The introduction of modern anticancer therapies, including targeted therapies (TTs), immune checkpoint inhibitors (ICIs), and antibody-drug conjugates (ADCs), has significantly improved survival across a wide range of malignancies. At the same time, these agents have expanded the spectrum of treatment-related adverse events, with ocular toxicities emerging as a clinically relevant and increasingly recognized complication. Ocular adverse events may affect multiple anatomical structures, including the ocular surface, cornea, anterior and posterior segments, and optic nerve, often reflecting drug class-specific biological mechanisms. The pathogenesis of ocular toxicity is multifactorial and includes on-target inhibition of signaling pathways expressed in ocular tissues, off-target effects on rapidly renewing epithelia, non-specific uptake of cytotoxic payloads in ADCs, immune-mediated inflammation associated with ICIs, and microvascular dysregulation observed with selected targeted agents, such as mitogen-activated protein kinase (MEK) inhibitors. Because ocular adverse events are inconsistently reported in clinical trials and frequently described through case reports or pharmacovigilance data, their true incidence is likely underestimated and management strategies remain heterogeneous. This narrative review provides an overview of the epidemiology, biological mechanisms, and clinical manifestations of ocular toxicities associated with contemporary anticancer therapies. In addition, it offers practical, mechanism-based recommendations for prevention, monitoring, and stepwise management, emphasizing the importance of multidisciplinary collaboration to preserve visual function while maintaining effective oncologic treatment.

ABSTRACT Background and Aims Microsatellite instability (MSI), programmed death‐ligand 1 (PD‐L1) expression, and Epstein–Barr virus (EBV) positivity are emerging biomarkers in gastric cancer prognosis and treatment selection, particularly in immunotherapy. This review evaluates their prognostic significance through a systematic review and meta‐analysis. Methods Relevant studies from PubMed, EMBASE, and the Cochrane Library (January 2010 to December 2024) were analyzed. Studies included assessing MSI, PD‐L1, and EBV status in gastric cancer using immunohistochemistry, PCR, or in situ hybridization, and reported outcomes such as overall survival (OS), disease‐free survival (DFS), or progression‐free survival. Data extraction adhered to PRISMA guidelines, and pooled analyses were conducted using a random‐effects model (DerSimonian‐Laird method). Heterogeneity was assessed using I2 statistics and Cochran's Q test. Results A total of 25 studies involving 6494 patients were reviewed. In localized gastric cancer, MSI‐high status was associated with significantly improved DFS (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.23–0.75; p = 0.004) but showed no significant impact on OS (HR, 0.78; 95% CI, 0.48–1.28; p = 0.33) compared to microsatellite stable/PD‐L1‐negative tumors. EBV‐positive/PD‐L1‐positive cancers demonstrated a prognosis similar to EBV‐negative/PD‐L1‐negative cases (OS: HR, 1.08; 95% CI, 0.81–1.45; p = 0.59). Conclusions In metastatic disease, MSI and EBV status were not associated with significant prognostic effects. MSI and EBV status have minimal prognostic value in gastric cancer, particularly for OS, but are essential for selecting candidates for immune checkpoint inhibitors. Standardizing biomarker evaluation is critical to enhancing their clinical relevance.

Lung cancer has a remarkably high global incidence and ranks among the most frequent malignancies, with mortality rates placing it first worldwide. Although lung cancer typically metastasizes to the brain, bone, adrenal glands, and liver, the advent and efficacy of novel treatments such as immunotherapy and tyrosine kinase inhibitors have been associated with an increasing incidence of metastases in atypical sites, including peritoneal involvement in Non-Small Cell Lung Cancer. Adenocarcinoma is the histological subtype most frequently responsible for peritoneal carcinomatosis. Little is known about the underlying pathogenic mechanisms leading to peritoneal implantation, and diagnosis is often delayed until advanced disease stages, as symptoms are frequently nonspecific and may be mistaken for the natural progression of advanced lung cancer under systemic oncological treatment. Diagnosis is primarily clinical when ascites develops, but imaging modalities such as computed tomography and fluorodeoxyglucose positron emission tomography/computed tomography can be highly informative. Cytological and molecular analysis of peritoneal fluid obtained via drainage also contributes to diagnosis. Treatment mainly relies on systemic therapy for lung cancer with peritoneal metastases, while loco-regional interventions are generally reserved for symptom control. Considerable progress is still needed in the prevention, early diagnosis, and optimal management of peritoneal carcinomatosis, and future research, despite the rarity of cases, should focus on these aspects. In this review, we aim to analyze the limited literature currently available and explore future directions in the approach to peritoneal carcinomatosis in Non-Small Cell Lung Cancer.

Immune-checkpoint inhibitor (ICI)-based immunotherapy has become one of the most effective and widely adopted therapeutic approaches in the field of onco-hematology. Among the various malignancies treated with immunotherapy, lung cancer stands out for the frequency and success of its use, ranging from the adjuvant, neoadjuvant, and perioperative settings to advanced metastatic disease. Despite its clinical success, the mechanisms underlying the full spectrum of immune-related adverse events (irAEs) remain poorly understood, with gastrointestinal (GI) toxicity among the most commonly observed complications. Timely recognition and management of these adverse events are therefore essential to prevent progression to severe, potentially irreversible clinical conditions. Corticosteroids continue to represent the mainstay of treatment for irAEs; however, emerging therapeutic agents are showing promise in improving outcomes and minimizing long-term toxicity. In this review, we will explore the primary GI immune-related toxicities associated with ICIs, discuss current management strategies, and examine their relationship with the use of immunotherapy in patients with non-small cell lung cancer (NSCLC).

PURPOSE:Psychological stress, here used as an umbrella term encompassing depression, anxiety, psychosocial stress, stressful life events, perceived stress, and job strain, is hypothesized to influence cancer development and prognosis, yet epidemiologic evidence is inconsistent. This umbrella review with secondary quantitative synthesis evaluated associations between stress-related exposures and cancer incidence and mortality. METHODS:PubMed was searched from inception to March 1, 2026, alongside Scopus, the Cochrane Library, citation tracking, and manual screening. Eligible studies included systematic reviews, meta-analyses, or pooled individual participant data analyses assessing depression, anxiety, psychosocial stress, stressful life events, perceived stress, or job strain in relation to cancer incidence or mortality, reporting adjusted HRs, RRs, or ORs. Random-effects models were used for secondary pooling. Overlap was assessed with corrected covered area, and evidence credibility with the Ioannidis framework. RESULTS:Fifteen publications met inclusion criteria; eight were quantitatively synthesized, representing over four million participants. Psychological stress was not significantly associated with overall cancer incidence (pooled RR/HR 1.06; 95% CI 0.99-1.14; I2 = 72.5%) or breast cancer incidence (RR/OR 1.13; 95% CI 0.95-1.34; I2 = 77.8%). In contrast, cancer mortality was consistently elevated across 4 analyses (RR/HR 1.23; 95% CI 1.19-1.27; I2 = 0%). Site-specific mortality risks ranged from HR 1.15 for lung cancer to HR 3.86 for leukemia. Review overlap was moderate (7.4%). Associations between depression/anxiety and cancer mortality reached Class I evidence. CONCLUSION:Psychological stress-related exposures were not significantly linked to cancer incidence in the available meta-analytic evidence, whereas depression, anxiety, and related distress were consistently associated with increased cancer mortality. These findings should be interpreted cautiously because residual confounding and measurement heterogeneity remain important limitations.

OBJECTIVES:Ampullary adenocarcinoma (AAC) is rare. Five-year survival rates of 30% to 70% are seen after resection. This broad range of survival could be explained by the morphologic heterogeneity in the 3 subtypes of AAC (pancreatobiliary, intestinal, and mixed subtype), which complicates the prediction of individual prognosis and clinical decision making with regard to adjuvant therapy. To date, there are no prospective studies to elucidate whether adjuvant chemotherapy improves survival in these patients. METHODS:The ADAPTA study is a phase II prospective single-arm multicenter cohort study including 200 patients with resected AAC (100 patients with intestinal subtype, and 100 with pancreatobiliary- and mixed subtype). All patients will be treated with CAPOX/ FOLFIRINOX, respectively. Outcomes will be compared after propensity score matching to the data of all patients in consecutive participating centers not treated according to the proposed regime. CONCLUSIONS:This pioneering prospective study aims to generate evidence on the impact of adjuvant chemotherapy tailored to the histopathologic subtypes of AAC. The outcomes of this trial could lead to changes in clinical guidelines or pave the way for future randomized controlled trials. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT06068023.

Background Early onset pancreatic cancer (EOPC), defined for the primary analysis as pancreatic ductal adenocarcinoma (PDAC) diagnosed before the age of 50 years, is an increasingly recognised clinical and epidemiological entity. Because published studies use heterogeneous age thresholds, the present review prespecified <50 years as the main definition and interpreted studies using other cutoffs in sensitivity or narrative analyses. Methods We systematically searched PubMed, EMBASE, and the Cochrane Library for studies published between January 1990 and December 2024 that reported outcomes specific to EOPC. Search terms were reformatted with standard quotation marks and included "pancreatic cancer", "pancreatic adenocarcinoma", "pancreatic ductal adenocarcinoma", "early onset", "young onset", "young adult", "age < 50", "age less than 50", and "premature". Meta-analytic procedures and epidemiological interpretation were re-reviewed with statistical/epidemiological input. Results 40 studies encompassing more than 285,000 patients were included. Global incident EOPC cases increased from 24,480 (1990) to 42,254 (2021), representing a 72·6% rise. Age-standardised prevalence rate increased by 17·0% (1·65 per 100,000 in 2021). EOPC patients have a 3·08% per year increase in the youngest age group (20-29 years) over 2010-2021. Germline pathogenic variants were identified in 17·3% of EOPC patients (vs 6·4% in older cohorts; OR 2·41, 95% CI 1·87-3·11). EOPC patients were more likely to receive treatment (OR 2·95, 95% CI 2·54-3·43; I2 = 13%) and showed modestly improved overall survival (pooled HR 0·89, 95% CI 0·80-0·99; I2 = 16%) compared with average or late onset disease. Conclusions EOPC is an increasingly recognised and clinically challenging subset of PDAC. The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.

Liposomal irinotecan (nal-IRI) has emerged as a cornerstone in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC), particularly in combination with 5-fluorouracil and leucovorin (5-FU/LV) following progression on gemcitabine-based therapy. Despite its demonstrated survival benefit, gastrointestinal toxicity—most notably diarrhea—remains a clinically significant adverse event that can compromise dose intensity, treatment adherence, and patient quality of life. Diarrhea associated with irinotecan-containing regimens is mechanistically complex, encompassing both acute cholinergic and delayed secretory components mediated by mucosal injury and enterohepatic recirculation of the active metabolite SN-38. The liposomal formulation alters the pharmacokinetic profile of the drug, prolonging systemic exposure while maintaining toxicity risks. This review provides a comprehensive and updated overview of the pathophysiology, incidence, and clinical implications of diarrhea in nal-IRI–based regimens. Evidence-based management strategies are discussed, including pharmacologic interventions, supportive care, dose modifications, and patient education. Emerging therapeutic approaches—including microbiome modulation and pharmacogenomic-guided therapy—are also explored. A multidisciplinary and proactive management approach is essential to optimize outcomes and minimize toxicity.

OBJECTIVES:Advanced pancreatic and gastric cancers are associated with high symptom burden and psychological distress, potentially threatening patients' sense of dignity. Although Dignity Therapy (DT) has mainly been used in end-of-life care, its potential role earlier in the disease trajectory is emerging. This exploratory study investigated the feasibility and potential impact of DT during active chemotherapy on emotional distress, dignity-related distress, and quality of life (QoL). METHODS:Thirty patients with advanced pancreatic or gastric cancer undergoing chemotherapy received a 3-session DT intervention over approximately 3 weeks. Emotional distress, dignity-related distress, and QoL were assessed at baseline (T0), post-intervention (T1), and 1-month follow-up (T2) using the Distress Thermometer, Patient Dignity Inventory, and EORTC Quality of Life Questionnaire-Core 30. Exploratory analyses assessed changes over time. RESULTS:Emotional distress decreased significantly from T0 (M = 6.67, SD = 1.47) to T1 (M = 3.13, SD = 1.43; p < .001) and remained lower at T2 (M = 3.50, SD = 1.53; p < .001). Dignity-related distress also decreased from T0 (M = 37.1, SD = 3.03) to T1 (M = 27.9, SD = 1.79; p < .001), with sustained improvement at T2 (M = 25.4, SD = 12.86; p < .01). QoL remained stable. Participants reported high acceptability of the intervention. SIGNIFICANCE OF RESULTS:DT during chemotherapy appears feasible and may improve emotional and dignity-related outcomes. Results should be interpreted cautiously due to the small sample size, attrition, and lack of a control group.

BackgroundModifiable lifestyle factors, including diet quality, are strongly associated with the incidence of gastrointestinal cancers. However, the impact of ultra-processed food (UPF) consumption after cancer diagnosis remains poorly understood, with scarce and fragmented evidence. In particular, the role of post-diagnostic UPF exposure in shaping survival outcomes and disease progression has not been systematically explored.MethodsWe conducted a scoping review with narrative synthesis of the available literature on post-diagnostic UPF consumption and clinical outcomes in gastrointestinal cancers. Eligible studies included adult patients with gastrointestinal malignancies, assessment of dietary exposure after diagnosis, and outcomes such as overall survival, cancer-specific mortality, recurrence, progression, and treatment-related outcomes.ResultsDirect evidence was extremely limited. The only available prospective study in colorectal cancer survivors showed that higher post-diagnostic UPF intake was not associated with overall or cancer-specific mortality but was associated with increased cardiovascular mortality, highlighting the relevance of competing risks in cancer survivorship. Furthermore, specific UPF subgroups showed adverse associations with colorectal cancer-specific mortality. Supportive studies suggested that dietary quality may deteriorate after treatment, with increasing UPF consumption over time. Mechanistic evidence supports a biologically plausible link between UPF exposure, metabolic dysfunction, chronic inflammation, microbiota alterations, and survivorship outcomes.ConclusionsDespite the increasing burden of gastrointestinal cancers and the widespread consumption of ultra-processed foods, post-diagnostic UPF exposure remains largely overlooked in oncologic research. Direct evidence is currently limited and mainly restricted to colorectal cancer survivors, where higher UPF intake has been associated with cardiovascular mortality but not consistently with cancer-specific outcomes. These findings, together with biological plausibility from mechanistic studies, support the need for prospective post-diagnostic cohorts and intervention trials integrating standardized dietary assessment into gastrointestinal cancer survivorship research.

Endoscopic surveillance plays a fundamental role in the long-term management of patients treated for colorectal cancer. Despite significant advances in surgical techniques, systemic therapies, and molecular diagnostics, recurrence and metachronous neoplasia remain clinically relevant challenges, particularly within the first three years following curative-intent treatment. This review summarizes current evidence and major guideline recommendations on endoscopic follow-up after colorectal resection, endoscopic removal of early-stage tumors, and non-operative management strategies. We describe the natural history of precursor lesions and their variable malignant potential, emphasizing the importance of accurate characterization, complete resection, and risk-adapted surveillance. The growing adoption of organ-preserving approaches, such as the watch-and-wait strategy following total neoadjuvant therapy for rectal cancer, and immunotherapy-induced complete responses in microsatellite instability-high/deficient mismatch repair tumors, necessitates more intensive and prolonged monitoring, including structured endoscopic follow-up. As these oncologic surveillance strategies become increasingly widespread, clearly defined clinical pathways and standardized protocols will be essential. We highlight how risk-stratified endoscopic follow-up is critical for the early detection of recurrence, prevention of new primary tumors, and the safe implementation of non-surgical management pathways. The aim is to define a clear algorithm supporting follow-up across distinct clinical contexts: Post-surgical, post-endoscopic resection, and in patients who are candidates for non-operative management. Future research will need to integrate molecular biomarkers, refine risk stratification models, and harmonize surveillance algorithms to ensure effective and personalized follow-up for patients with colorectal cancer.

Genitourinary malignancies are characterized by marked heterogeneity in tumor biology, clinical behavior and therapeutic outcomes. Despite significant progress in surgical and systemic treatments, resistance to therapy remains a major challenge, highlighting the need to identify additional host-related determinants of disease progression and treatment response. Within this framework, converging experimental and clinical evidence indicates that host-associated microbial ecosystems may influence key biological processes involved in tumor-host interactions, including immune modulation, metabolic regulation and inflammatory pathways. Altered microbial profiles have been associated with oncogenic signaling, changes in the tumor microenvironment and differences in clinical benefit from systemic therapies, particularly immunotherapeutic approaches. This review brings together preclinical, translational and clinical evidence on the involvement of microbiota in renal, prostate, bladder and testicular cancers, with attention to biological mechanisms and clinically meaningful correlations with disease characteristics. While current data are largely observational, early interventional studies suggest that modulation of microbial ecosystems may influence therapeutic activity in selected clinical settings. Collectively, these findings support microbiota as a relevant component of genitourinary cancer biology with potential implications for precision medicine approaches.

BACKGROUND:Cholangiocarcinoma is an aggressive biliary tract cancer with a median overall survival of approximately 1 year with first-line gemcitabine plus cisplatin. Actionable genomic alterations are frequent in intrahepatic disease and provide a rationale for genotype-directed therapy. METHODS:We searched PubMed (MEDLINE), Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from January 1, 2010, through June 30, 2025, for randomized trials, large prospective cohorts, and pivotal phase 2 studies evaluating chemotherapy, targeted therapy, or immunotherapy in cholangiocarcinoma. Two reviewers independently screened records and extracted data. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Evidence was synthesized qualitatively. FINDINGS:Seven phase 3 trials define contemporary first-line management. Gemcitabine plus cisplatin with durvalumab improved overall survival compared with chemotherapy alone (12.9 vs. 11.3 months; hazard ratio, 0.76) without increasing grade 3 or higher toxicity. In biomarker-selected populations, fibroblast growth factor receptor inhibitors achieved objective response rates of 35%-42% and median progression-free survival of 6.9-9.0 months after platinum therapy; ivosidenib improved progression-free survival in isocitrate dehydrogenase 1-mutant disease (2.7 vs. 1.4 months; hazard ratio, 0.37). Dual B-Raf proto-oncogene, serine/threonine kinase (BRAF) and MEK inhibition, trastuzumab deruxtecan in human epidermal growth factor receptor 2 (HER2)-positive disease, and pembrolizumab in microsatellite instability-high tumors also demonstrated clinically meaningful activity. In a 32-trial network meta-analysis, genotype-matched therapy reduced the risk of progression vs. fluorouracil, leucovorin, and oxaliplatin (hazard ratio, 0.44). CONCLUSIONS:Chemoimmunotherapy is the reference first-line regimen for biomarker-unselected advanced cholangiocarcinoma. Early comprehensive genomic profiling is essential to enable timely, matched targeted therapy and maximize population-level benefit. FUNDING:This study has no funding to declare.

Objectives: Ampullary adenocarcinoma (AAC) is rare. Five-year survival rates of 30% to 70% are seen after resection. This broad range of survival could be explained by the morphologic heterogeneity in the 3 subtypes of AAC (pancreatobiliary, intestinal, and mixed subtype), which complicates the prediction of individual prognosis and clinical decision making with regard to adjuvant therapy. To date, there are no prospective studies to elucidate whether adjuvant chemotherapy improves survival in these patients. Methods: The ADAPTA study is a phase II prospective single-arm multicenter cohort study including 200 patients with resected AAC (100 patients with intestinal subtype, and 100 with pancreatobiliary- and mixed subtype). All patients will be treated with CAPOX/ FOLFIRINOX, respectively. Outcomes will be compared after propensity score matching to the data of all patients in consecutive participating centers not treated according to the proposed regime. Conclusions: This pioneering prospective study aims to generate evidence on the impact of adjuvant chemotherapy tailored to the histopathologic subtypes of AAC. The outcomes of this trial could lead to changes in clinical guidelines or pave the way for future randomized controlled trials. Trial registration: ClinicalTrials.gov Identifier: NCT06068023.

We report 5-year results of the phase III randomized TRIPLETE study. Eligible patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) received first-line modified fluorouracil, leucovorin, oxaliplatin (mFOLFOX)/panitumumab (control group, n = 217) versus modified fluorouracil, leucovorin, oxaliplatin, irinotecan (mFOLFOXIRI)/panitumumab (experimental group, n = 218). We present overall survival (OS) and updated outcomes in the intention-to-treat population. The median follow-up was 60.2 months (IQR, 49.3-70.0). The median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049). OS outcomes favored the experimental group regardless of clinical features. No differences in objective response rate (primary end point; 75%/78%, odds ratio, 0.84 [95% CI, 0.54 to 1.31]; P = .442), early tumor shrinkage rate (P = .954), depth of response (P = .573), no residual tumor resection rate (P = .329), and progression-free survival (HR, 0.95 [95% CI, 0.78 to 1.16]; P = .606) were confirmed. Among patients alive at the time of disease progression, the median postprogression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%), as well as nonpalliative locoregional treatments (control/experimental: 16%/16%). Upfront mFOLFOXIRI/panitumumab significantly improves OS compared with mFOLFOX/panitumumab in patients with RAS/BRAF wild-type mCRC.

BACKGROUND Colorectal cancer is a major public health issue, with liver metastasis marking a critical and prognostically significant pathway for disease progression. This meta-analysis evaluated the association between surgical intervention for colorectal liver metastases and survival outcomes to inform multidisciplinary treatment decisions. We performed a thorough search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from their inception until February 1, 2024. Included studies enrolled at least 20 patients and compared overall survival (OS) and/or progression-free survival (PFS) between surgical and non-surgical management, reporting hazard ratios (HRs) with 95% confidence intervals (CIs) or providing sufficient time-to-event data to estimate HRs. We pooled HRs using a random-effects model. Of 2935 records, 67 studies involving 368380 patients were included, most of which were retrospective cohorts. Surgical resection was associated with improved OS (pooled HR = 0.38, 95%CI: 0.34-0.43) and PFS (pooled HR = 0.46, 95%CI: 0.31-0.66). Subgroup analyses indicated a consistent direction of association across several study-level characteristics. Given substantial heterogeneity and the predominance of observational data, residual confounding by indication cannot be excluded; therefore, pooled estimates should be interpreted as associations in selected patients. Prospective studies incorporating contemporary systemic therapy and tumor biology are warranted to refine patient selection and treatment sequencing. AIM To provide an aggregate prognostic value for surgery for liver metastases, incorporating HRs with 95%CIs from multivariate or univariate analyses available in the included studies. METHODS Sensitivity analysis was conducted even with meta-regression based on participant ethnicity (Asian vs non-Asian), number of patients, median follow-up, publication year (pre-2015 vs 2015-2024), paper quality (high vs low), and study design (retrospective vs prospective). Heterogeneity among studies was assessed using Cochran’s Q test, with P < 0.05 or I 2 > 50% indicating significant heterogeneity, in which case a random-effects model (Der Simonian-Laird method) was applied. Otherwise, a fixed effects model was used. HR < 1 indicated improved survival in patients undergoing resection of liver metastases. Data were analyzed using the Review Manager (RevMan) software, version 5.4, The Cochrane Collaboration, 2020. Publication bias and small-study effects were assessed by visual inspection of funnel plots, Egger’s regression test, and rank-correlation testing; Duval and Tweedie’s trim-and-fill method was applied as a sensitivity analysis. Clinically, the attenuation of the pooled effect estimate after trim-and-fill adjustment suggests that the magnitude of survival benefit associated with surgery may be partially overestimated due to small-study effects or selective publication. However, the direction of the association remained consistent, supporting an association between surgical resection and improved survival in carefully selected patients. RESULTS Of the 2935 records identified, 67 studies with data from 368380 patients (ranging from 21 to 72376) were included in the meta-analysis. Most of the included studies (55 out of 67) were retrospective series, whereas 12 out of 67 were prospective (either clinical trials or prospective cohorts). The treatment strategies in the included studies consisted of upfront surgery followed by adjuvant therapy or preceded by neoadjuvant or conversion therapy (including three studies in which patients received hepatic artery infusion chemotherapy). Data regarding systemic therapies were unavailable for 17 studies. Data on the overall resection rate were available for 62 of the 67 studies. Resection rates ranged from 8% to 100% (median, 45%), whereas R0 resections ranged from 2% to 87% (median, 14%). The median follow-up period ranged from 4 months to 120 months (median, 37 months); however, it was not available in 42% of the papers. CONCLUSION Among the evaluable studies, the publication quality was classified as low (36%), moderate (46%), or high (18%). The association between surgery for colorectal liver metastases and survival outcomes is described in subsequent sections. Outcomes were analyzed using multivariate analysis in 90% of the cases.

BACKGROUND:International guidelines recommend 5FU/LV, Nal-IRI + 5FU/LV, FOLFIRI, FOLFOX, or (m)FOLFIRINOX as second-line (2L) chemotherapy for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after failure of gemcitabine+Nab-paclitaxel (GnP). However, a head-to-head comparison has not been performed. PATIENTS AND METHODS:We conducted an observational cohort study of consecutive mPDAC patients treated with 2L chemotherapy after GnP failure at 41 Italian centers. Progression-free survival (PFS) and overall survival (OS) were compared using inverse probability of treatment weighting. Interpretable artificial intelligence methods were applied to optimize treatment allocation. A counterfactual Cox model was trained on baseline characteristics to estimate 12-month PFS under each regimen, and an Optimal Policy Tree (OPT) was derived to generate treatment recommendations, validated in a test set. Net-benefit curves evaluated clinical utility. RESULTS:Among 704 eligible patients, 56 (8.0%) received 5FU/LV, 153 (21.7%) FOLFIRI, 209 (29.7%) FOLFOX, 209 (29.7%) Nal-IRI + 5FU/LV, and 77 (10.9%) FOLFIRINOX. FOLFIRINOX was associated with the longest PFS and OS. Median PFS was comparable among doublets (3.5 months FOLFOX, 3.6 FOLFIRI, 3.3 Nal-IRI + 5FU/LV), though Nal-IRI + 5FU/LV showed a long-term benefit. The OPT recommended Nal-IRI + 5FU/LV for patients with head/body tumors, Eastern Cooperative Oncology Group performance status (PS) 0, or CA19.9 < 109 U/mL in those with PS > 0. Net-benefit analysis showed that the OPT consistently outperformed uniform treatment strategies, achieving a 2.5 percentage-point net benefit at a threshold probability of ∼9%. CONCLUSIONS:FOLFIRINOX appears the most effective option for carefully selected, fit patients eligible for 2L chemotherapy after GnP failure. Interpretable artificial intelligence-derived treatment policies may provide superior net clinical benefit compared to uniform approaches and guide individualized therapy, warranting integration with upcoming targeted strategies such as RAS inhibitors.

BACKGROUND:Antibody-drug conjugates (ADCs) are increasingly used across solid tumors, including lung cancer, but drug-related interstitial lung disease (ILD)/pneumonitis has emerged as a clinically relevant and potentially fatal toxicity. METHODS:This narrative review summarizes evidence from clinical trials, pooled analyses, pharmacovigilance studies, mechanistic investigations, and consensus recommendations on the epidemiology, pathophysiology, diagnosis, risk factors, and management of ADC-related ILD. RESULTS:ILD has been most extensively characterized with trastuzumab deruxtecan (T-DXd), for which pooled analyses report an incidence of approximately 10-15%, a median onset of 5-6  months, and a fatal-event rate of about 2.2%. However, pulmonary toxicity is not restricted to HER2-directed ADCs and has also been reported with deruxtecan-based agents targeting TROP2 and HER3, as well as with non-deruxtecan ADCs. Pharmacovigilance data from 1,277 cases showed that ILD, pneumonitis, and acute respiratory distress syndrome accounted for 40.6%, 27.9%, and 7.6% of pulmonary events, respectively; acute respiratory distress syndrome had the earliest onset and highest case-fatality. Mechanistic data support antigen-independent, dose-dependent ADC uptake by alveolar macrophages through Fcγ receptors, followed by intracellular payload release and cytokine-mediated lung injury. Risk is influenced by ADC type, payload, dose, age, pre-existing lung disease, and concomitant pulmonary-toxic therapies. CONCLUSIONS:ADC-related ILD is a class-relevant toxicity requiring baseline risk assessment, serial high-resolution chest computed tomography, prompt treatment interruption, grade-based corticosteroid therapy, and multidisciplinary management. Structured surveillance and early intervention may substantially reduce severe and fatal outcomes.

The gut microbiome has emerged as a critical determinant of immune-checkpoint inhibitor (ICI) efficacy. A narrative review of 95 clinical studies (2015–2025) shows that patients with greater gut microbial diversity and relative enrichment of commensals such as Akkermansia, Ruminococcus, and other short-chain fatty acid producers experience longer progression-free and overall survival, particularly in melanoma and non-small-cell lung cancer. Broad-spectrum antibiotics given within 30 days of ICI initiation and over-the-counter mixed probiotics consistently correlate with poorer outcomes. Early phase I/II trials of responder-derived fecal microbiota transplantation in ICI-refractory melanoma achieved objective response rates of 20–40%, while pilot high-fiber or plant-forward dietary interventions improved immunologic surrogates such as CD8+ tumor infiltration. Machine-learning classifiers that integrate 16S or metagenomic profiles predict ICI response with an area under the ROC curve of 0.83–0.92. Methodological heterogeneity across sampling, sequencing, and clinical endpoints remains a barrier, underscoring the need for standardization and larger, well-powered trials.