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Introduction The preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant SCRT combined with chemotherapy and PD-1 inhibitor in LACC.Methods and analysis TORCH-C is a randomised, prospective, multicentre, double-arm, open, phase II trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisciplinary team. 120 patients will be randomised 1:1 to the intervention or control arm. The patients in the control arm will receive four cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by four cycles of CAPOX and PD-1 inhibitor (serplulimab). Both arms will receive curative surgery, followed by four cycles of CAPOX. The primary endpoint is pathological complete regression.TORCH-C (TORCH-colon) trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer.Ethics and dissemination This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12).Trial registration number NCT05732493

For patients with locally recurrent rectal cancer (LRRC), the response rate to chemoradiotherapy is 40%–50%. Additionally, only approximately 40%–50% of patients with recurrent rectal cancer are able to undergo R0 resection. Recent studies in locally advanced rectal cancer (LARC) have shown promising synergistic effects when combining immunotherapy (PD-1/PD-L1 antibodies) with neoadjuvant chemoradiotherapy (nCRT). Therefore, incorporating immunotherapy into the treatment regimen for LRRC patients has the potential to further improve response rates and prognosis. To investigate this, the TORCH-R trial was conducted. This prospective, single-arm, two-cohort, phase II trial focuses on the use of hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients without or with oligometastases. The trial will include two cohorts: cohort A consists of rectal cancer patients who are treatment-naive for local recurrence, and cohort B includes patients with progressive disease after first-line chemotherapy. Cohort A and cohort B patients will receive 25–40 Gy/5 Fx irradiation or 15–30 Gy/5 Fx reirradiation for pelvic recurrence, respectively. Subsequently, they will undergo 18 weeks of chemotherapy, toripalimab, and stereotactic ablative radiotherapy (SABR) for all metastatic lesions between chemoimmunotherapy cycles. Decisions regarding follow-up of complete response (CR), radical surgery, sustained treatment of non-resection, or exiting the trial are made by a multidisciplinary team (MDT). The primary endpoint of this study is the local objective response rate (ORR). The secondary endpoints include the extrapelvic response rate, duration of response, local recurrence R0 resection rate, progression-free survival (PFS), overall survival (OS), and safety and tolerability. Notably, this trial represents the first clinical exploration of inducing hypofractionated radiotherapy, chemotherapy, and immunotherapy in LRRC patients.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05628038, identifier NCT05628038.

Introduction Current standard treatment for patients with early rectal cancer is radical surgical resection. Although radical surgery provides effective local tumour control, it also increases the mortality risk and considerable adverse effects, including bowel, bladder, sexual dysfunction and loss of anal function, especially in patients with low-lying rectal cancer. Recent studies have shown promising synergistic effects of the combination of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and radiotherapy in improving tumour regression. For patients who reach a clinical complete response (cCR) after neoadjuvant therapy, a ‘Watch & Wait’ (W&W) approach can be adopted to preserve anorectal function and improve quality of life. Thus, this study aims to explore the efficacy and safety of radiotherapy combined with chemotherapy and PD-1 antibody in patients with low early rectal cancer.Methods and analysis TORCH-E study is designed as a multicentre, prospective, phase II trial of short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor in patients with cT1-3bN0M0 low rectal cancer. The trial was initiated in December 2022 and is currently recruiting patients, with an anticipated completion of participant enrolment by June of the following year. The enrolled 34 patients will receive SCRT (25 Gy/5 Fx), followed by four cycles of capecitabine plus oxaliplatin chemotherapy and PD-1 antibody (toripalimab) and finally receive surgery or the W&W strategy. The primary endpoint is the complete response (CR) rate, that is, the rate of pathological complete response (pCR) plus cCR. The secondary endpoints include organ preservation rate, 3-year local recurrence-free survival rate, 3-year disease-free survival rate, 3-year overall survival rate, grade 3–4 adverse effects rate and patients’ quality of life.Ethics and dissemination This trial has been approved by the Ethics Committee of Fudan University Shanghai Cancer Center. Trial results will be disseminated via peer-reviewed journals and conference presentations.Trial registration number NCT05555888 (ClinicalTrials.gov).

Combination strategies to improve immunotherapy response in microsatellite stable metastatic colorectal cancer (MSS mCRC) remain an unmet need. Several single-arm clinical trials have shown promising synergistic effects between regorafenib and ICIs; however, some contradictory results have also been reported. Randomized controlled trials are needed to further validate the combination of regorafenib with ICIs. In addition, low-dose radiotherapy has been demonstrated to induce local immune responses by reprogramming the tumor microenvironment when combined with high-dose radiotherapy and ICIs. In this study, we designed a prospective, randomized, controlled phase II trial to investigate the efficacy and safety of regorafenib in combination with high/low-dose radiotherapy plus toripalimab in MSS mCRC compared to regorafenib alone. Patients with MSS metastatic adenocarcinoma of the colon or rectum will be enrolled and randomly assigned into two arms: a control arm and an experimental arm. Patients in the control arm will receive regorafenib monotherapy (120 mg once daily on days 1-21 of each 28 days cycle). Patients in the experimental arm will first receive one cycle of regorafenib (80 mg once daily on days 1-21 of each 28 days cycle) and toripalimab (240mg, q3w), followed by high-dose (4-8 fractions of 8-12Gy) and low-dose (1-10Gy at 0.5-2Gy/fraction) radiotherapy, and then continue regorafenib and toripalimab treatment. The primary endpoint is the objective response rate, and the secondary endpoints are disease control rate, duration of remission, median progress-free survival, median overall survival, and adverse events. Recruitment started in August 2023 and is ongoing.Clinical Trial Registrationhttps://clinicaltrials.gov/study/NCT05963490?cond=NCT05963490&rank=1, identifier NCT05963490.

Background: The watch-and-wait (W&W) strategy is a novel treatment option for patients with rectal cancer who have a strong desire for organ preservation. The study aimed to explore the long-term outcomes of the W&W strategy in a large cohort of rectal cancer patients who achieved a clinical complete response (cCR) after consolidation total neoadjuvant therapy (TNT), and to compare with patients who achieved a pathological complete response (pCR) after radical surgery. Methods: The W&W group comprised patients who were assessed as having a cCR after consolidation TNT and adopted the W&W strategy. Patients who underwent standard resection and achieved a pCR were compared as a reference. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan–Meier analysis with log-rank test was used to compare survival outcomes. Results: We included 89 and 171 patients in the W&W and pCR groups, respectively. The median follow-up period was 45 and 58 months for the W&W and pCR groups, respectively. After IPTW adjustment, the 2-year local regrowth/recurrence rate for the W&W and pCR groups were 9.9% and 2.0%, respectively ( p < 0.001). The W&W and pCR groups had similar 5-year outcomes, including overall survival, disease-free survival, and distant metastasis-free survival (all p > 0.05). No significant difference was observed in the rates of distant metastasis between patients in the W&W group with local regrowth and those without local regrowth (25% versus 6.2%, p = 0.119). Conclusion: Patients who were managed with a W&W strategy after consolidation TNT had favorable survival outcomes, which were similar to those of patients with a pCR. The rate of local regrowth in W&W patients was lower in our study than in other studies as a result of the implementation of consolidation TNT.

Abstract Background For patients with locally advanced (T3-4/N +) rectal cancer (LARC), the standard treatment is neoadjuvant chemoradiotherapy combined with total mesorectal resection, which greatly decreases local recurrence but does not improve overall survival. For patients who achieve a complete clinical response (cCR) after nCRT, a “Watch & Wait” (W&W) approach can be received to improve quality of life. Currently, total neoadjuvant therapy (TNT) has been demonstrated to increase the complete response rate and achieve early control of distant metastasis. Recent studies have shown promising synergistic effects of the combination of immunotherapy (PD-1/PD-L1 antibodies) and radiotherapy. Thus, for LARC patients, the combination of immunotherapy and TNT is likely to further improve the rate of complete response and prognosis. The disparities between induction therapy and consolidation therapy need to be investigated. Methods TORCH is a randomized, prospective, multicentre, double-arm, phase II trial of short-course radiotherapy (SCRT) combined with chemotherapy and immunotherapy in LARC. 130 LARC patients will be treated with the TNT approach and assigned to the consolidation arm and induction arm. The consolidation arm will receive SCRT, followed by 6 cycles of capecitabine plus oxaliplatin (CAPOX) and Toripalimab. The induction arm will first receive 2 cycles of CAPOX and Toripalimab, then receive SCRT, followed by 4 cycles of CAPOX and Toripalimab. Both groups will receive curative surgery or the W&W strategy. The primary endpoint is the complete response rate (rate of pCR plus cCR). The secondary endpoints include the grade 3–4 acute adverse effects rate, 3-year disease-free survival (DFS) rate, 3-year local recurrence-free survival (LRFS) rate, 3-year OS rate, rate of surgical complications and quality of life (QoL) scores. The “pick the winner” method is used to investigate the better treatment regimen. The trial was opened on 13th April 2021, and the first patient was recruited on 6th May 2021. Discussion TORCH will investigate whether SCRT combined with chemotherapy and Toripalimab can achieve better complete response rates, good tolerance and prognosis in LARC patients. This is the first clinical trial to compare the efficacy of induced immunotherapy and consolidative immunotherapy based on the TNT strategy. Trial registration Trial Registration Number and Date of Registration: ClinicalTrials.gov NCT04518280 , August 15, 2020.

For locally advanced (T3-4/N+M0) rectal cancer (LARC), neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) is the standard treatment. It was demonstrated to decrease the local recurrence rate and increase the tumor response grade. However, the distant metastasis remains an unresolved issue. And the demand for anus preservation and better quality of life increases in recent years. Radiotherapy and immunotherapy can be supplement to each other and the combination of the two treatments has a good theoretical basis. Recently, multiple clinical trials are ongoing in terms of the combination of nCRT and immunotherapy in LARC. It was reported that these trials achieved promising short-term efficacy in both MSI-H and MSS rectal cancers, which could further improve the rate of clinical complete response (cCR) and pathological complete response (pCR), so that increase the possibility of ‘Watch and Wait (W&W)’ approach. However, the cCR and pCR is not always consistent, which occurs more frequent when nCRT is combined with immunotherapy. Thus, the efficacy evaluation after neoadjuvant therapy is an important issue for patient selection of W&W approach. Evaluating the cCR accurately needs the combination of multiple traditional examinations, new detective methods, such as PET-CT, ctDNA-MRD and various omics studies. And finding accurate biomarkers can help guide the risk stratification and treatment decisions. And large-scale clinical trials need to be performed in the future to demonstrate the surprising efficacy and to explore the long-term prognosis.

Background: According to the lung cancer staging project, T2b (>5–7 cm) and T3 (>7 cm) non-small cell lung cancers (NSCLC) should be reclassified into T3 and T4 groups. The objective of this study was to evaluate the effect of surgery alone or surgery plus adjuvant radiation (SART) on survival of node-negative patients with NSCLC >5 cm.Methods: We identified 4557 N0 patients with NSCLC >5 cm in the Surveillance, Epidemiology, and End Results database from 2004 to 2014. Overall survival (OS) and cancer–specific survival (CSS) were compared among patients who underwent surgery alone and SART. The proportional hazards model was applied to evaluate multiple prognostic factors.Results: 1,042 and 525 patients who underwent surgery alone and SART, respectively were enrolled after propensity-score matching. OS and CSS favored surgery alone rather than SART. Multivariate analysis showed that the number of lymph nodes examined more than six was associated with better OS and CSS for NSCLC >5 cm, especially in patients treated with surgery alone. Lobectomy should be recommended as the primary option for NSCLC >5 to 7 cm, whereas its superiority was not significant over sublobectomy for NSCLC >7 cm.Conclusion: Surgery alone should be recommended as the first choice for patients with NSCLC >5 cm. The number of examined lymph nodes should be more than six in patients with NSCLC >5 cm, especially for those who undergo surgery alone. For patients with NSCLC >7 cm who could not tolerate lobectomy, sublobectomy might be an alternative surgical procedure.

Background Immune checkpoint inhibitors (ICIs) induce better tumor regression in melanoma with programmed cell death 1 ligand 1 (PD-L1) high expression, but there has been an upsurge of failed responses. In this study, we aimed to explore the additional mechanisms possibly accounting for ICIs resistance and interventional strategies to overcome the resistance in melanoma with PD-L1 high expression.Methods Melanoma xenografts and cytotoxicity assays were used to investigate function of SOX2 in regulating antitumor immunity. The activity of the janus kinase-signal transducer and activator of transcriptions (JAK-STAT) pathway was investigated by western blots, quantitative PCR and luciferase assay. Epigenetic compounds library screen was employed to identify inhibitors that could decrease SOX2 level. The effect of histone deacetylase inhibitor SAHA in antitumor immunity alone or in combination with immunotherapy was also determined in vitro and in vivo. Prognostic impact of SOX2 was analyzed using transcriptional profiles and clinical data download from the Gene Expression Omnibus and The Cancer Genome Atlas repository.Results We uncovered a role of SOX2 in attenuating the sensitivity of melanoma cells to CD8+ T-cell killing. Mechanistically, SOX2 inhibited phosphatases suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase non-receptor type 1 (PTPN1) transcription, induced duration activation of the JAK-STAT pathway and thereby overexpression of interferon stimulated genes resistance signature (ISG.RS). By targeting the SOX2-JAK-STAT signaling, SAHA promoted the antitumor efficacy of IFNγ or anti-PD-1 in vitro and in vivo. Moreover, SOX2 was an independent prognostic factor for poor survival and resistant to anti-PD-1 therapy in melanoma with PD-L1 high expression.Conclusions Our data unveiled an additional function of SOX2 causing immune evasion of CD8+ T-cell killing through alleviating the JAK-STAT pathway and ISG.RS expression. We also provided a rationale to explore a novel combination of ICIs with SAHA clinically, especially in melanoma with PD-L1 and SOX2 high expression.

N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention in recent years. The m6A modification affects multiple aspects of RNA metabolism, ranging from RNA processing, nuclear export, RNA translation to decay. Emerging evidence suggests that m6A methylation plays a critical role in cancer through various mechanisms. Moreover, m6A methylation has provided more possibilities for the early diagnosis and treatment of cancers. In this review, we focus on m6A-associated mechanisms and functions in several major malignancies and summarize the dual role of m6A methylation as well as its prospects in cancer.

According to “Technical Criterion for Ecosystem Status Evaluation” issued by State Environmental Protection Administration, on the basis of Arcgis platform, using the comprehensive evaluation index method, the paper takes Dongsheng district as a case, selected biological richness index, vegetation coverage index, land stress index, water network denseness index and pollution load index to evaluate the quality of ecological environment. The evaluation result shows that the ecological environment quality of Dongsheng district is "normal", the degree of vegetation coverage is moderate, the biological diversity is general, and it is suitable for human to live, but sometimes exist restrictive factors limit human existence. The ecological index value increased from 52.06 of 2005 to 53.11 in 2014, and land ecological environment quality of Dongsheng district has rising trend from the overall view, but the amplitude variations in the ecological environment condition has no obvious change, land ecological environment is good, the land ecosystem structure is complete, and its function is basically perfect.

Rare earth elements are an important strategic resource. As one of the most valuable member, lanthanum plays a key role in lanthanide. However, trace Al(III) impurity in lanthanum materials can seriously damage the performance of lanthanum materials. In this paper, a nitrogen-containing activated carbon, AC-PN-700, was synthesized using pine needle as raw material and KOH as activator. The ACPN-700 was characterized by surface area analyzer, elemental analysis and FT-IR. The adsorption and selective ability of AC-PN-700 towards Al(III) were investigated. The BET specific surface area of AC-PN-700 was 596.4 m².g-1, and the average pore diameter was 2.7nm. Depend on its large specific surface, well-developed internal pore structure and abundant nitrogen-containing functional groups, the AC-PN-700 possesses strong adsorption affinity and excellent recognition selectivity towards Al(III). The adsorption capacity of AC-PN-700 towards Al(III) could reach to 3.89mg.g-1, removal rate towards Al(III) was almost 100%, and relative selectivity coefficients with respect to La(III) is 9.5. The empirical Freundlich isotherm was found to describe well the equilibrium adsorption data. In addition, AC-PN-700 possesses better regeneration ability and reusability. [ABSTRACT FROM AUTHOR]