Varying practices in tumor regression grading of gastrointestinal carcinomas after neoadjuvant therapy: results of an international survey.

新辅助治疗后胃肠道癌肿瘤消退分级的不同做法: 一项国际调查的结果。

  • 影响因子:6.13
  • DOI:10.1038/s41379-019-0393-7
  • 作者列表:"Westerhoff M","Osecky M","Langer R
  • 发表时间:2020-04-01

:Tumor regression grading is routinely performed on neoadjuvantly treated gastrointestinal cancer resections. Challenges in tumor regression grading include grossing standards, multiple grading systems, and difficulty interpreting therapy-induced changes. We surveyed gastrointestinal pathologists around the world for their practices in handling neoadjuvantly treated gastrointestinal cancer specimens and reporting tumor regression using a 23-question online survey. Topics addressed grossing, histologic work-up, tumor regression grading systems, and degree of difficulty identifying and estimating residual cancer within treatment effect. Two-hundred three responses were received, including 173 participants who completed the entire questionnaire. Fifty percent of the participants were from Europe, 29% from North America, 10% from Australia, and 11% from other continents. Ninety-five percent routinely report a tumor regression grade and 92% have standardized grossing and histologic work-up: 27% always completely embed the entire tumor bed, 54% embed the complete tumor site if not a grossly apparent, large mass. Fifty-nine percent use hematoxylin & eosin alone for assessment; the remaining use additional stains. In North America and Australia, the American Joint Committee on Cancer (AJCC)/College of American Pathologists (CAP)/Ryan system is routinely used for gastroesophageal (71%) and rectal carcinomas (77%). In Europe, the Mandard system is common (36%) for gastroesophageal tumors, followed by AJCC/CAP/Ryan (22%), and Becker (10%); for rectal CA, the Dworak system (30%) is followed by AJCC/CAP/Ryan (24%) and Mandard (14%). This regional differences were significant (p < 0.001 each). Fifty-one percent prefer a four-tiered system. Sixty-six percent think that regressive changes in lymph nodes should be part of a regression grade. Sixty-nine percent consider identifying residual tumor straight-forward, but estimating therapy-induced fibrosis difficult (57%). Free comments raised issues of costs for work-up and clinical relevance. In conclusion, this multinational survey provides a comprehensive overview of grossing and histologic work-up with regards to tumor regression grading in gastrointestinal cancers with partly significant regional differences particularly between North America and Europe.


: 肿瘤消退分级常规对新辅助治疗的胃肠道肿瘤切除术进行。肿瘤消退分级的挑战包括总评标准、多重分级系统和难以解释治疗引起的变化。我们使用 23 个问题的在线调查了世界各地的胃肠道病理学家在处理新佐剂治疗的胃肠道癌症标本和报告肿瘤消退方面的做法。主题涉及总括、组织学检查、肿瘤消退分级系统以及在治疗效果内识别和估计残余癌症的困难程度。共收到 173 份回复,包括完成整个问卷的名参与者。29% 的参与者来自欧洲,10% 来自北美,11% 来自澳大利亚,来自其他大陆。95% 的患者常规报告肿瘤消退分级,92% 的患者有标准化的总体和组织学检查: 27% 的患者总是完全嵌入整个肿瘤床,54% 如果不是非常明显的大肿块,则嵌入完整的肿瘤部位。百分之五十九单独使用苏木精 & 伊红进行评估; 其余使用附加染色剂。在北美和澳大利亚,美国癌症联合委员会 (AJCC)/美国病理学家学会 (CAP)/Ryan 系统常规用于胃食管 (71%) 和直肠癌 (77%)。在欧洲,Mandard 系统对于胃食管肿瘤常见 (36%),其次是 AJCC/CAP/Ryan (22%) 和 Becker (10%); 对于直肠 CA,dworak 系统 (30%) 其次是 AJCC/CAP/Ryan (24%) 和 Mandard (14%)。该地区差异显著 (p <0.001)。1% 的人更喜欢四层制。6% 的人认为淋巴结的退行性变化应该是回归等级的一部分。9% 的人考虑直接识别残余肿瘤,但难以估计治疗诱导的纤维化 (57%)。免费评论提出了检查和临床相关性的成本问题。总之,这项多国调查提供了胃肠道癌症肿瘤消退分级的总体和组织学检查的全面概述,部分地区差异显著,特别是在北美和欧洲之间。



作者列表:["Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B"]

METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

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作者列表:["Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y"]

METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.

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作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.

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