrinkage of the primary tumor was associated with a decreased nodal tumor load. Higher Dworak grade did not correlate with tumor downstaging, nor with higher CRM or prolonged DFS. This implies that tumor mass decrease was sometimes due to fragmentation rather than shrinkage of the primary tumor. Lastly, the presence of tumor deposits was clearly associated with reduced DFS (p = 0.01). Assessment of tumor shrinkage after RCT via tumor downstaging and CRM is a good way of predicting DFS in rectal cancer, and shrinkage of the primary tumor is associated with a decreased nodal tumor load. Assessing regression based on the amount of tumor in relation to stromal fibrosis does not accurately discern tumor fragmentation from tumor shrinkage, which is most likely the reason why Dworak grade had less prognostic relevance.
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Affiliation(s)
- Monirath Hav
- Department of Pathology, Calmette Hospital, #3, Monivong Boulevard, Phnom Penh, Cambodia,
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Jung KU, Kim HC, Park JO, Park YS, Park HC, Choi DH, Cho YB, Yun SH, Lee WY, Chun HK. Adjuvant chemotherapy after neoadjuvant chemoradiation and curative resection for rectal cancer: is it necessary for all patients? J Surg Oncol 2014; 111:439-44. [PMID: 25488390 DOI: 10.1002/jso.23835] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 10/09/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND The benefit of adjuvant chemotherapy for patients with locally advanced rectal cancer who have received neoadjuvant concurrent chemoradiation therapy (CCRT) and undergone curative resection remains unclear. METHODS This study was a retrospective review of prospectively collected data. Patients with locally advanced rectal cancer who underwent curative surgery after neoadjuvant CCRT between January 2006 and March 2011 were identified. Four hundred forty-one patients who completed adjuvant chemotherapy (chemo group) were compared with 35 patients who did not receive any adjuvant treatment (nonchemo group). RESULTS The 5-year disease-free survival (DFS) was significantly higher in the chemo group (78.5% vs. 63.1%, P = 0.016). After stratification of the patients according to nodal status, these differences were no longer significant, but there were trends toward inferior DFS in the nonchemo group in all survival curves. In multivariate Cox regression analysis, no adjuvant chemotherapy (HR, 2.306; 95% CI, 1.101-4.829; P = 0.027) emerged as an independent prognostic factor associated with decreased DFS. CONCLUSIONS Adjuvant chemotherapy was significantly associated with increased DFS among patients who had undergone neoadjuvant CCRT and radical resection for locally advanced rectal cancer. Adjuvant chemotherapy should be considered in every patient after neoadjuvant CCRT irrespective of the final pathology stage.
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Affiliation(s)
- Kyung Uk Jung
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Cienfuegos JA, Rotellar F, Baixauli J, Beorlegui C, Sola JJ, Arbea L, Pastor C, Arredondo J, Hernández-Lizoáin JL. Impact of perineural and lymphovascular invasion on oncological outcomes in rectal cancer treated with neoadjuvant chemoradiotherapy and surgery. Ann Surg Oncol 2014; 22:916-23. [PMID: 25190129 DOI: 10.1245/s10434-014-4051-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. METHODS A total of 324 patients with LARC were treated with CRT and operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification and the presence of PLVI was histologically studied. RESULTS At a median follow-up of 79.0 months (range 3-250 months), a total of 80 patients (24.7%) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2 and 74.9 %, respectively. The 5- and 10-year disease-free survival (DFS) was 75.1 and 71.4%, respectively. A significant correlation was found between the TRG and survival (log rank, p < 0.001). The 10-year OS was 32.7% for grade 1, 63.8% for grade 2, 75.0% for grade 3, 90.4% for grade 3+, and 96.0%,for grade 4. The 10-year DFS was 31.8% for grade 1, 58.6% for grade 2, 70.4% for grade 3, 88.4% for grade 3+, and 97.1% for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, the TRG was an independent prognostic factor for OS and DFS. CONCLUSIONS The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.
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Affiliation(s)
- J A Cienfuegos
- Department of General Surgery, Clínica Universidad de Navarra, School of Medicine, University of Navarra, Pamplona, Spain,
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