Search Results (4,677)

Early-onset colorectal cancer is increasing, making reproductive health an increasingly relevant survivorship issue. While immune checkpoint inhibitors have altered the management of deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) colorectal cancer, their implications for reproductive-age women remain insufficiently defined. We performed a focused narrative review, structured in line with the SANRA framework, to clarify this specific clinical domain. Immunotherapy may reshape female oncofertility counseling through two distinct mechanisms: direct reproductive uncertainty, including established endocrine toxicities and hypothesized, but currently unproven, direct gonadal effects; and indirect pathway-modifying effects, such as the potential avoidance of pelvic radiotherapy or radical surgery in selected patients with locally advanced dMMR/MSI-H rectal cancer. Anatomical organ preservation should not be automatically equated with functional fertility preservation. The key clinical message is that reproductive counseling should not be restricted to historically gonadotoxic chemotherapy. Instead, early multidisciplinary guidance should explicitly distinguish CRC-specific evidence from extrapolated or theoretical concerns, integrate fertility preservation strategies when clinically feasible, and address pelvic and sexual health, contraception, washout, endocrine follow-up, and future pregnancy planning. Until prospective CRC-specific reproductive data become available, immunotherapy should not be presented as either reproductively neutral or fertility-preserving. Full article

Background/Objectives: Despite standard perioperative chemotherapy, recurrence remains frequent in resectable gastric cancer (GC). We investigated the clinical impact of integrating immunotherapy into the neoadjuvant component of perioperative treatment, particularly on pathological complete response (pCR), in this setting. Methods: We conducted a systematic review and meta-analysis of phase II–III trials and real-world studies evaluating immune checkpoint inhibitors (ICIs) added to perioperative chemotherapy versus chemotherapy alone in resectable GC. Two independent reviewers screened PubMed and Scopus; review articles and single-arm studies were excluded. Pooled odds ratios (ORs) were estimated using random-effects models, and heterogeneity was assessed with the I² statistic. Overall, six studies including 2890 patients were analyzed. Results: The addition of ICIs significantly enhanced tumor regression, increasing ypT0–T2 rates (OR 1.61, 95% CI 1.11–2.33; p = 0.012) and reducing ypT3–T4 residual disease (OR 0.62, 95% CI 0.44–0.87; p = 0.0051). A favorable trend toward nodal downstaging was observed (ypN0–1 OR 1.57; ypN2–3 OR 0.60), although these differences did not reach statistical significance. Notably, pathological complete response (pCR) rates more than tripled with chemo-immunotherapy (OR 3.39, 95% CI 2.21–5.20; I² = 38.9%; p < 0.0001). The magnitude of benefit was particularly striking in PD-L1-positive tumors (OR 3.26; p < 0.0001). pCR improvement was strongest with PD-1 inhibitors (OR 4.10; p < 0.0001), while remaining significant with PD-L1 inhibitors (OR 2.62; p < 0.0001). Treatment benefit was consistent across age groups (<65 and ≥65 years) and performance status (ECOG PS 0–1). R0 resection rates were not significantly different. Conclusions: Overall, the addition of ICIs to perioperative chemotherapy substantially increases pathological response and tumor downstaging in resectable GC. These findings support further investigation of immunotherapy-based perioperative strategies. However, the present evidence is mainly driven by pathological endpoints, and the role of pCR as a surrogate for long-term survival in gastric cancer remains uncertain. Therefore, mature survival data are needed before definitive conclusions regarding clinical practice can be drawn. Full article

Background/Objectives: Metastases from cutaneous malignancies to the female genital tract and pelvic lymph nodes are rare clinical entities that frequently masquerade as primary gynecologic tumors, leading to significant diagnostic challenges. The distinction between primary and metastatic disease is critical, yet complex, given the varying patterns of spread exhibited by different skin cancers. This study aims to provide a tumor-specific overview of these metastatic patterns to guide diagnosis and therapy. Methods: We conducted a narrative review informed by a systematic literature search of MEDLINE/PubMed, Embase, Scopus, and Web of Science for records regarding primary cutaneous melanoma, cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), Merkel cell carcinoma (MCC), and cutaneous lymphomas metastasizing to the female genital tract (FGT) or pelvic lymph nodes. Data were synthesized qualitatively to identify organotropic patterns, diagnostic pitfalls, and management outcomes across these distinct malignancies. Results: The analysis reveals distinct metastatic niches: cutaneous melanoma shows a predilection for the ovary, often mimicking epithelial ovarian carcinoma, whereas cSCC and MCC typically involve pelvic lymph nodes via contiguous spread from inguinal basins. Histologic evaluation with broad immunohistochemical panels is mandatory to confirm the diagnosis, as imaging alone lacks specificity. Crucially, the introduction of immune checkpoint inhibitors and targeted therapies has significantly improved survival in advanced melanoma, cSCC, and MCC, altering the role of pelvic surgery. Conclusions: Management of cutaneous malignancies metastatic to the pelvis is shifting from a focus on radical surgery to a systemic-first approach. Pelvic metastasectomy should be reserved for selected oligometastatic cases or symptom control within a multidisciplinary framework. Clinicians must maintain a high index of suspicion in patients with a history of skin cancer to avoid overtreatment and optimize quality of life. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC), the predominant malignant subtype of kidney cancer, is the leading cause of death among renal cell carcinoma patients. Although a subset of ccRCC patients benefit from select immune checkpoint inhibitors (ICIs), prognosis remains poor. While PD-1 and PD-L1 have been extensively studied, the prevalence and distribution of other immune checkpoints (ICs) and their relationship with epithelial-to-mesenchymal transition (EMT) remain poorly characterised. Here, we investigated the interplay between twenty ICs and EMT markers and assessed their combined prognostic relevance in ccRCC patients. Methods: Transcriptomic profiling and integrated bioinformatic analyses were performed, including differential expression, correlation analyses, survival analyses, forest plot analyses, ROC curve evaluation, and OncoPrint visualisation, complemented by analysis of single-cell RNA sequencing data, immunohistochemistry, and multiplex secretory IC (LegendPlex) assays. Results: Transcriptomic profiling of over 500 ccRCC tumours versus normal kidney tissue revealed dysregulation of ICs, particularly LAG3 and NT5E. Notably, expression of ICs, including LAG3 and NT5E, was associated with poor overall survival in 415 ccRCC patients. ICs that synergised with the EMT phenotype provided improved prognostic discrimination compared to individual ICs. Correlation analyses, single-cell RNA sequencing, and immunohistochemistry demonstrated an association between EMT-associated tumours and expression of LAG3 and NT5E. ROC analysis indicated modest prognostic performance of LAG3 and NT5E. Conclusions: Collectively, this study identifies an EMT–IC axis in ccRCC and demonstrates its relevance to tumour biology and patient outcomes, highlighting LAG3 and NT5E as potential prognostic markers and therapeutic targets that warrant further investigation. Full article

This study develops a stochastic queueing framework to model the dynamical interaction between proliferating tumor cells and the adaptive immune system, incorporating the critical phenomenon of immune checkpoint inhibition. The immune response is conceptualized as a multi-server service system where CD8+ T cells and natural killer cells act as parallel servers eliminating cancerous cells, while tumor cell division follows a controlled birth process with logistic growth constraints. The novelty lies in embedding a state-dependent immune evasion mechanism through a dimensionless checkpoint parameter $\kappa \in [0,1]$ that modulates the effective killing rate as a function of tumor burden via the saturation function $\varphi \left(n\right)=n/(K+n)$. The resulting process $\left\{N\right(t),t\ge 0\}$ constitutes a non-homogeneous birth–death Markov chain with the following transition rates: $\begin{array}{ccc}\hfill {\lambda }_n& =\lambda \left(1-{\displaystyle \frac{n}{K}}\right){\mathbb{1}}_{\{n<K\}},{\mu }_n\hfill & \hfill =\left\{\begin{array}{cc}n\mu (1-\kappa \varphi (n\left)\right),\hfill & 1\le n<c,\hfill \\ c\mu (1-\kappa \varphi (n\left)\right),\hfill & n\ge c,\hfill \end{array}\right.\end{array}$ We derive the exact stationary distribution in closed form, establishing the fundamental stability condition ${\rho }_{\mathrm{eff}}=\lambda /\left[c\mu (1-\kappa )\right]<1$ for tumor elimination. The expected tumor burden L and mean elimination time W are computed explicitly. A critical threshold ${\kappa }_c=1-\lambda /\left(c\mu \right)$ emerges, above which the immune system loses control regardless of other parameters. Heavy-traffic analysis reveals quadratic divergence $L\sim K/{(1-{\rho }_{\mathrm{eff}})}^2$ as ${\rho }_{\mathrm{eff}}\to 1^{-}$, explaining catastrophic tumor escape. Extensive Monte Carlo simulations ($n={10}^4$ replications) validate theoretical predictions with relative errors <5% and p-values $>0.05$ from two-sample t-tests. The model provides quantitative tools for optimizing checkpoint inhibitor dosages and predicting patient-specific responses in immuno-oncology. Full article

Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal and heterogeneous primary liver malignancy with a dismal prognosis. Approximately 70% of patients are diagnosed at locally advanced or metastatic stages, therefore missing the opportunity for curative surgery, and conventional chemotherapy offers limited survival benefits. Immunotherapy, especially immune checkpoint blockade, represents a promising strategy, yet its efficacy as monotherapy in iCCA remains modest primarily due to the profoundly immunosuppressive and desmoplastic tumor microenvironment. This review examines the immune cell infiltration landscape of iCCA, focusing on the distinct roles of lymphoid cells and myeloid cells in shaping immune evasion. We then analyze key factors affecting immune responses, such as tumor-intrinsic driver mutations, immune regulatory mechanisms, and acquired resistance. Furthermore, we summarize current clinical advances in iCCA immunotherapy, including immune checkpoint inhibitor monotherapy, bispecific antibodies, combination strategies with chemotherapy or targeted therapy, cancer vaccines, and adoptive cell therapy. Despite some progress, the overall response to immunotherapy remains suboptimal, and future strategies need to focus on deciphering context-specific resistance mechanisms and enhancing the tumor-specific immune response. Full article

Immune checkpoint inhibitor (ICI)-based combinations have become central systemic treatment options for advanced hepatocellular carcinoma (HCC) and are now being integrated into selected intermediate-stage settings. As tumor responses have improved, some patients who were not initially candidates for curative-intent treatment may later become candidates for resection, ablation, or liver transplantation. However, radiographic response alone does not define curative-intent candidacy, and no shared framework currently guides how post-immunotherapy response should be translated into a treatment decision. Terminology also differs regionally: Asian literature frames a resection-anchored paradigm, whereas Western practice uses transplant-anchored downstaging. This narrative review proposes a multidisciplinary framework for immunotherapy-based conversion to curative-intent treatment in HCC. We first clarify the lexicon of conversion, downstaging, bridging, neoadjuvant therapy, post-ICI transplantation, and drug-free or treatment-free status. We then summarize conversion-relevant evidence across key clinical decision settings, including transarterial chemoembolization (TACE)-unsuitable intermediate-stage disease, portal vein tumor thrombus or macrovascular invasion, borderline-resectable or locally advanced disease, and transplant downstaging or bridging. The central framework defines curative-intent transition through the intersection of three domains: technical suitability, oncologic suitability, and physiologic or liver-reserve suitability. Biomarkers, imaging response, tumor-marker kinetics, liver function, and treatment-related toxicity are discussed as inputs into candidacy rather than as response measures alone. Finally, we propose a multidisciplinary workflow and highlight lessons from pancreatic cancer, biliary tract cancer, and colorectal liver metastases. As an expert-opinion-based framework, this approach should structure multidisciplinary discussion rather than serve as validated selection criteria; harmonized terminology, prospective conversion registries, and conversion-specific endpoints are needed for prospective validation. Full article

Background: Carbon-ion radiotherapy (CIRT) is an effective local treatment for hepatocellular carcinoma (HCC); however, evidence on systemic immunotherapy after CIRT and the role of CIRT following immunotherapy remains limited. This study aimed to assess clinical outcomes and sequencing of CIRT and systemic immunotherapy in real-world practice. Methods: We retrospectively analyzed 41 patients with HCC who received CIRT and systemic immunotherapy (atezolizumab plus bevacizumab or durvalumab plus tremelimumab). Patients were categorized into three groups: (i) systemic immunotherapy for recurrent HCC after CIRT (n = 20), (ii) curative-intent CIRT after systemic immunotherapy (n = 10), and (iii) CIRT for residual or insufficiently responding lesions (≤3 lesions) after systemic immunotherapy (n = 11). Results: In group (i), 14 of 20 patients achieved complete or partial responses. These responders had low tumor burden (within the up-to-7 criteria) and preserved liver function (modified albumin–bilirubin grade 1/2a) at treatment initiation and demonstrated significantly longer progression-free and overall survival than those with stable or progressive disease. In group (ii), 4 of 10 patients achieved a clinical complete response and became drug-free; notably, all had solitary intrahepatic tumors at immunotherapy initiation. In group (iii), the rate of transition to clinical complete response was low, and disease control remained limited. Conclusions: Systemic immunotherapy demonstrated high effectiveness in recurrent HCC following CIRT, particularly in patients with low tumor burden and preserved liver function. Moreover, curative-intent CIRT after immunotherapy may benefit patients with solitary intrahepatic tumors but appears limited in those with insufficient response to immunotherapy, including residual oligolesions. Full article

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC). However, many patients eventually develop resistance to systemic therapy, highlighting the need for novel strategies that can restore or sustain antitumor immunity. Near-infrared photoimmunotherapy (PIT) has emerged as a tumor-selective locoregional treatment that not only induces targeted tumor cell death but also promotes antitumor immune activation through immunogenic cell death. This narrative review summarizes current evidence regarding PIT for recurrent oral cancer and explores the immunological rationale for sequential ICI–PIT–ICI therapy (ICI–PIT–ICI sequence). Within this framework, PIT-induced tumor antigen release and inflammatory activation may reinitiate elements of the cancer-immunity cycle, whereas continued PD-1 blockade may help sustain newly activated tumor-reactive T-cell responses. To illustrate this concept, we present two cases of recurrent oral cancer treated with the ICI–PIT–ICI sequence. Both patients achieved durable clinical and radiological complete responses following PIT and subsequent nivolumab continuation. Longitudinal analyses of peripheral immune surrogate markers demonstrated a biphasic temporal pattern characterized by transient increases in inflammatory markers, including neutrophil-to-lymphocyte ratio, C-reactive protein, platelet-to-lymphocyte ratio, and systemic immune-inflammation index, followed by recovery trends in absolute lymphocyte count and lymphocyte-to-monocyte ratio during continued PD-1 blockade. These observations support the biological plausibility of PIT as an immune-modulating intervention with potential immune-reprogramming effects. Although hypothesis-generating, the ICI–PIT–ICI sequence may represent a promising strategy integrating locoregional tumor destruction with systemic immune modulation in recurrent oral cancer. Further prospective studies incorporating peripheral and tissue-based immune profiling are warranted. Full article

Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a “lipid peroxidation threshold” framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision “threshold engineering” that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells. Full article

Mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers exhibit high mutational burden and abundant neoantigen formation, generating a highly immunogenic tumour microenvironment characterised by dense lymphocytic infiltration and strong sensitivity to immune checkpoint inhibition. In metastatic colorectal cancer, PD-1 blockade produces durable responses almost exclusively in dMMR tumours, establishing mismatch repair status as a predictive biomarker for immunotherapy responsiveness. Recent studies extending immune checkpoint inhibitors (ICIs) into the neoadjuvant setting for localised dMMR colorectal cancer have produced major pathological response rates exceeding 90%, with pathological complete response (pCR) rates frequently surpassing 60%, challenging traditional oncologic staging frameworks, particularly with respect to lymph node assessment. Baseline clinical nodal staging in dMMR tumours is complicated by immune-mediated lymphadenopathy. Reactive lymphoid hyperplasia driven by tumour antigen exposure frequently produces enlarged lymph nodes that mimic metastatic disease on cross-sectional imaging. Following neoadjuvant immunotherapy, treatment-related immune activation may further increase nodal size or metabolic activity, while pathological examination often reveals sterilised nodes or immune infiltration without viable tumour. Consequently, conventional radiologic criteria for nodal metastasis demonstrate limited specificity in this context. The discordance between imaging findings and pathological outcomes raises important implications for staging accuracy, response assessment, and treatment planning. This review examines the biological basis of lymphatic involvement in dMMR colorectal cancer, evaluates the performance of current imaging modalities for nodal staging, and summarises emerging evidence from neoadjuvant immunotherapy trials. Particular emphasis is placed on the interpretation of lymph node findings in the era of immune checkpoint blockade and the implications for surgical decision-making, organ preservation, and future staging paradigms. Full article

Opioids are frequently prescribed for cancer pain management, yet accumulating evidence suggests that opioid exposure may be associated with inferior outcomes in patients also undergoing treatment with immune checkpoint inhibitors (ICIs). To synthesize mechanistic and clinical evidence linking opioids to the PD-1/PD-L1 axis, the literature was searched up to 18 January 2026, with study selection and data extraction focused on (i) cancer-cell and immune-cell effects of opioid agonism or antagonism on PD-1/PD-L1 biology, and (ii) clinical studies reporting ICI outcomes (progression-free survival, overall survival, or treatment duration) with concomitant opioid exposure. Preclinical studies support multiple, non-mutually exclusive mechanisms: opioids can induce PD-L1 in tumour cells, modulate innate-inflammatory pathways (including TLR4-linked cascades), promote dysfunctional T-cell phenotypes that reduce responsiveness to PD-1 blockade, and show context- and opioid-dependent effects. Clinical cohorts and meta-analytic datasets in non-small cell lung cancer and other tumour types report associations between opioid exposure (including higher morphine-equivalent dosing) and worse ICI outcomes. The intersection of opioid signaling with PD-1/PD-L1 biology likely operates across cancer cell-intrinsic and immune cell-intrinsic pathways, providing a mechanistic rationale for prospective evaluation of opioid-sparing strategies and/or peripheral opioid antagonism as adjuncts to checkpoint blockade. Full article

Imaging techniques used for the care of cutaneous melanoma patients have greatly changed over the past century, from symptom-driven radiography toward a multimodality framework integrated for staging, directing surgery, and systemic therapy, and surveillance. Historically, clinical evaluation and skin exams have been the tenets of melanoma diagnosis and staging. In recent years, noninvasive imaging, such as dermoscopy, total-body photography and reflectance confocal microscopy, has expanded the diagnostic toolset for primary melanoma detection. Concurrently, several imaging techniques have been developed to detect metastases and follow disease progression, including computed tomography (CT), magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), lymphoscintigraphy, and single-photon emission computed tomography/computed tomography (SPECT/CT). The use of immune checkpoint inhibitors has also altered imaging interpretation by introducing atypical response patterns, including pseudoprogression, requiring immune-adapted assessment frameworks such as Immune Response Evaluation Criteria in Solid Tumors (iRECIST). While there is a strong consensus for high-risk patients, imaging techniques and surveillance schedules for low-risk patients (stage I/II) remain controversial due to limited supporting evidence and conflicting data on costs and patient benefit. The development of new technologies, including image-guided surgery, non-FDG PET tracers, phone apps, artificial intelligence-assisted image analysis, and radiomics, may further change melanoma imaging. The aim of this review is to detail the historical evolution of melanoma imaging, the development of new imaging techniques, and their role and future in clinical practice. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs), including rheumatic manifestations affecting 5–10% of treated patients. Managing rheumatic irAEs is challenging, as the use of glucocorticoids (GCs) or disease-modifying antirheumatic drugs (DMARDs) raises concerns about potentially impairing ICI antitumour efficacy. The oncological safety of DMARDs used specifically for rheumatic irAE management remains poorly characterised. Our objective was to evaluate the oncological safety profile of various rheumatic irAE treatment strategies. Methods: This single-centre retrospective observational study included 55 patients out of 104 who underwent rheumatological evaluation between July 2016 and October 2022. Patients were categorised into three groups: symptomatic treatment alone (analgesics/NSAIDs, n = 11), systemic glucocorticoids (GCs) only (n = 27), and conventional synthetic or biological disease-modifying antirheumatic drugs (csDMARDs and/or bDMARDs, n = 17). Overall survival (OS) and progression-free survival (PFS) were compared using a Kaplan–Meier analysis. Results: The three most frequent rheumatic irAE patterns were undifferentiated arthritis (n = 20), rheumatoid arthritis-like presentations (n = 14), and polymyalgia rheumatica (n = 11). Patients in the DMARD group had more severe irAEs (CTCAE grade ≥3: 30% vs. 15%, p < 0.01) and a higher baseline CRP (27.5 vs. 17.4 mg/L, p < 0.05), reflecting greater disease burden at treatment initiation. No significant difference was observed between groups for OS (p = 0.22) or PFS (p = 0.31) over a median follow-up of 34 months. Conclusions: No detrimental oncological safety signal was identified across rheumatic irAE treatment strategies, including GCs combined with csDMARDs or bDMARDs. These results support the cautious use of DMARDs as GC-sparing agents when clinically indicated, consistent with current EULAR and ESMO guidelines, and underline the need for prospective trials to optimise immunosuppressive management in ICI-treated patients. Full article

Rare subtypes of gastroesophageal malignancies represent a small but biologically meaningful fraction of upper gastrointestinal cancers. Although most therapeutic algorithms are derived from conventional squamous cell carcinoma and adenocarcinoma, uncommon entities such as variants of squamous cell carcinoma, lymphoepithelioma-like carcinoma, adenosquamous carcinoma, neuroendocrine carcinoma, and others display distinct clinicopathologic, immunologic, and molecular features that may influence prognosis and therapeutic decision-making. This review synthesizes current evidence regarding the epidemiology, histopathology, molecular alterations, and emerging therapeutic vulnerabilities across these rare subtypes. Importantly, these tumors frequently exhibit aggressive clinical behavior and are often managed by extrapolation from more common histologies due to the absence of prospective data. Increasing integration of genomic profiling, immune characterization, and biomarker-driven stratification is essential to refine diagnoses, expand precision therapeutic strategies, and improve outcomes. Recognition of these rare subtypes in routine practice is critical, as even small molecularly defined populations may carry disproportionate biological and translational significance within oncology. Full article