Search Results (332)

Background: Neoadjuvant therapy (NAT) is increasingly investigated in operable pancreatic ductal adenocarcinoma (PDAC), yet its role in strictly resectable disease remains controversial. Randomized trials have been conducted both in borderline resectable and resectable PDAC and have demonstrated survival advantages, while evidence in strictly resectable tumors remains poor. We conducted an umbrella review of systematic reviews and meta-analyses (SRMAs) to comprehensively evaluate the highest level of available evidence on NAT versus upfront surgery in operable PDAC. Methods: We performed an umbrella review of completed SRMAs assessing neoadjuvant chemotherapy (NAC) and/or chemoradiotherapy (NACRT) in resectable and borderline resectable PDAC. MEDLINE/PubMed, Embase, and Cochrane Library were searched from inception through November 2025. Eligible SRMAs reported at least one clinical outcome, including overall survival (OS), disease-free/event-free survival (DFS/EFS), resection rate, R0 resection, nodal status, or perioperative outcomes. Methodological quality was appraised using AMSTAR-2 and ROBIS tools. Overlap among SRMAs was quantified using the Corrected Covered Area (CCA), and RCT-only evidence was prioritized for causal inference. Evidence credibility was graded using an Ioannidis-style classification framework. Results: Thirty-four SRMAs published between 2010 and 2025 were included. In strictly resectable PDAC, RCT-only meta-analyses showed no definitive OS benefit for NAT compared with upfront surgery (pooled HR approximately 0.85, 95% CI 0.68–1.05), although a significant improvement in EFS was observed (HR approximately 0.77, 95% CI 0.65–0.90). Trial sequential analyses suggested insufficient information size for conclusive OS benefit in resectable disease. Conversely, in pooled resectable and borderline resectable populations, NAT significantly improved OS (HR approximately 0.66, 95% CI 0.52–0.85), with subgroup analyses indicating that the survival advantage was primarily driven by borderline resectable tumors. NAT consistently increased R0 resection and node-negative (pN0) rates and reduced non-curative explorations. However, neoadjuvant strategies were associated with treatment-related attrition and, in some analyses, lower overall resection rates. Comparative evidence suggested improved pathological outcomes with chemoradiotherapy versus chemotherapy alone, without a consistent survival advantage. Conclusions: Current high-level evidence supports NAT as the preferred strategy for borderline resectable PDAC, demonstrating consistent survival and pathological benefits. In strictly resectable disease, NAT improves disease-control endpoints and pathological surrogates, but a definitive OS advantage has not been consistently demonstrated in RCT-only syntheses. This should not be interpreted as evidence of equivalence between NAT and a surgery-first strategy, given the heterogeneity, limited power, and therapeutic-era effects of the available literature. Treatment decisions in resectable PDAC should therefore be individualized, balancing potential oncologic benefits against attrition risk. Future adequately powered randomized trials employing contemporary multi-agent regimens are needed to clarify the survival impact of NAT in strictly resectable disease. Full article

Background and Objectives: Neoadjuvant chemoradiotherapy is a key component of the treatment strategy for locally advanced rectal cancer (LARC), both through its direct impact on oncological prognosis and by increasing the likelihood of sphincter-preserving surgery. Oncological prognosis improves dramatically following a complete pathological response to neoadjuvant therapy. Identifying predictors of response to neoadjuvant therapy has been a challenge over the past two decades, and these factors have not been fully identified. This study aimed to analyze the clinical, biological, and therapeutic factors associated with tumor response following neoadjuvant therapy in patients with locally advanced rectal cancer, with the aim of identifying independent predictors of the absence of a complete pathological response and optimizing personalized treatment strategies. Materials and Methods: This retrospective study included a cohort of 122 patients (81 men and 41 women), with a mean age of 63.5 years, diagnosed with locally advanced rectal cancer at two centers with expertise in colorectal surgery between January 2018 and December 2023. Patients received neoadjuvant treatment in two regimens: long-course chemoradiotherapy with oral radiosensitizing chemotherapy (82 patients) and total neoadjuvant therapy consisting of chemoradiotherapy followed by consolidation chemotherapy (40 patients). A series of clinical, biological, and therapeutic variables was analyzed for their association with pathological responses. Results: According to the Ryan score, the overall complete response rate following neoadjuvant therapy was 17.2%. pCR was observed more frequently in patients treated with total neoadjuvant therapy than in those treated with standard chemoradiotherapy. Elevated pre-treatment CEA levels were independently associated with a higher risk of unfavorable tumor response. The radiation dose and interval between completion of radiotherapy and surgery were significantly associated with tumor regression. Conclusions: These results underscore the importance of personalizing neoadjuvant therapy to improve cancer prognosis. Furthermore, optimizing tumor regression could lead to the potential expansion of sphincter-preserving resection techniques, which would have a direct and significant impact on the quality of life of these patients. Full article

Objectives: This study aimed to compare the results obtained by endorectal ultrasound (ERUS) and magnetic resonance imaging (MRI) with the pathologic staging of the operative specimen in patients with lower and middle rectal cancer not treated with neoadjuvant therapy and undergoing surgery. Methods: From 2011 to 2022, all the consecutive patients with lower/middle rectal cancer who underwent surgery-first treatment were evaluated. The results of diagnostic examinations and the definitive pathological examination were considered and compared. Results: One hundred and one patients were enrolled in the study. The mean age was 72.5 (SD ± 9.7) years. F:M = 1:2. Mean distance from the anal orifice was 87 (SD ± 9.7) mm. Mean tumoral cranio-caudal extension was 35 (SD ± 12.5) mm. According to the T-stage, the κ coefficient showed a fair concordance between MRI and Pathology (κ = 0.294) and moderate between ERUS and Pathology (κ = 0.534). According to the N-stage, MRI was related to a lower concordance (κ = 0.138) than ERUS (κ = 0.337) with Pathology. Comparing ERUS with MRI, κ was higher in staging T (κ = 0.410), showing a moderate agreement. Stage N was related to a fair agreement between the two imaging methods (κ = 0.237). Conclusions: MRI and ERUS have similar results in performing the TN staging in patients with lower and middle rectal cancer who did not undergo neoadjuvant chemoradiotherapy. ERUS might be a valid option for staging patients who cannot have the possibility to perform an MRI. Full article

Background: Localized soft tissue sarcoma (STS) is primarily treated with surgical resection with or without radiotherapy (RT), while the role of chemotherapy (CT) as a radiosensitizer remains unclear. We report our single-institution experience with combined chemoradiotherapy (CCRT) in treating localized STS. Methods: We conducted a retrospective analysis of patients with localized STS treated at Mayo Clinic with mitomycin, cisplatin, and doxorubicin (MitoAP) concurrently with RT between 1/1/85 and 12/12/19. Results: We identified 179 patients (median age 58 years; median tumor size 9.5 cm), with 83.8% of tumors located in the extremities or trunk. Among them, 77.1% received perioperative CT in addition to CCRT, with 95% of those treated in the neoadjuvant setting. Median RT dose was 50 Gray. The 5-year disease-specific survival (DSS) was 77.9% (95% confidence interval, CI: 70.8–83.4%). The addition of perioperative CT to CCRT was associated with improved DSS compared with CCRT alone (p = 0.01, Hazard Ratio, HR: 0.48, 95% CI: 0.27–0.85). Median post-CCRT tumor viability was 30% and did not differ by CT use (p = 0.39), but varied significantly by histology (p < 0.001). Conclusions: Our institutional protocol utilizing two cycles of MitoAP with RT was well tolerated. DSS in our cohort was similar to historical data using perioperative RT alone, suggesting no clear benefit from CCRT. However, the majority of patients in our cohort were classified as high risk, which may have attenuated a potential survival benefit in the absence of appropriate comparative controls. Furthermore, additional perioperative CT to CCRT was associated with improved DSS and differential histology-specific responses in tumor viability, suggesting that a more aggressive neoadjuvant and perioperative approach may be beneficial in selected patients. Full article

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resection rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resection was achieved in 94.5%. In the W&W cohort (n = 21), local regrowth occurred in 33.3% (95% CI, 14.6–57.0%) over a median follow-up of 4.96 years. Total mesorectal excision (TME)-free survival at 5 years was 73.1% (95% CI, 55.0–97.2%). Estimated 5-year OS was 81.1% (95% CI, 75.5–87.2%) and 5-year DFS was 75.2% (95% CI, 69.0–82.0). In multivariable analysis, non-R0 resection (HR 6.06, 95% CI, 1.99–18.42), MRI circumferential resection margin positivity (HR 3.11, 95% CI, 1.53–6.33), and MRI extramural vascular invasion positivity (HR 1.97, 95% CI, 1.05–3.91) remained independent predictors of DFS. Conclusions: Institutional sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance. Full article

Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery has become the standard treatment for oesophageal cancer. However, data on the outcomes of neoadjuvant immunochemotherapy (nICT) in geriatric patients (≥70 years) who face higher perioperative risks are limited. Objective: This study aimed to compare the perioperative outcomes of nICT versus nCRT in elderly patients with locally advanced oesophageal squamous cell carcinoma (ESCC). Method: This retrospective cohort study included 132 geriatric patients (median age: 72 years) treated with nICT (n = 51) or nCRT (n = 81) followed by esophagectomy at Sichuan Cancer Hospital (2021–2024). Intraoperative outcomes, postoperative pathologic stages, and complications, including pneumonia and anastomotic leakage, were assessed. Propensity score matching (PSM), overlap weighting (OW), and inverse probability of treatment weighting (IPTW) were used to adjust for baseline covariate imbalances in the sensitivity analysis. Results: Pathologic ypT0 stage tended to be higher in the nCRT group (p = 0.014), whereas ypN0 was higher in the nICT group (p = 0.035). No significant differences in intraoperative or postoperative outcomes between the two groups, except for pulmonary complications (p > 0.05). Compared with nCRT patients, nICT patients had significantly lower pulmonary complication rates (13.7% vs. 32.1%, p = 0.030), and multivariable analysis confirmed these findings (adjusted OR = 0.26; 95% CI: 0.08–0.85; p = 0.026). Sensitivity analyses showed consistent results. Conclusions: The safety of nICT is comparable to that of nCRT in geriatric ESCC patients, with significantly fewer pulmonary complications. These findings support nICT as a valuable alternative for elderly populations. Full article

With the introduction of total neoadjuvant therapy (TNT) in locally advanced rectal cancer treatment, multidisciplinary treatment options have become more diverse than before, and many challenges remain unresolved. A randomized clinical study in intermediate-risk locally advanced rectal cancer showed that neoadjuvant full-dose systemic chemotherapy with response-adapted omission of radiation therapy is non-inferior to concurrent chemoradiotherapy. Given that preoperative systemic chemotherapy provides an additional layer of local disease control, the traditional role and extent of neoadjuvant radiation therapy could be strategically re-evaluated within the TNT framework. In this context, a risk-adapted approach featuring selective reduction in elective nodal irradiation volume, particularly of the lateral pelvic lymph nodes, may offer a promising middle ground for treatment personalization. Drawing parallels from surgical practice—where total mesorectal excision is standard but lateral pelvic lymph node dissection is reserved for selected cases—this perspective advocates for similar selectivity in radiation therapy targeting, focusing on mesorectal and presacral regions while judiciously omitting lateral nodes in appropriately selected patients. This approach could maintain oncologic safety by focusing radiation therapy on limited but essential volumes. With modern intensity-modulated radiation therapy, reducing the target volume translates directly to enhanced organs-at-risk sparing, thereby mitigating radiation-induced toxicity. When combined with induction chemotherapy response assessment to refine patient selection, this approach can offer a biologically informed, personalized treatment paradigm that balances disease control with quality of life. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor survival outcomes. Resection is the sole definitive management; however, most PDACs are diagnosed with unresectable disease including metastatic, locally advanced (LAPC) or borderline resectable (BRPC). Recently, neoadjuvant therapy has demonstrated potential in downstaging these tumours for resection. This literature review explores current and novel approaches in the management of BRPC and LAPC. Methods: A systematic search of Medline, Embase, Cochrane Central and Emcare databases was conducted on 7 April 2025. Inclusion criteria were primary articles that explored current and novel therapies that led to downstaging of BRPC and LAPC to resection, as well as resection outcomes and oncological outcomes associated with this. Articles that explored other pancreatic cancer subtypes or either resectable or metastatic disease were excluded. All meta-analyses were performed using a random-effects model based on the inverse variance method. Results: A total of 88 studies involving 8585 patients were included in the review, predominately from retrospective studies (57%, n = 50). Neoadjuvant regimens incorporating chemotherapy or radiotherapy, whether sequential or concurrent, demonstrated the highest proportions of R0 resections with N0 status. Overall, most modalities showed evidence of survival benefit following resection compared to non-operative management, with pooled differences demonstrated for chemotherapy alone (HR 0.33, 95% CI 0.25–0.44) and sequential chemotherapy and radiotherapy (HR 0.49, 95% CI 0.25–0.95). However, no significant differences between these modalities were demonstrated. Other modality-specific conclusions regarding survival benefit could not be elucidated. Conclusions: The rising incidence and global mortality from PDAC underscore the significance of identifying approaches to optimise the management of BRPC and LAPC. This review emphasises the importance of neoadjuvant therapy, both current and novel with surgical resection, which may warrant further investigation in future clinical trials. However, it is important to acknowledge the clinical heterogeneity of current data, which may introduce bias. Nevertheless, these findings can help to inform guidelines on the management of BRPC and LAPC. Full article

Background: Liquid biopsy using circulating tumor DNA (ctDNA) is rapidly reshaping gastrointestinal (GI) oncology. The highest-impact applications are molecular residual disease (mRD) detection after curative-intent therapy and early recognition of progression or resistance during systemic treatment. Methods: We performed a structured, clinically oriented narrative synthesis by using explicit search, eligibility, evidence prioritization, and clinical interpretation rules, integrating landmark prospective cohorts, randomized ctDNA-guided strategy trials where available, meta-analyses, key methodological research (e.g., pre-analytics, assay design, and clonal hematopoiesis (CH)/clonal hematopoiesis of indeterminate potential (CHIP)), and selected trial registries. Results: In resected colorectal cancer (CRC), postoperative ctDNA positivity is among the strongest known biomarkers of recurrence risk; large prospective studies demonstrate clear separation of disease-free survival (DFS)/overall survival (OS) between mRD+ and mRD− patients. In stage II colon cancer, randomized data (DYNAMIC) show that a ctDNA-guided strategy reduces adjuvant chemotherapy exposure without compromising long-term outcomes. In metastatic CRC, ctDNA supports early response monitoring and resistance tracking; ctDNA-selected anti-EGFR rechallenge provides a model of biomarker-driven actionability (CHRONOS). In gastroesophageal cancers, longitudinal ctDNA dynamics correlate with relapse risk and treatment efficacy, and in esophageal squamous cell carcinoma, ctDNA after neoadjuvant chemoradiotherapy informs residual disease risk and adjuvant stratification. In pancreatic ductal adenocarcinoma and hepatobiliary malignancies, sensitivity is constrained by low shedding and background cell-free DNA (cfDNA), yet ctDNA positivity remains clinically meaningful, and emerging data in resected extrahepatic cholangiocarcinoma (STAMP-linked analyses) show that ctDNA dynamics during adjuvant therapy predict recurrence. Conclusions: ctDNA is a clinically validated biomarker for mRD in CRC, whereas in other GI cancers, it remains a promising but methodologically heterogeneous tool whose clinical utility is tumor- and context-dependent. The next phase requires interventional trials demonstrating outcome improvement, harmonized sampling and reporting standards, and rigorous control of confounders (notably CH/CHIP). Full article

Background/Objectives: The standard surgical treatment of muscle-invasive bladder cancer (MIBC) comprises neoadjuvant systemic therapy followed by radical cystectomy (RC). However, a notable number of patients achieve a favorable response to neoadjuvant systemic therapy, a finding associated with improved outcomes, and questioning the necessity of RC in this subset of patients. The objective of this review is to summarize the available evidence regarding the feasibility, efficacy and toxicity of bladder-preserving chemoradiotherapy (CRT) following clinical response (CR) to neoadjuvant systemic therapy in patients with MIBC. Methods: A literature search was performed using the PubMed database to identify studies evaluating the use of CRT for bladder preservation in MIBC patients with CR following neoadjuvant therapy. Results: Clinical complete response (cCR) rates to neoadjuvant systemic treatment ranged from 31% to 87.5%, with subsequent CRT enabling 50–97% of responders to retain their bladder. Long-term outcomes were favorable for cCR patients, with 3- to 5-year overall survival (OS) ranging from 65% to 89%, disease-free survival (DFS) of 64–86%, and bladder-intact survival up to 80%. Achievement of cCR, T2 tumor stage, absence of concomitant carcinoma in situ or hydronephrosis, and complete transurethral resection of the bladder tumor (TURBT) were prognostic factors for improved oncologic outcomes. Treatment-related toxicity was generally acceptable, concerning mainly hematological and gastrointestinal events, while severe late toxicity was uncommon. Conclusions: Bladder-preserving CRT is a promising, effective, and well-tolerated option for MIBC patients achieving CR to neoadjuvant systemic therapy. While further prospective validation and longer follow-up are required before it can universally replace radical cystectomy in this subset of patients, advances in neoadjuvant treatments, imaging and molecular biomarkers may improve response assessment and patient selection for bladder preservation. Full article

Background: Total neoadjuvant therapy (TNT) is increasingly administered in rectal cancer, but compared with concurrent chemoradiotherapy (CRT), data regarding the gastrointestinal (GI) toxicity profile and clinical predictors remain limited. Objectives: To evaluate GI toxicity associated with TNT compared with CRT and to explore clinical predictors of these adverse events (AEs). Methods: This retrospective study included 201 patients with rectal cancer treated with TNT (n = 157) and CRT (n = 44). GI AEs (nausea, vomiting, diarrhea) were graded according to CTCAE v5.0. In the analysis of factors associated with GI AEs, multiple clinical and pathological variables were included using multivariable logistic regression. Results: The composite endpoint “any GI AEs grade ≥ 1” was more frequent in the TNT group compared with the CRT group (33.1% vs. 15.9%; RR = 2.08; 95% CI 1.02–4.25; p = 0.038). Nausea was significantly more frequent in the TNT group (28.7% vs. 9.1%; RR = 3.15; 95% CI 1.20–8.30; p = 0.012), whereas vomiting (9.6% vs. 2.3%; p = 0.203) and diarrhea (17.8% vs. 9.1%; p = 0.242) did not reach statistical significance. In multivariable logistic regression, TNT (OR = 2.65; 95% CI 1.08–6.53; p = 0.032) and female sex (OR = 2.03; 95% CI 1.05–3.77; p = 0.033) were identified as independent predictors of grade ≥ 1 GI AEs. For nausea, TNT remained significant (OR = 4.37; 95% CI 1.45–13.20; p = 0.0089). Upper rectal tumor location was significantly associated with vomiting (p = 0.0054). No grade 3–4 GI AEs were observed in either treatment group. Conclusions: TNT was associated with a higher incidence of mild GI AEs, predominantly driven by nausea, without an increase in severe toxicities. TNT and female sex were identified as independent clinical predictors of an increased risk of GI AEs, while tumor location in the upper third of the rectum was associated with a higher occurrence of vomiting. Full article

Background: The management of rectal cancer has evolved toward response-adapted strategies, including organ preservation in selected patients achieving a clinical complete response (cCR) after neoadjuvant treatment. However, most available evidence derives from clinical trials, and data from real-world clinical practice remain limited. Methods: We conducted a retrospective observational cohort study including consecutive patients with rectal adenocarcinoma treated at a tertiary referral center between January 2021 and December 2025. Baseline clinical, tumor-related, and treatment characteristics were collected. Tumor response was assessed using clinical, endoscopic, and radiological criteria. The primary endpoint was the rate of clinical complete response and the implementation of watch-and-wait strategies. Secondary endpoints included recurrence patterns and exploratory oncologic outcomes according to baseline tumor characteristics. Results: A total of 229 patients were identified, of whom 148 were evaluable for treatment response. Clinical complete response was documented in 56 patients (37.8%), and a watch-and-wait strategy was implemented in 42 patients (28.4%). Higher cCR rates were observed in patients with stage I–II disease and in tumors measuring < 4 cm on baseline magnetic resonance imaging, with cCR rates exceeding 55% in this subgroup. Tumors ≥ 4 cm showed substantially lower response rates. Clinical complete responses were observed across both short-course radiotherapy plus chemotherapy and long-course chemoradiotherapy regimens in patients with small tumors and early-stage disease. Tumor distance from the anal verge was not consistently associated with response. With a median follow-up of 26 months in the watch-and-wait group, five recurrences were observed, including three local recurrences. Conclusions: In this real-world cohort, baseline tumor size and clinical stage were the main determinants of clinical complete response and eligibility for organ-preservation strategies in rectal cancer. Small tumors (<4 cm) showed high response rates regardless of neoadjuvant regimen. These findings support response-adapted, individualized treatment strategies and highlight the importance of tumor burden in selecting candidates for non-operative management in routine clinical practice. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer, with poor outcomes following neoadjuvant chemoradiotherapy (NCRT). Neoadjuvant chemoimmunotherapy (NCIT) has emerged as a promising strategy, but reliable predictive biomarkers remain lacking. This study aimed to develop an AI-driven pathomic model for NCIT response prediction and explore its biological mechanisms. Methods: We analyzed 269 H&E-stained whole-slide images (WSIs) from 198 ESCC patients (104 from Tongji Hospital, 94 from TCGA). Using ResNet152, we segmented WSIs into four tissue categories (tumor cells, stroma, lymphocytes, and necrosis), extracted spatially weighted pathomic features, and constructed the ECiT score via logistic regression. An integrated model combining the ECiT score with clinical variables (T stage, P53 status) was developed. Mechanistic analyses were performed using TCGA-ESCA and GSE160269 datasets. Results: The integrated model achieved AUCs of 0.897 (training) and 0.809 (temporal validation), outperforming clinical (AUC = 0.624) and pathomic-only (AUC = 0.751) models. Mechanistically, a high ECiT score correlated with enhanced immune activation (elevated CD4⁺ memory T cell infiltration), while low scores were linked to endoplasmic reticulum (ER) stress-unfolded protein response (UPR) activation. EIF2S3 was identified as a key molecular mediator, correlating with three pathomic features, UPR activation, and poor prognosis. Conclusions: This study may offer a preliminary indicator that could assist in personalized clinical decision-making. Correlative evidence suggests that the EIF2S3-mediated ER stress–UPR axis represents a potential candidate therapeutic target to overcome NCIT resistance, generating testable hypotheses to advance precision oncology for resectable locally advanced ESCC. Full article

Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair–proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair–deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations—including RNA editing—act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy. Full article

Locally advanced rectal cancer (LARC) presents a clinical challenge due to lack of reliable molecular biomarkers for early diagnosis, prognosis, and prediction of response to neoadjuvant chemoradiotherapy (nCRT). Long non-coding RNAs (lncRNAs) have emerged as promising candidates due to their characteristics and regulatory roles. H19, NEAT1, MALAT1 and HOTAIR are lncRNAs deregulated in gastrointestinal cancers, with insufficient data on their biomarker potential in LARC. The study aimed to analyze the diagnostic, prognostic and predictive utility of H19, NEAT1, MALAT1 and HOTAIR in LARC. Relative expression was evaluated by RT-qPCR in tumor and non-tumor tissues from 25 LARC patients before and after nCRT. H19, NEAT1, and MALAT1 showed significantly altered expression in tumor tissue, as well as non-tumor tissue before and after nCRT. H19 expression was significantly higher in tumor vs. non-tumor tissue before treatment and demonstrated moderate potential to discriminate between tumor and non-tumor. None of the lncRNAs showed statistically significant predictive values for nCRT response or association with treatment outcomes in our study, which was limited by the small number of responders. Our results suggest that H19 might be considered as a potential therapeutic target in LARC. Further studies with larger patient groups are required to confirm its diagnostic and prognostic utility. Full article