Weijuan Deng

TNF rs1799964 as a Predictive Factor of Acute Toxicities in Chinese Rectal Cancer Patients Treated With Chemoradiotherapy

AbstractAcute toxicity is the main dose-limiting factor in the chemoradiotherapy of rectal cancer patients and depends on several pro-inflammatory factors, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-&agr;). It is unknown whether genetic factors, such as single-nucleotide polymorphisms (SNPs) in the IL-1, IL-6, and TNF genes, are also associated with acute toxicity in the process.We genotyped 5 potentially functional SNPs in these 3 genes (TNF rs1799964, TNF rs1800629, IL-6 rs1800796, and IL-1 rs1143623, IL-1 rs1143627) and estimated their associations with severe acute radiation injury (grade ≥2) in 356 rectal cancer patients.We found a predictive role of the TNF rs1799964 T variant allele in the development of acute injury (for CT vs CC: adjusted odds ratio [OR]u200a=u200a4.718, 95% confidence interval [CI]u200a=u200a1.152–19.328, Pu200a=u200a0.031; for TT vs CC: adjusted ORu200a=u200a4.443, 95% CIu200a=u200a1.123–17.581, Pu200a=u200a0.034). In the dominant model, for CT/TT vs CC, the adjusted ORu200a=u200a4.132, 95% CIu200a=u200a1.069–15.966, and Pu200a=u200a0.04.Our results suggested that genetic variants in the TNF gene may influence acute injury in rectal cancer patients treated with chemoradiotherapy and may be a predictor for personalized treatment. Additional larger and independent studies are needed to confirm our findings.

T3 subclassification using the EMD/mesorectum ratio predicts neoadjuvant chemoradiation outcome in T3 rectal cancer patients

OBJECTIVEnTo evaluate the feasibility of the EMD (extramural depth)/mesorectum ratio as a marker for T3 rectal cancer and its ability to predict tumour response to neoadjuvant chemoradiation and survival.nnnMETHODSnFrom 2010 to 2016, 284u2009T3 rectal cancer patients who underwent high resolution MRI before neoadjuvant chemoradiation were enrolled. The EMD was defined as the distance from the outer edge of the muscularis propria to the outermost edge of the tumour. The measurement of the tumour EMD and mesorectum was in the same layer and their ratio was calculated. Receiver operating characteristic analysis and relative area under the curve statistics were used to choose the cut-off value. The association of the EMD/mesorectum ratio and other MRI or clinical factors with the tumour regression grade (TRG) was analysed. Cox regression analysis was used to estimate independent risk factors for disease-free survival (DFS) and overall survival (OS).nnnRESULTSnThe mean EMD/mesorectum ratio was 0.47 ± 0.3. We chose an EMD/mesorectum ratio of 0.5 in further analyses after receiver operating characteristic analysis. Of 284 patients, 177 (62.3%) had an EMD/mesorectum ratioxa0≤xa00.5. Patients with an EMD/mesorectum ratioxa0≤xa00.5 had a higher TRG 0-1 rate than patients with a ratioxa0>0.5 (53.1% vs 36.4%, p = 0.006). A multivariate analysis identified that an EMD/mesorectum ratioxa0>0.5 [hazardxa0ratioxa0(HR) 2.020; p = 0.028] and ypTNM II-III (HR 3.550; p = 0.017) were independent prognostic factors to indicate decreased DFS. For OS, only patients with TRG 2-3 had decreased OS compared with patients with TRG 0-1 (HR 2.959; p = 0.035).nnnCONCLUSIONnWhen the EMD/mesorectum ratio was applied to categorize T3 rectal cancer patients, the ratio of 0.5 can be used as a cut-off value for T3 rectal cancer. Patients with a ratioxa0≤xa00.5 had a higher response rate and better DFS. However, further validation is needed in a larger sample of patients. Advances in knowledge: The EMD/mesorectum ratio may serve to predict tumour response to neoadjuvant chemoradiation and survival in T3 rectal cancer patients.

Can tumor regression grade influence survival outcome in ypT3 rectal cancer

PurposeLocally advanced rectal cancer (LARC) patients achieving ypT3 status following neoadjuvant chemoradiation are considered to have poor response with minimal downstaging. However, residual cancer cell amounts vary in the subserosa/perirectal fat. Tumor regression grading (TRG) is an evaluation method based on the proportion of fibrosis and residual cancer cells. The aim of this study is to assess the influence of TRG in ypT3 rectal cancer patients who received neoadjuvant chemoradiation.MethodsWe retrospectively reviewed 325 LARC patients who received neoadjuvant chemoradiation and surgery. TRG scores were recorded by two independent pathologists. Among these patients, 143 were staged as ypT3. We analyzed TRG and other clinicopathological factors and their relationship with survival outcome including overall survival (OS) and disease-free survival (DFS).ResultsAmong 143 ypT3 patients, 44 (30.8xa0%) were TRG1, 84 (58.7xa0%) were TRG2 and 15 (10.5xa0%) were TRG3. Seventy-nine (55.3xa0%) of these patients had metastatic lymph nodes. In univariate analysis, TRG was not associated with DFS (TRG2 vs TRG1, Pxa0=xa00.852; TRG3 vs TRG1, Pxa0=xa00.593) or OS (TRG2 vs TRG1, Pxa0=xa00.977; TRG3 vs TRG1, Pxa0=xa00.665). Palliative surgery (HR 3.845; 95xa0% CI 1.670–8.857; Pxa0=xa00.002) and metastatic lymph nodes after surgery (HR 5.894; 95xa0% CI 1.142–3.48; Pxa0=xa00.015) were significantly associated with decreased DFS, while palliative surgery was the only factor associated with worse OS (HR 6.011; 95xa0% CI 2.150–16.810; Pxa0=xa00.001). Palliative surgery (HR 3.923; 95xa0% CI 1.696–9.073; Pxa0=xa00.001) and metastatic lymph nodes (HR 2.011; 95xa0% CI 1.152–3.512; Pxa0=xa00.014) also showed prognostic significance for DFS in multivariate analysis.ConclusionsResidual cancer cells evaluated by TRG score after neoadjuvant chemoradiation do not influence survival outcome in ypT3 rectal cancer patients. However, lymph node status is a significant prognostic factor in ypT3 patients.

Radiosensitization by irinotecan is attributed to G2/M phase arrest, followed by enhanced apoptosis, probably through the ATM/Chk/Cdc25C/Cdc2 pathway in p53-mutant colorectal cancer cells

Irinotecan, an analog of camptothecin, which is an inhibitor of topoisomerasexa0I, is currently used in the treatment of metastatic colorectal cancer. Camptothecin derivatives have been demonstrated to exert radiosensitizing effects on several types of cancer cells. However, to date, at least to the best of our knowledge, few studies have examined these effects in colorectal cancer cell lines. In the present study, we examined the radiosensitizing effects of irinotecan on the p53-mutant colorectal cancer cell lines, HT29 and SW620, and explored the potential underlying mechanisms. Drug cytotoxicity tests revealed that the 24xa0h half-maximal inhibitory concentrations (IC50s) of irinotecan as a single agent were 39.84xa0µg/ml (HT29 95% CI, 38.27-41.48) and 96.86xa0µg/ml (SW620 95% CI, 89.04-105.4); finally, concentrations <2xa0µg/ml were used in the subsequent experiments. Clonogenic assays revealed that irinotecan exerted radiosensitizing effects on the HT29 and SW620 cells, and the sensitivity enhancement ratios (SERs) at 2xa0Gy increased with increasing concentrations (SER at 2xa0Gy, 1.41 for the HT29 cells, 1.87 for the SW620 cells; with irinotecan at 2xa0µg/ml). Subsequently, the cells were divided into 4xa0groups: The control group, irinotecan group, radiation group and combination group. Compared with the control, irinotecan and radiation groups, the combination group had the slowest cell growth rate and the most obvious foci of Ser139p‑γH2AX. Combined treatment resulted in a firstly decreased and then increased M phase arrest and led to the most significant G2/M phase arrest, followed by the most significant increase in apoptosis. The results of western blot analysis indicated that the expression levels of proteins related to the DNA damage response system (Ser1981p‑ATM, Ser345p‑Chk1, Thr68p‑Chk2 and Ser139p‑γH2AX) and the cell cycle (Tyr15p‑Cdc2 and cyclinxa0B1) exhibited the greatest increase in the combined group. In addition, the expression of Ser216p‑Cdc25C was also increased in the combined group, indicating that irinotecan likely radiosensitized the p53-mutant HT29 and SW620 cells through the ATM/Chk/Cdc25C/Cdc2 pathway.

Disparities in survival for right-sided vs. left-sided colon cancers in young patients: a study based on the Surveillance, Epidemiology, and End Results database (1990–2014)

Purpose To investigate whether young patients exhibit different characteristics and survival according to tumor location and stage using data from the Surveillance, Epidemiology, and End Results (SEER) database. Patients and methods Young patients (20–49 years old) with stage I–III colon cancers were identified from the SEER program from 1990 to 2014. Kaplan–Meier survival analysis and Cox proportional hazards regression were used to analyze the data. Subset analyses were also done among different age and stage subgroups. Results Of 8197 patients, 3709 (45.2%) had right-sided colon cancers (RCCs). Patients with RCCs were more likely to be male, to be younger, and to have more poorly differentiated and more advanced tumors. The Kaplan–Meier survival curves and univariate survival models revealed that left-sided colon cancers (LCCs) had lower mortality for all stages combined and stage III, but higher mortality for stage II, compared with right-sided tumors. However, multivariate Cox regression models showed no significant survival differences by location for all patients (adjusted hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.86–1.05; P=0.34) or for stage I (adjusted HR, 1.47; 95% CI, 0.82–2.63; P=0.20). Stage II left-sided cancers had higher mortality (adjusted HR, 1.24; 95% CI, 1.00–1.54; P=0.048), whereas stage III left-sided cancers had lower mortality (adjusted HR, 0.86; 95% CI, 0.77–0.97; P=0.01). For 20- to 39-year-old patients, a significant difference was only found in stage II disease, with a higher mortality for left-sided tumors (adjusted HR, 1.82; 95% CI, 1.12–2.97; P=0.02). However, for 40- to 49-year-old patients, a significant difference was only found in stage III disease, with a lower mortality for left-sided tumors (adjusted HR, 0.83; 95% CI, 0.72–0.95; P=0.008). Conclusion In patients younger than 50 years, there were no significant differences in mortality between RCCs and LCCs for all stages combined after adjusting for multiple clinicopathological features. However, RCCs had lower mortality in stage II (especially in 20- to 39-year-old patients) and higher mortality in stage III (especially in 40- to 49-year-old patients).

Adjuvant chemoradiotherapy versus adjuvant chemotherapy for R1 resected gastric cancer: a retrospective cohort study

OBJECTIVEnThe aim of this study was to compare the effects of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) on the survival of locally advanced gastric cancer (LAGC) patients treated with R1 resection.nnnMETHODSnThe patients with LAGC and microscopically positive margins after a potentially curative gastrectomy in Fudan University Shanghai Cancer Centre were retrospectively identified. The patients who were referred to our hospital for adjuvant CRT after an R1 resection elsewhere were also included. The patients were divided into either the CRT group or ChT group according to the treatment strategy. We, then, examined the patient survival results and patterns of recurrence for each group.nnnRESULTSnThere were 114 LAGC patients treated with an R1 resection identified (CRT, n = 33; ChT, n = 81). The baseline characteristics between the two groups were not different. The estimated 3u2009year recurrence-free survival and overall survival in the CRT and ChT groups were 45.1% vs 31.8% (p = 0.09) and 49.6% vs 39.4% (p = 0.20), respectively. The results indicated that only nodal status was an independent prognostic factor (hazard ratio 4.04, 95%u2009confidence intervalxa02.06-7.93). The risk of locoregional recurrence was increased in the ChT group. The subgroup analysis revealed that patients with pN0-2 GC showed a better recurrence-freexa0survival due to adjuvant CRT (hazard ratio 0.19, 95%u2009confidence intervalxa00.04-0.90; p = 0.022).nnnCONCLUSIONnAdjuvant CRT improves locoregional control and may benefit patients with pN0-2 GC after R1 resection. The nodal status may be the most important predictor for patient selection. Advances in knowledge: Nodal status may be the most important predictor for patient selection. Compared with adjuvant ChT, LAGC patients with pN0-2 disease may further benefit from additional radiotherapy after R1 resection.