AbstractPurpose: Evidence for radiotherapy (RT) in oligoprogressive hepatocellular carcinoma (OP-HCC) is limited. We evaluated the efficacy and safety of progression-directed RT (PDRT) alongside ongoing first-line systemic therapy (FLST) in patients with OP-HCC. Patients and Methods: Patients who developed OP-HCC during FLST were enrolled and received PDRT with a biologically effective dose of at least 60 Gy while continuing FLST. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), toxicities, and quality of life (QoL). Results: From March 2024 through May 2025, 36 patients were enrolled from 10 cancer centers. At a median follow-up time of 10.9 months, median PFS time was 7.0 months (95% confidence interval 4.9–9.7), with 3-, 6-, and 9-month PFS rates of 73.7%, 64%, and 38.8%, respectively. Type of FLST and albumin–bilirubin (ALBI) grade at oligoprogression were independently associated with PFS. Median OS and DOR times were not reached; 1-year OS rates were 86.4%, and 3-, 6-, and 9-month DOR rates were 84.6%, 79.6%, and 70.8%, respectively. ORR and DCR were 64.7% and 98.0%, respectively. QoL measures generally remained stable, except for transient increases in fatigue and pain scores 1 month after PDRT. RT-related toxicities (mostly grades 1–2) occurred in 16 patients (44.4%), including grade ≥3 events in four patients (11.1%). Conclusions: Maintaining FLST with PDRT was effective, safe, and preserved QoL, supporting its feasibility for OP-HCC. FLST type and baseline ALBI grade may provide risk stratification and prognosis for PFS.

Purpose:This study aimed to compare the long-term efficacy and safety of nanoparticle albumin-bound paclitaxel plus nedaplatin (NP) versus docetaxel plus nedaplatin (TP) as induction chemotherapy (IC) for locally advanced nasopharyngeal carcinoma (LA NPC). Methods:In this retrospective analysis, treatment-naïve patients with stage III-IVa NPC who received IC with either NP or TP regimen between December 2018 and January 2021 were enrolled. Propensity score matching (PSM) was applied to balance baseline characteristics, resulting in 70 matched pairs. Efficacy endpoints included overall survival (OS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). Treatment-related adverse events (AEs) were graded per CTCAE v5.0. Results:After a median follow-up of 68.6 months, the 5-year OS (89.98% vs 86.98%, P=0.610), LRFS (94.06% vs 96.69%, P=0.424), and DMFS (91.33% vs 85.61%, P=0.308) rates were comparable between the NP and TP groups. Multivariable analysis confirmed that the treatment regimen was not an independent prognostic factor. The toxicity profiles, however, differed significantly. The TP group had a higher incidence of any-grade neutropenia (68.6% vs 50.0%, P=0.047), while the NP group was associated with more frequent any-grade peripheral sensory neuropathy (57.1% vs 0.0%, P<0.001) and myalgia (45.7% vs 1.4%, P<0.001). The rates of severe (grade 3-4) hematological toxicities were similar between the groups. Conclusion:The NP regimen demonstrated comparable long-term survival outcomes to the TP regimen as IC for LA NPC, with a distinct toxicity profile. NP may serve as a valuable alternative, offering a favorable hematological toxicity profile and eliminating the need for corticosteroid premedication, albeit with a higher incidence of low-grade neurotoxicity and myalgia.

BACKGROUND:The optimal regimen and chemotherapy intensity are still under investigation for neoadjuvant treatment of locally advanced rectal cancer (LARC). The CinClare trial has demonstrated improved pathologic complete response (pCR) with the addition of irinotecan to neoadjuvant chemoradiotherapy (CRT) guided by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype in LARC. Here, we report the 5-year follow-up outcomes of the CinClare study. METHODS:From November 2015 to December 2017, this randomized, open-label, multicenter, phase III trial enrolled 360 patients with LARC and assigned them in a 1:1 ratio to CapIriRT (radiation with capecitabine combined with irinotecan followed by irinotecan and capecitabine) or CapRT (radiation with concurrent capecitabine followed by oxaliplatin and capecitabine). Irinotecan dosing was guided by UGT1A1 genotype (80 mg/m2 for *1/*1 and 65 mg/m2 for *1/*28). The endpoints, including local control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS), were analyzed using the log-rank test, Cox proportional hazards regression and restricted mean survival time (RMST) test at the data cut-off date of June 2023. RESULTS:With a median follow-up of 60 months, the CapIriRT group showed numerically higher 5-year LC (95.6% vs. 93.9%), 5-year DMFS (83.9% vs. 77.9%), 5-year DFS (77.7% vs. 70.6%), and 5-year OS rates (82.9% vs. 76.1%) than the CapRT group. Further RMST test also showed a statistically significant difference in DFS (P < 0.05) and a borderline difference in OS (P = 0.050). Among the UGT1A1 *1/*1 population, the CapIriRT group had significantly improved 5-year rates of DMFS, DFS, and OS (all P < 0.05). Patients achieving pCR also had significantly longer DFS and OS compared to non-pCR patients (P < 0.05). CONCLUSIONS:The addition of irinotecan guided by UGT1A1 genotype to a standard capecitabine-based scheme brings clinical benefits with improved LC, DMFS, DFS, and OS. Patients with the UGT1A1 *1/*1 genotype derived notable benefit from irinotecan, with improved survival outcomes. Achievement of pCR is crucial as it is associated with improved long-term survival. These findings support the integration of genomic testing into clinical practice to achieve a personalized irinotecan dosing regimen, which can optimize efficacy and safety. TRIAL REGISTRATION:ClinicalTrials.gov (NCT02605265).

To investigate how lncRNA plasmacytoma variant translocation 1 (PVT1) contributed to the pathogenesis of gallbladder adenocarcinoma (GBA). Bioinformatics techniques were used to analyze differentially expressed lncRNA, and downstream miRNA and mRNA were identified using databases. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were utilized to analyze the RNA and protein expressions in different cells. The binding relationships between different genes were confirmed utilizing luciferase assay and RNA Immunoprecipitation (RIP) assay. Cell growth and migration were examined through CCK-8, colony formation, and Transwell assays. Several in vivo experiments were utilized to determine how the PVT1/miR-2355-5p/AGO1 pathway on tumor growth. Elevated PVT1 was observed in GBA cells, which may further aggravate cell malignant properties. Based on bioinformatics analysis, an interaction between miR-2355-5p and either PVT1 or AGO1 was identified, which was confirmed utilizing dual luciferase reporter assays and RIP assays. Silencing PVT1 (si-PVT1) led to a reduction in AGO1 expression, while depletion of miR-2355-5p reversed this effect. In vivo, PVT1 knockdown significantly inhibited tumor growth, an effect that was reversed by miR-2355-5p downregulation. This study showed that PVT1 facilitated GBA progression via the modulation of the miR-2355-5p/AGO1 axis. These findings underscored the potential therapeutic significance of targeting the lncRNA PVT1 in the treatment of GBA.

More than 50% of patients with colorectal cancer (CRC) exhibit radioresistance, indicating the need for further research on the disease. Therefore, the aim of this study is to identify radioresistance genes and elucidate the underlying molecular mechanisms using patient-derived organoids (PDOs). Transcriptome analyses are performed on radio-resistant and -sensitive PDOs, CRC cells, and xenograft tissues to screen for radioresistant genes. Additionally, the genetic homology between PDOs and clinical tissues is verified using whole-exome sequencing. Functional experiments are performed to validate the roles of the candidate genes using cellular, organoid, and animal models. Forkhead box P4 (FOXP4) is identified as a differentially expressed genes between the radio-sensitive and -resistant groups that is linked to radioresistance. Further experiments show that FOXP4 promoted radioresistance by suppressing ferroptosis. Mechanistically, FOXP4 regulated GPX4 transcription by binding to the promoter region of GPX4 via the forkhead domain to inhibit the onset of ferroptosis. Doxorubicin (DOX) inhibited FOXP4 expression by promoting its ubiquitination and degradation, eventually increasing radiosensitivity. Notably, DOX combined with irradiation attenuated the compensatory increase in FOXP4 expression and increased radiotherapy efficacy. Conclusively, the combination therapy provides a new strategy for enhancing therapeutic efficacy in CRC.

Objective:Several studies have been conducted on the effects and toxicity of adding oxaliplatin to fluorouracil-based or capecitabine-based chemoradiotherapy (CRT) regimens as significantly increasing the toxic response without benefit to survival. In this study, we further explored the role of these two postoperative CRT regimens in patients with pathological stage N2 rectal cancer. Methods:This study was a subgroup analysis of a randomized clinical trial. A total of 180 patients with pathological stage N2 rectal cancer were eligible, 85 received capecitabine with radiotherapy (RT), and 95 received capecitabine and oxaliplatin with RT. Patients in both groups received adjuvant chemotherapy [capecitabine and oxaliplatin (XELOX); or fluorouracil, leucovorin, and oxaliplatin (FOLFOX)] after CRT. Results:At a median follow-up of 59.2 [interquartile range (IQR), 34.0-96.8] months, the three-year disease- free survival (DFS) was 53.3% and 64.9% in the control group and the experimental group, respectively [hazard ratio (HR), 0.63; 95% confidence interval (95% CI), 0.41-0.98; P=0.04]. There was no significant difference between the groups in overall survival (OS) (HR, 0.62; 95% CI, 0.37-1.05; P=0.07), the incidence of locoregional recurrence (HR, 0.62; 95% CI, 0.24-1.64; P=0.33), the incidence of distant metastasis (HR, 0.67; 95% CI, 0.42-1.06; P=0.09) and grade 3-4 acute toxicities (P=0.78). For patients with survival longer than 3 years, the conditional overall survival (COS) was significantly better in the experimental group (HR, 0.39; 95% CI, 0.16-0.96; P=0.03). Conclusions:Our results indicated that adding oxaliplatin to capecitabine-based postoperative CRT is safe and effective in patients with pathological stage N2 rectal cancer.

BACKGROUND:Accurate prediction of response to neoadjuvant chemoradiotherapy (nCRT) is very important for treatment plan decision in locally advanced rectal cancer (LARC). The aim of this study was to investigate whether self-attention mechanism based multi-sequence fusion strategy applied to multiparametric magnetic resonance imaging (MRI) based deep learning or hand-crafted radiomics model construction can improve prediction of response to nCRT in LARC.METHODS:This retrospective analysis enrolled 422 consecutive patients with LARC who received nCRT before surgery at two hospitals. All patients underwent multiparametric MRI scans with three imaging sequences. Tumor regression grade (TRG) was used to assess the response of nCRT based on the resected specimen. Patients were separated into 2 groups: poor responders (TRG 2, 3) versus good responders (TRG 0, 1). A self-attention mechanism, namely channel attention, was applied to fuse the three sequence information for deep learning and radiomics models construction. For comparison, other two models without channel attention were also constructed. All models were developed in the same hospital and validated in the other hospital.RESULTS:The deep learning model with channel attention mechanism achieved area under the curves (AUCs) of 0.898 in the internal validation cohort and 0.873 in the external validation cohort, which was the best performed model in all cohorts. More importantly, both the deep learning and radiomics model that applied channel attention mechanism performed better than those without channel attention mechanism.CONCLUSIONS:The self-attention mechanism based multi-sequence fusion strategy can improve prediction of response to nCRT in LARC.

Background The heterogeneity of colorectal cancer (CRC) is the main cause of the disparity of drug sensitivity and the variability of prognosis. Pyroptosis is closely associated with the development and prognosis of various tumors, including CRC. Dividing CRC into distinct subgroups based on pyroptosis is a worthwhile topic for improving the precision treatment and prognosis prediction of CRC. Methods We classified patients into two clusters using the consensus clustering based on the pyroptosis-related genes (PRGs). Next, the prognostic signature was developed with LASSO regression analysis using the screened genes from differentially expressed genes (DEGs) by univariate and multivariate Cox analyses. According to the pyroptosis-related score (PR score) calculated with the signature, patients belonged to two groups with distinct prognosis. Moreover, we assessed the immune profile to explore the relationship between the signature and immunological characteristics. Two single cell sequencing databases were adopted for further exploration of tumor immune microenvironment (TME). In addition, we applied our own cohort and Drugbank to explore the correlation of the signature and clinical therapies. We also studied the expression of key genes by immunohistochemistry. Results The signature performed well in predicting the prognosis of CRC as the high area under curve (AUC) value demonstrated. Patients with a higher PR score had poorer prognosis and higher expression of immune checkpoints but more abundant infiltration of immune cells. Combining with the indicator of therapeutic analysis, they might benefit more from immune checkpoint blockade (ICB) and neo-adjuvant chemoradiotherapy (nCRT). Conclusion In conclusion, our study is based on genomics and transcriptomics to investigate the role of PRGs in CRC. We have established a prognostic signature and integrated single-cell data to study the relationship between the signature with the TME in CRC. Its clinical application in reliable prediction of prognosis and personalized treatment was validated by public and own sequencing cohort. It provided a new insight for the personalized treatment of CRC.

目的 探讨术后单纯放疗和术后放化疗治疗软组织肉瘤(STS)的临床结局和不良反应方面的差异,以及影响STS患者预后的因素.方法 回顾性分析浙江省肿瘤医院2012年5月至2019年5月首诊确诊为原发性STS的患者,术后接受辅助放疗,伴或不伴术后化疗.共入组100例患者,将其分为术后单纯放疗组(52例)与术后放化疗组(48例),中位随访时间为65个月(24～124个月).统计两组患者的无局部复发生存(LRFS)期、无远处转移生存(DMFS)期、总生存(OS)期和治疗相关不良反应.采用Kaplan-Meier法计算生存率,log-rank检验进行单因素分析,Cox模型行多因素分析.结果 多因素分析显示,肿瘤最长径是肿瘤局部复发的独立预测因素(HR=4.80,95％CI=1.16～19.85,P=0.031),同时也是远处转移(HR=4.67,95％CI 为 1.53～14.26,P=0.007)和患者 OS 期(HR=4.10,95％CI为1.35～12.48,P=0.013)的独立预测因素.另外,接受放化疗患者的骨髓抑制程度显著高于单纯放疗患者(P＜0.001).结论 在患者样本量有限的情况下,与单纯放疗相比,放化疗在远处转移或生存率方面没有改善,不良反应增加,但总体耐受性尚好.有必要进行大规模人群的前瞻性随机研究,并对组织学亚型进行亚组分析,以确保获得更有参考价值的结果.

Purpose This study was performed to investigate the association of Glasgow prognostic score (GPS), combined positive score (CPS), and clinicopathological characteristics of locally advanced rectal cancer. Methods Between February 2012 and February 2018, 103 patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and total mesorectal excision (TME) were retrospectively evaluated. Results According to the classification of the GPS, 85 (82.5%), 13 (12.6%), and 5 patients (4.9%) were classified as a score of 0, 1, and 2, respectively. Patients were classified into the GPS-low group (GPS of 0, n = 85) and GPS-high group (GPS of 1 or 2, n = 18) with an area under the curve of 0.582 for overall survival (OS). The mean programmed death-ligand 1 (PD-L1) CPS of the whole group was 2.24 (range, 0–70). The PD-L1 CPS of the GPS-high group was higher than the GPS-low group (P < 0.001). Multivariate analysis by Cox proportional hazards model indicated that GPS was associated with OS and disease-free survival (DFS). Furthermore, PD-L1 CPS was associated with DFS (hazard ratio, 1.050; 95% confidence interval, 1.017–1.083; P = 0.003). Conclusion Elevated GPS was related to the PD-L1 CPS. GPS and PD-L1 CPS were associated with the prognosis of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME.

Abstract Purpose To evaluate the role of programmed death-ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) signaling pathway in locally advanced rectal cancer (LARC). Methods Between February 2012 and February 2018, 103 patients with LARC treated by neoadjuvant chemoradiotherapy (neoCRT) and total mesorectal excision (TME) were included. PD-L1, mTOR and p-mTOR of pair-matched pre-neoCRT biopsies and post-neoCRT surgical tissue were evaluated by immunohistochemistry. Results The mean combined positive score (CPS), tumor proportion score (TPS) and immune cell score (IC) of pre-neoCRT were 2.24 (0–70), 1.87 (0–70) and 0.67 (0–10), respectively. The mean CPS, TPS and IC of post-neoCRT were 2.19 (0–80), 1.38 (0–80) and 1.60 (0–20), respectively. Significant difference was observed in terms of IC between pre-neoCRT and post-neoCRT (p = 0.010). The 5-year disease-free survival (DFS) rate of the whole group was 62.4%. Multivariate analysis by Cox model indicated that pre-neoCRT TPS [hazard ratio (HR) 1.052, 95% confidence interval (CI) 1.020–1.086, p = 0.001] and post-neoCRT CPS (HR 0.733, 95% CI 0.555–0.967, p = 0.028) were associated with DFS. In the 89 patients without pathological complete response, p-mTOR and IC were upregulated after neoCRT. Conclusions For patients with LARC treated by neoCRT and TME, p-mTOR and IC were upregulated after neoCRT. Pre-neoCRT TPS and post-neoCRT CPS were independent prognostic predictors of DFS.

Importance:Several studies have explored the efficacy and toxic effects of concurrent 5-fluorouracil (5-FU)- or capecitabine-based chemoradiotherapy (CRT) with or without oxaliplatin in the neoadjuvant setting. Addition of oxaliplatin to 5-FU or capecitabine elicited similar outcomes but with significantly increased toxic effects; however, there is a need for randomized clinical trials comparing 2 CRT regimens for patients receiving CRT in the adjuvant setting. Objective:To explore the efficacy and toxic effects of oxaliplatin combined with postoperative concurrent capecitabine and radiotherapy (RT) for pathological stage II and III rectal cancer. Design, Setting, and Participants:This multicenter randomized clinical trial enrolled patients from 7 centers in China between April 1, 2008, and December 30, 2015. Patients with pathologically confirmed stage II and III rectal cancer were randomized (1:1) to receive concurrent CRT with capecitabine or capecitabine plus oxaliplatin. Analysis was conducted from December 31, 2019, to March 15, 2020. Interventions:RT comprised 45 to 50 Gy in 25 fractions of 1.8 to 2.0 Gy over 5 weeks. In the capecitabine with RT group, concurrent chemotherapy included 2 cycles of capecitabine (1600 mg/m2) on days 1 to 14 and 22 to 35. The capecitabine and oxaliplatin with RT group received identical postoperative RT to that in the capecitabine with RT group combined with capecitabine (1300 mg/m2) on days 1 to 14 and 22 to 35 and a 2-hour infusion of oxaliplatin (60 mg/m2) on weeks 1, 2, 4, and 5. Patients in both groups received adjuvant chemotherapy (capecitabine or fluorouracil and oxaliplatin) after CRT. Main Outcomes and Measures:The primary end point was 3-year disease-free survival (DFS). Results:A total of 589 patients (median [IQR] age, 55 [47-52] years; 375 [63.7%] men and 214 [36.3%] women) were enrolled, including 294 patients randomized to the capecitabine with RT group and 295 patients randomized to the capecitabine and oxaliplatin with RT group. Median (IQR) follow-up was 68 (45-96) months. Most patients had stage III disease (574 patients [75.9%]). Three-year DFS was 76.3% for the capecitabine with RT group and 74.1% for the capecitabine and oxaliplatin with RT group, and 5-year DFS was 72.0% for the capecitabine with RT group and 71.1% for the capecitabine and oxaliplatin with RT group (hazard ratio [HR], 1.07; 95% CI, 0.79-1.44; P = .68). There was no significant difference between groups in overall survival (HR, 0.93; 95% CI, 0.64-1.34; P = .70) or local recurrence (HR, 0.61; 95% CI, 0.31-1.22; P = .16). More grade 3 and 4 acute toxic effects were observed in the capecitabine and oxaliplatin with RT group than in the capecitabine with RT group (114 patients [38.6%] vs 84 patients [28.6%]; P = .01). Conclusions and Relevance:This randomized clinical trial found that addition of oxaliplatin to capecitabine-based postoperative CRT did not improve the efficacy of treatment but increased the risk of severe acute toxic effects. This finding highlights the basic role of postoperative capecitabine with RT for patients with locally advanced rectal cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT00714077.

Colorectal cancer (CRC) is one of the most common types of malignancy and the third most commonly diagnosed form of cancer worldwide, ranking as the fourth leading cause of cancer-associated mortality. MicroRNA (miR)-576-5p has been reported to be highly expressed in patients with CRC; however, its biological role remains unclear. The present study aimed therefore to investigate the biological role and underlying mechanism of miR-576-5p in CRC cell line SW480. The viability of SW480 cells following transfection with miR-576-5p mimic or inhibitor was analyzed using MTT assay. Wound healing and Transwell assays were performed to determine the cell migratory and invasive abilities, respectively. A dual luciferase reporter assay was used to verify the predicted binding site between miR-576-5p and Wnt5a. Reverse transcription-quantitative PCR and western blotting were used to analyze the expression levels of miR-576-5p, E-cadherin, N-cadherin, vimentin, Snail1, Wnt5a, beta-catenin, c-myc, cyclin D1 and p/t-c-Jun. Using bioinformatics analysis, high expression of miR-576-5p was found not only in tumor tissues, compared with the normal tissue, but also in CRC cells, compared with NCM460 cells. Furthermore, the inhibition of miR-576-5p expression significantly decreased the cell viability and the migratory and invasive abilities of SW480 cells, and suppressed the epithelial-to-mesenchymal transition (EMT). In addition, miR-576-5p could interact with Wnt5a and regulate the expression level of Wnt5a in order to influence the activity of Wnt/beta-catenin signaling. The results from rescue experiments further demonstrated that the effect of miR-576-5p overexpression on cell metastasis and EMT was reversed by Wnt5a overexpression or treatment with XAV-939, which is an inhibitor of the Wnt/beta-catenin signaling pathway. In conclusion, the findings from the present study suggested that inhibition of miR-576-5p may suppress SW480 cell metastasis and EMT by targeting Wnt5a and regulating the Wnt5a-mediated Wnt/beta-catenin signaling pathway, providing a potential therapeutic target for the treatment of CRC.

3603 Background: Adding UGT1A1-guided irinotecan to capecitabine-based neoadjuvant chemoradiotherapy (CRT) significantly increased the pathological complete response (pCR) rate nearly doubling [J Clin Oncol. 2020 Dec 20;38(36):4231-4239]. Here, results of long-term outcome are reported. Methods: Eligible patients with clinical stage II/III rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomized to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by a cycle of oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with *1*1 or 65 mg/m2 for patients with *1*28, followed by a cycle of irinotecan and capecitabine. Surgery was scheduled for 8 weeks after completion of CRT. Five cycles of adjuvant XELOX chemotherapy were administered regardless of the pathologic result. Patients were stratified by UGT1A1 genotype (*1*1 vs. *1*28) clinical T stage (cT3 vs. cT4) and tumor distance from the anal verge (≤5 cm vs. > 5 cm). The primary end point of pCR was reached. Survival time was calculated from the date of randomization to the date of event or the last follow-up. Secondary endpoints were defined as local failure for local control (LC), tumor recurrence or death from any cause for disease-free survival (DFS), and death from any cause for overall survival (OS). Results: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). A total of 311 patients underwent surgery and pCR was achieved in 80 patients, another 10 patients undergo a watch-and-wait approach after achieving cCR. With a median follow-up time of 48 months (Q25-Q75, 41-55 months), 57 deaths (33 and 24), 17 local failures (11 and 6) and 69 distant metastases (37 and 32) were observed, respectively. Overall, the 4y LC rate were 93% and 96% in control and experimental groups, with estimated LC HR of 0.53 (95% confidence interval [CI], 0.20-1.43), the 4y DFS rates were 69% and 74% (HR = 0.74, 95% CI 0.49-1.10), and the 4y OS were 80% and 85%, (HR = 0.70, 95% CI 0.42-1.19), respectively. In the subgroup analysis, irinotecan showed a significant improvement in DFS (HR = 0.77, 95% CI 0.61-0.98) and OS (HR = 0.71, 95% CI 0.51-0.98) in UGT1A1 *1*1 patients. Conclusions: The addition of irinotecan to standard capecitabine-based CRT had a tendency towards improving LC, DFS, and OS, but without reaching statistical significance. UGT1A1 *1*1 patients seem to benefit the most from irinotecan. Molecular studies and subsequent therapies should be considered. Clinical trial information: NCT02605265.

PURPOSE Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 ( UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively ( P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.

胆系恶性肿瘤主要包括胆囊癌及胆管癌,在亚洲国家较为常见.胆系恶性肿瘤的预后很差,手术是唯一可能治愈的治疗方法,但术后复发转移比例高.在过去的几十年中,我们对这一类恶性肿瘤的分子生物学有了一定的了解,诊断技术也有了很大的发展,但术后辅助治疗一直没有明确的方案.该文拟就胆系恶性肿瘤的术后辅助化疗、辅助放化疗和预后因素等问题,综述其现状和研究进展,并讨论未来的治疗策略.

Background: Our previous study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant chemoradiotherapy and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a randomized, open-label, multicenter, phase 3 trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to the control arm (CapRT arm): pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT; or the experimental arm (CapIriRT arm): radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Findings: Of the 360 patients initial enrolled, 356 were evaluated in mITT dataset (both 178 in two arms). Surgery was performed in 87% and 88% of patients in two arms, with 39% and 31% of patients got abdominoperineal resection respectively. The pCR rates were 18% (27/154) in CapRT arm and 34% (53/157) in CapIriRT arm (risk ratio 1.93; 95% CI 1.28–2.89, p=0.001), additional 4 and 6 patients were marked as complete clinical response (cCR). therefore, the overall CR rates were 17% and 33%, respectively. The most common grade 3-4 toxicities during CRT were leukopenia (3% vs. 25%), neutropenia (2% vs. 20%), and diarrhoea (2% vs. 13%). The overall rate of surgical complications were not significantly different between arms (11% vs. 15%). Interpretation: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable.Trial Registration: ClinicalTrials.gov, number NCT02605265Funding Information: This study was funded by grants from Fudan University Shanghai Cancer Center (YJLC201601) and National Natural Science Foundation of China (81773357). We thank the patients, investigators, and institutions involved in this study.Competing Interest Declaration: I/We declare no competing interests.Ethical Approval Statement: The study was approved by the central ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China)

The treatment strategy for elderly patients with locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to identify the significance of adjuvant chemotherapy (AC) for elderly patients with LARC after neoadjuvant chemoradiotherapy (nCRT) and surgical resection. Between February 2002 and December 2012, a total of 43 patients aged ≥70 years with LARC following nCRT and surgery were retrospectively reviewed. The median follow-up time was 51 months (range 15-161 months). All patients completed the programmed chemoradiotherapy, of which 20 patients (46.5%) received 5-fluorouracil-based AC, and other 23 patients (53.5%) received no adjuvant chemotherapy. The 5-year overall survival and disease-free survival rates for AC group and non-adjuvant chemotherapy (NAC) group were 74.7% vs 63.4% (P = .562) and 73.4% vs 66.3% (P = .445), respectively. More patients in AC group suffered from severe leucopenia than that in NAC group (60% vs 17.4%, P = .004). For elderly patients with LARC following nCRT and surgery, AC may not benefit for survival, but increase treatment related leucopenia.

Objective: Optimal approaches to patients with local recurrence of rectal cancer are unclear in China. This study aimed to evaluaty-30te the clinical outcomes and toxicity associated with different treatment regimens for patients with local recurrence of rectal cancer. Methods: A retrospective chart review of patients with local recurrence of rectal cancer and previous radical surgical treatment between March 2010 and December 2017 with curative intent was performed. Disease-related endpoints included treatment progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 5.0, and complications were scored according to the Clavien-Dindo classification. Results: A total of 71 patients met the inclusion criteria in this study. The recurrence sites were mainly local recurrence in the pelvic cavity and regional lymph node metastasis. Twenty patients received chemoradiotherapy combined with surgery, 10 underwent surgery alone, and others received chemoradiotherapy-alone (n = 27) and chemotherapy-alone (n = 14) treatment. A clear difference was found in PFS between surgery/chemoradiotherapy with surgery and chemoradiotherapy/chemotherapy groups (26.6 months vs 14.1 months, P = 0.033). The PFS of patients in the surgery combined with chemoradiotherapy, surgery alone, and chemotherapy/chemoradiotherapy groups was 65.2 months, 20.2 months, and 14.2 months, respectively (P = 0.042). The multivariate analysis of PFS demonstrated that surgery was an independent factor. The proportion of patients with distant metastases after chemoradiotherapy/chemotherapy was higher than that of patients undergoing surgery (36.6% vs 21.4%, P = 0.179). The OS of patients in the surgery combined with chemoradiotherapy, surgery alone, and chemotherapy/chemoradiotherapy groups was 89.4 months, 66.0 months, and 62.8 months, respectively (P = 0.189). Radiation treatment and surgery did not increase extra severe toxicities. Conclusion: Surgery combined with chemoradiotherapy was a beneficial treatment mode for managing patients with locally recurrent, nonmetastatic rectal cancer. It was associated with better local disease control, no increase in toxicity, and prolonged survival among patients with locally recurrent rectal cancer.

Objective: To analyze the pathological features and their influence on the clinical outcome of non-nasopharyngeal EBV-associated carcinomas. Methods: One hundred and twenty cases of non-nasopharyngeal EBV-associated carcinoma confirmed by in situ hybridization were identified at Zhejiang Cancer Hospital from January 1, 2006 to May 1, 2018, and the clinicopathological data were collected and analyzed using Kaplan-Meier survival analysis, Cox univariate and multivariate analysis. Results: One hundred and twenty cases were involved in the study; the male to female ratio was 1∶1; patients' age range was 24 to 89 years (median 50 years). The primary sites were large parotid glands (62 cases), lung(26 cases), stomach(15 cases), and others (oral, oropharynx, larynx, cervix, liver; totally 17cases). Non-nasopharyngeal EBV-associated cancer could be divided into two histological types according to the amount of interstitial lymphocytes: type Ⅰ was "lymphoepithelial-like carcinoma" and rich in stromal lymphocytes; type Ⅱ lacked lymphocytic infiltration. Ninety-eight primary tumor samples could be classified morphologically: 43 cases were as type Ⅰ and 55 cases as typeⅡ; the distribution of type Ⅰ was 57.4% (27/47) in large parotid glands, 20.8% (5/24) in lung, 4/13 in stomach, and 7/14 in other sites. Complete treatment and survival data were obtained for 114 patients. According to the TNM staging criteria of WHO, 52 patients were at early stages (Ⅰ-Ⅱ) and 62 were at advanced stages (Ⅲ-Ⅳ); 102 patients underwent surgery. Seventy-four patients received adjuvant chemotherapy before or after surgery, and 52 patients received local radiotherapy. Kaplan-Meier survival analysis showed that patients with type Ⅱ EBV-associated carcinoma had a worse prognosis than patients with type Ⅰtumors (P=0.010 2). In addition, vascular invasion(P=0.021 8),neural recidivism(P=0.000 1),advanced stage(P=0.017 1),lymph node metastasis (P=0.005 0) and chemotherapy (P=0.013 2) were poor prognostic factors; female patients had better survival than male (P=0.028 4). Cox multivariate regression analysis found that lymph node metastasis (95%CI: 1.489-13.830, P=0.007 6) and neural recidivism (95%CI: 1.228-6.544, P=0.014 7) were independent adverse prognostic factors. Cox multivariate regression analysis after stratification by site revealed that radiotherapy was a preferable prognostic factor for EBV-associated carcinoma of the large salivary glands (95%CI: 0.003-0.569, P=0.016 8). Conclusion: EBV associated carcinoma can be divided into two types, for which type Ⅰ was with abundant interstitial lymphocytes and type Ⅱ was lack of interstitial lymphocytes. TypeⅡ EBV-associated carcinoma has a worse prognosis than type Ⅰ. Radiation therapy can prolong the survival time of patients with primary EBV-associated carcinoma of large salivary glands.