Search of Predictors of Radiosensitivity in Rectal Adenocarcinoma

2021 ◽  
Vol 66 (5) ◽  
pp. 39-44
Author(s):  
M. Vologirova ◽  
N. Volchenko ◽  
I. Zamulaeva ◽  
I. Droshneva ◽  
A. Boyko ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Regression ◽  
Rectal Adenocarcinoma ◽  
Treatment Method ◽  
Clinical Situation ◽  
Preoperative Chemoradiotherapy ◽  
Fourth Degree ◽  
Immunohistochemical Markers ◽  
Degree Of Differentiation ◽  
E Cadherin

Purpose: To analyze a number of immunohistochemical markers as predictors of the radiosensitivity of rectal adenocarcinoma. Material and methods: The study included 122 patients with histologically verified rectal adenocarcinoma, varying degrees of differentiation, and the stage of the tumor process I-IIIC, T2-T4b /N0-N2b/ M0, with the localization of the tumor in the lower-middle-ampullary parts of the rectum. Predictors included in the research: Ki67, p53, EGFR, Bcl2, COX2, P21, E-cadherin. Preoperative chemoradiotherapy was performed up to 48–50 Gy with the use of medications (5-FU, Cisplatin) as a radio modifiers. The analysis was carried out according to the degree of severity of therapeutic pathomorphosis (according to Mandard), a decrease in the stage before surgery. Results: A full course of preoperative chemoradiotherapy followed by surgery was performed at 121 patients, one patient died of concomitant cardiac pathology during the break. The first degree of Mandard pathomorphosis (complete resorption) registered at 12 patients. The second degree (preservation of a few tumor cells against the background of fibrotic changes) – at 27 patients. The third degree (a large number of preserved tumor cells against the background of the predominance of fibrosis) – at 38 patients. The fourth degree (tumor cells predominate over fibrotic changes) – at 27 patients. The fifth degree (complete absence of signs of tumor regression, absence of fibrosis) – at 2 patients. A decrease in the stage of the tumor process according to the preoperative comprehensive examination registered in 114 (94.2%) patients, in 9 (7.4%) patients – there was no dynamics. During the observation period from 2006 until nowadays, 10 people are known to have died. Years in remission range from 3 months to 22 years. According to the results of multivariate and multiple regression analyses, it is possible to successfully predict the effectiveness of chemoradiotherapy, both with the use of biomarkers (Ki67, p53, EGFR, Bcl2, COX2, P21, E-cadherin), and traditional indicators (histological type, stage of the disease, gender, degree of differentiation). It turned out, that both traditional indicators and immunohistochemical indicators work equally well, regardless of each other. Conclusion: Studied immunohistochemical predictors of radiosensitivity of rectal adenocarcinoma, allow to assess the degree of radiosensitivity or radioresistance of the tumor in each patient before the start of preoperative chemoradiotherapy by doing so, it warns us about the effectiveness or ineffectiveness of chemoradiotherapy in a specific clinical situation, which allows us to individualize the approach to treatment, choosing a more suitable treatment method for the patient: neoadjuvant chemotherapy or surgery.

Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial

2014 ◽  
Vol 32 (15) ◽  
pp. 1554-1562 ◽  
Author(s):  
Emmanouil Fokas ◽  
Torsten Liersch ◽  
Rainer Fietkau ◽  
Werner Hohenberger ◽  
Tim Beissbarth ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Tumor Cells ◽  
Rectal Carcinoma ◽  
Distant Metastasis ◽  
Cumulative Incidence ◽  
Tumor Regression ◽  
Preoperative Chemoradiotherapy ◽  
Regression Grading ◽  
Clinicopathologic Parameters

Purpose We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months. Patients and Methods TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS). Results Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P = .005 and P = .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN+) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P < .001 and P = .035, respectively) and DFS (P < .001 and P = .039, respectively), whereas local recurrence was significantly affected by ypN status (P < .001) and lymphatic invasion (P = .026). Conclusion Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting.

Gene and MicroRNA Expression Are Predictive of Tumor Response in Rectal Adenocarcinoma Patients Treated With Preoperative Chemoradiotherapy

2016 ◽  
Vol 232 (2) ◽  
pp. 426-435 ◽  
Author(s):  
Caterina Millino ◽  
Isacco Maretto ◽  
Beniamina Pacchioni ◽  
Maura Digito ◽  
Antonino De Paoli ◽  
...  
Keyword(s):  
Tumor Response ◽  
Rectal Adenocarcinoma ◽  
Preoperative Chemoradiotherapy ◽  
Microrna Expression

scholarly journals Plasmid DNA-based Alphavirus Vaccines

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 29 ◽  
Author(s):  
Kenneth Lundstrom
Keyword(s):  
Tumor Cells ◽  
Plasmid Dna ◽  
Transgene Expression ◽  
Tumor Regression ◽  
Infectious Agents ◽  
Application Range ◽  
Mammalian Cell Lines ◽  
High Level ◽  
Rna Replicon

Alphaviruses have been engineered as vectors for high-level transgene expression. Originally, alphavirus-based vectors were applied as recombinant replication-deficient particles, subjected to expression studies in mammalian and non-mammalian cell lines, primary cell cultures, and in vivo. However, vector engineering has expanded the application range to plasmid DNA-based delivery and expression. Immunization studies with DNA-based alphavirus vectors have demonstrated tumor regression and protection against challenges with infectious agents and tumor cells in animal tumor models. The presence of the RNA replicon genes responsible for extensive RNA replication in the RNA/DNA layered alphavirus vectors provides superior transgene expression in comparison to conventional plasmid DNA-based expression. Immunization with alphavirus DNA vectors revealed that 1000-fold less DNA was required to elicit similar immune responses compared to conventional plasmid DNA. In addition to DNA-based delivery, immunization with recombinant alphavirus particles and RNA replicons has demonstrated efficacy in providing protection against lethal challenges by infectious agents and tumor cells.

scholarly journals Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies

Antioxidants ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 407 ◽  
Author(s):  
Emily Hays ◽  
Benjamin Bonavida
Keyword(s):  
Nitric Oxide ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Tumor Regression ◽  
Cytotoxic T Cells ◽  
Resistance Mechanisms ◽  
Binding Activity ◽  
No Donors ◽  
Dna Binding Activity ◽  
Immune Resistance

In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

scholarly journals Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

2019 ◽  
Vol 27 (5) ◽  
pp. 1569-1587 ◽  
Author(s):  
Jing Zhang ◽  
Yu Yang ◽  
Shen’ao Zhou ◽  
Xueyan He ◽  
Xuan Cao ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Tumor Regression ◽  
Cell Types ◽  
Tight Contact ◽  
Cancer Cell Death ◽  
Microtubule Targeting Agents ◽  
Patient Responsiveness ◽  
Smac Mimetics

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

Fusion Hybrid of Dendritic Cells and Engineered Tumor Cells Expressing Interleukin-12 Induces Type 1 Immune Responses against Tumor

2005 ◽  
Vol 91 (6) ◽  
pp. 531-538 ◽  
Author(s):  
Meiqing Shi ◽  
Liping Su ◽  
Sigou Hao ◽  
Xulin Guo ◽  
Jim Xiang
Keyword(s):  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Regression ◽  
Interleukin 12 ◽  
Myeloma Cells ◽  
Th1 Cytokine

Aims and Background Dendritic cell (DC)-tumor fusion hybrid vaccinees that facilitate antigen presentation represent a novel powerful strategy in cancer immunotherapy. Preclinical studies have demonstrated that IL-12 promotes specific antitumor immunity mediated by T cells in several types of tumors. In the present study, we investigated the antitumor immunity derived from vaccination of fusion hybrids between DCs and engineered J558/IL-12 myeloma cells secreting Th1 cytokine IL-12. Methods The expression vector pcDNA-IL-12 was generated and transfected into J558 myeloma cells and then bone marrow-derived DCs were fused with engineered J558/IL-12 cells. The antitumor immunity derived from vaccination of the fusion hybrid DC/J558/IL-12 was evaluated in vitro and in vivo. Results DC/J558/IL-12 cells secreted recombinant IL-12 (1.6 ng/mL), and inoculation of BALB/c mice with DC/J558/IL-12 hybrid induced a Th1 dominant immune response and resulted in tumor regression. Immunization of mice with engineered DC/J558/IL-12 hybrid elicited stronger J558 tumor-specific cytotoxic T lymphocyte (CTL) responses in vitro as well as more potent protective immunity against J558 tumor challenge in vivo than immunization with the mixture of DCs and J558/IL-12, J558/IL-12 and J558, respectively. Furthermore, the antitumor immunity mediated by DC/J558/1L-12 tumor cell vaccination in vivo appeared to be dependent on CD8+ CTL. Conclusions These results demonstrate that the engineered fusion hybrid vaccines that combine Th1 cytokine gene-modified tumor cells with DCs may be an attractive strategy for cancer immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document