Programmed death ligand-1 (PD-L1) is a widely used biomarker for immunotherapy in melanoma. The expression of PD-L1 in melanoma cells is known to vary considerably among and within patients' tumor samples. Recent studies suggest that there may be a link between PD-L1 expression and the differentiation status of melanoma cells which is known to fluctuate in response to external stimuli and to be influenced by a multitude of regulators. Here, we systematically review which differentiation regulators affect PD-L1 expression in melanoma.

Deep learning methods, including deep representation learning (DRL) approaches such as variational autoencoders (VAEs), have been widely applied to cancer omics data to address the high dimensionality of these datasets. Despite remarkable advances, cancer is a complex and dynamic disease, making it challenging to study, and the temporal resolution of cancer progression captured by omics-based studies remains limited. In this systematic literature review, we explore the use of DRL, particularly the VAE, in cancer omics studies for modeling time-related processes, such as tumor progression and evolutionary dynamics. Our work reveals that these methods most commonly support subtyping, diagnosis, and prognosis in this context, but rarely emphasize temporal information. We observed that the scarcity of longitudinal omics data currently limits deeper temporal analyses that could enhance these applications. We propose that applying the VAE as a generative model to study cancer in time, particularly focusing on cancer staging, could lead to meaningful advancements in our understanding of the disease.

Early detection of colorectal cancer (CRC) via population-based screening programs can reduce incidence and mortality. Current screening approaches are limited by cost, accessibility, compliance, and colonoscopy capacity. Blood-based screening of circulating tumor (ct) DNA may resolve some of these limitations. This systematic review evaluated the screening potential of blood-based ctDNA assays in asymptomatic screening populations. We systematically searched the PubMed database (final search June 20th, 2025) for studies detecting advanced adenomas (AAs) or CRC in asymptomatic cohorts, where a blood-based ctDNA assay had been evaluated with data on specificity, sensitivity, and/or AUC at early stages of disease. Newcastle-Ottowa scale was used for quality assessment. Only 20 studies of 454 unique hits met our inclusion criteria. Of these, 12 studies used assays targeting specific DNA alterations, while the remaining 8 studies used complex assays. Generally, comprehensive assays such as Shield, ColonSecure, and FMBT-CRC had the best performance for early-stage CRC detection with sensitivities of 71%-85% and specificities of 88%-90%. Despite being tested in a small cohort, the Coloscape assay was the only assay to reach sufficient AA detection with 59% sensitivity and 92% specificity. None of the reviewed ctDNA assays demonstrated sufficient sensitivities for both AA and early-stage CRC detection to be considered future screening tools. Screening tools based on ctDNA assays have not proved superior to fecal-based immunochemical test (FIT) yet. Future studies need to test ctDNA screening tools in large, prospective, asymptomatic cohorts emphasizing AA, and early-stage CRC.

Background: POLE-mutated endometrial carcinomas are associated with exceptionally favorable outcomes, forming the basis for treatment de-escalation in early-stage disease. Nevertheless, rare adverse clinical courses have been reported. This study describes an unusual case of late metastatic recurrence in a POLE-mutated tumor and provides a review of similar cases in the literature. Methods: We present a detailed clinical, radiological, pathological, and molecular description of a patient who developed metastatic recurrence 16 years after initial surgery. A systematic literature search was conducted to identify reports of recurrence, progression, or cancer-related death in POLE-mutated endometrial carcinoma, with extraction of recurrence patterns, genomic features, treatment, and outcomes. Results: The patient experienced sequential pulmonary, cerebral, and leptomeningeal metastases despite harboring a canonical POLE hotspot mutation, proficient mismatch repair status, wild-type TP53, no additional known driver mutation beyond PTEN alterations. The literature review identified a small number of similarly adverse cases. Reported recurrences were heterogeneous, though distant and occasionally central nervous system involvement were noted. Conclusions: While POLE-mutated tumors overall retain an excellent prognosis, rare cases may follow an atypical and aggressive course. Improved molecular annotation and integrated risk-stratification models are needed to better identify this minority of higher-risk patients.

Tumour mutation burden (TMB) is an emerging pan-cancer biomarker with predictive value for immune checkpoint inhibitor (ICI) outcomes, yet evidence is inconsistent due to methodological variability and cut-off thresholds. This systematic review and meta-analysis evaluated the impact of TMB on overall survival (OS) and progression-free survival (PFS) across solid tumours in ICI-treated cohorts and its predictive relevance in non-ICI-treated cohorts.

The application of immune checkpoint inhibitors (ICIs) in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following tyrosine kinase inhibitor (TKI) resistance remains controversial. Prior studies often obscured immunobiological heterogeneity by analyzing exon 19 deletions and L858R mutations in aggregate. This study conducts the first meta-analysis specifically focusing on the EGFR L858R subtype to systematically evaluate ICI efficacy (monotherapy vs. combinations) in the post-TKI setting.

Tumor mutational burden (TMB) is a predictive biomarker for immune checkpoint inhibitors (ICIs). Its clinical utility in head and neck squamous cell carcinoma (HNSCC) is limited by differences in detection approaches and inconsistent cut-off values. In this meta-analysis, we systematically reviewed multiple high-quality studies to assess the predictive value of tissue-based TMB (tTMB) and blood-based TMB (bTMB) for treatment response of ICIs.

Lynch syndrome predisposes to multiple cancer types, including urological malignancies. However, no evidence-based recommendations for surveillance of urological malignancies currently exist. In this systematic review, we aim to describe the current evidence regarding surveillance for these cancers. A systematic literature search was conducted using MEDLINE, searching for urological malignancies, Lynch syndrome, and surveillance including the results of the surveillance methods. Sensitivity and specificity were calculated, when possible, preferably for pooled data from each surveillance method. The risk of bias was assessed using the Newcastle–Ottawa Scale. After full text-screening, nine studies published in 2008–2025 met the inclusion criteria, including two on prostate cancer and seven on urothelial cancer. Prostate cancer-antigen (PSA) surveillance led to 38 prostate cancer diagnoses in 865 individuals with Lynch syndrome, with 71% being clinically significant prostate cancers. In 1564 individuals, 11 urothelial carcinomas were diagnosed by different surveillance methods and 15 diagnoses were missed. Sensitivity of urinalysis, urine cytology, urine MSI, and CT and cystoscopy was 11%, 30%, 100%, and 100% respectively. Specificity was 90%, 97%, 99%, and 100% respectively for these methods. Further data is needed but for prostate cancer surveillance PSA shows promise, while for MSH2 carriers at least, urine microsatellite instability analysis shows promise as a urothelial cancer surveillance test.

The clinical relevance of HER2 expression profile in solid cancers has expanded with the evolving landscape of HER2 targeting agents. This systematic review and meta-analysis aim to detail the prevalence of HER (over)expression in prostate cancer and identify patient/disease subgroups with enriched HER2 overexpression.

Clinical application of chimeric antigen receptor (CAR)-T cells, especially those targeting CD19, stands as a breakthrough in treating relapsed or refractory B-cell acute lymphoblastic leukemia. Yet, preventing immune-related adverse events, like severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remains a significant concern. This meta-analysis looked at the efficacy and safety of interleukin-6 knockdown CAR-T therapy. The study's primary outcomes included the incidence of CRS, ICANS, and the number of patients achieving an early complete response (CR) and overall response (OR) rates at one-month post-infusion of anti-CD19 shRNA-engineered CAR-T cells. The random-effects model was used to estimate summary effects. Certainty of evidence was assessed using GRADE. Out of 275 studies screened, 7 studies were eligible (n = 178 patients). The pooled OR and CR rates were 88% (95% CI: 81-92) and 84% (95% CI: 78-89), respectively, with no heterogeneity detected. Among 147 patients, 116 (78%, 95% CI: 68-85) developed CRS, whereas 46 (28%, CI: 21%-35%) out of 178 were affected by severe grades (≥3). While ICANS was detected in 13 out of 159 patients (13%, CI: 2%-51%, I2 = 69.5%), three studies confirmed the absence of severe grade ICANS. According to GRADE assessment, current analysis presents low certainty of evidence supporting investigated outcomes, except for ICANS (any grade) that was deemed very low. More importantly, as all included studies were conducted in China, the findings may not be readily generalizable to other healthcare systems and ethnically diverse populations. Therefore, our confidence in the effect estimates is limited and it may vary from true estimates.

To characterize the clinical, histopathologic, and molecular-genetic characteristics of Lynch syndrome (LS)-associated gastrointestinal disease in the pediatric population.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer due to its strong resistance to chemotherapeutic agents that induce apoptosis. As conventional treatments gradually lose their effectiveness over time, necroptosis has become a key therapeutic target worth exploiting. Necroptosis is a regulated cell death independent of caspases. It is driven by the receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like pseudokinase (MLKL) signaling axis. This systematic review summarizes the complex role of necroptosis in PDAC. We clarify how necroptosis can be triggered or manipulated pharmacologically, and how it can be induced by accumulating reactive oxygen species (ROS). We also critically analyze its tumor-promoting side. Persistent necroptotic signaling reshapes the tumor microenvironment (TME) by releasing damage-associated molecular patterns (DAMPs) and activating inflammatory cascades. We also highlight the growing clinical significance of necroptosis-related genes (NRGs), long non-coding RNAs (lncRNAs), and specific biomarkers such as fermitin family member 1 (FERMT1). Finally, we propose a new, context-dependent therapeutic framework. This framework proposes a combination of strategies for controlling necroptosis induction and immunomodulatory agents, offering a reasonable strategy for PDAC management.

The prevalence and invasiveness of cutaneous squamous cell carcinoma (cSCC), one of the most prevalent non-melanoma skin malignancies, are increasing annually. Effective biomarkers and targeted therapeutics for locally advanced, metastatic cSCC (i.e., tumors that are difficult to manage surgically due to extensive local invasion or distant spread) as well as for recurrent cSCC are still lacking, despite surgical resection being the primary therapy approach. Circular RNA (circRNA) has drawn a lot of interest lately in relation to cancer and development. There is evidence that circRNA can regulate biological processes like cell migration, invasion, and proliferation by acting as microRNA (miRNA) sponges. Furthermore, because of its tissue-specific expression, high stability, and wide range of regulatory roles, circRNA has demonstrated considerable relevance as a diagnostic marker and possible therapeutic target. This study provides a systematic review of the literature regarding the expression profiles of circRNAs in cSCC, the associated circRNA-miRNA-mRNA regulatory networks and molecular mechanisms, the involved signaling pathways, and their potential as therapeutic targets and diagnostic biomarkers. These findings may offer new approaches to the diagnosis, monitoring, and prognosis of cSCC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the primary contributors to global cancer mortality. Elevated expression of centrosomal protein 55 (CEP55) is frequently observed in NSCLC and is closely linked to tumorigenesis and disease progression. However, the prognostic value of CEP55 in NSCLC has not been fully established. The current meta-analysis assessed how increased CEP55 expression may influence prognosis in patients diagnosed with NSCLC. METHODS: Eligible studies were retrieved via a systematic search across major biomedical databases. Additionally, validation cohorts were retrieved from the Gene Expression Omnibus (GEO) database. To quantify the prognostic relevance of CEP55, hazard ratios (HRs) and 95% confidence intervals (CIs) were synthesized from eligible studies. The Newcastle-Ottawa Scale was leveraged to assess the methodological quality of the included studies. This review was registered with PROSPERO (CRD420251006676). RESULTS: A total of 18 independent study cohorts (6 literature-derived and 12 database-derived) involving 4,829 patients were included. The meta-analysis revealed that elevated CEP55 expression was significantly associated with poorer overall survival (OS) in NSCLC patients [HR = 1.22, 95% CI: 1.13–1.32]. Subgroup analysis by histological subtype showed that CEP55 serves as an independent predictor of poor OS in lung adenocarcinoma (LUAD) [HR = 1.28, 95% CI: 1.20–1.37], whereas its prognostic utility in lung squamous cell carcinoma (LUSC) was not statistically significant [HR = 0.98, 95% CI: 0.90–1.06]. Multivariate analysis further confirmed CEP55 as an independent risk factor for LUAD, with its prognostic impact being particularly evident in early-stage disease characteristics—including Stage I, limited tumor infiltration (T1–T2), and the absence of distant metastasis (M0)—as well as in patients with negative surgical margins or those who had not received chemotherapy. CONCLUSION: CEP55 may act as a potential indicator for predicting disease progression and survival outcomes in NSCLC, particularly in LUAD. Further investigation into the underlying mechanisms of CEP55 is necessary.

BACKGROUND: Advanced/recurrent endometrial cancer (EC) poses a significant therapeutic challenge. Immune checkpoint inhibitor (ICI) combined with chemotherapy (CT) represents a promising first-line approach, yet the predictive value of deficient/proficient mismatch repair (dMMR/pMMR) status and PD-L1 expression in therapeutic efficacy remains unclear. This study aimed to systematically evaluate the predictive value of dMMR/pMMR status and PD-L1 expression for progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent EC treated with ICI + CT. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) from four databases (PubMed, Embase, Cochrane Library, Web of Science) was performed. PFS and OS were synthesized as hazard ratios (HRs) with 95% confidence intervals (CIs) using Review Manager 5.4. RESULTS: Five RCTs (2,707 patients) were included in this meta-analysis. Compared with CT alone, ICI + CT significantly improved PFS in all subgroups: dMMR (HR = 0.36, 95% CI:0.28–0.45, P < 0.00001), pMMR (HR = 0.78, 95% CI:0.70–0.87, P = 0.009), PD-L1-positive (HR = 0.52, 95% CI:0.38–0.70, P < 0.0001), and PD-L1-negative (HR = 0.66, 95% CI:0.44–0.98, P = 0.04). For OS, only the dMMR subgroup showed a significant benefit (HR = 0.41, 95% CI:0.28–0.61, P < 0.00001), with no improvement observed in pMMR patients (HR = 0.88, 95% CI:0.73–1.07, P = 0.20). CONCLUSION: For advanced/recurrent EC, ICI + CT enhanced PFS across dMMR/pMMR and PD-L1 expression subgroups, with OS benefit apparently confined to dMMR patients and not observed in pMMR patients. These results present the clinically valuable predictive value of MMR status for ICI + CT efficacy and suggest that PD-L1expression did not influence the benefit of ICI on patient PFS, which deserve high clinical attention. TRIAL REGISTRATION: https://inplasy.com/inplasy-2026-03-0015/ , identifier INPLASY202630015.

Somatotropinomas are a subtype of pituitary adenomas that have a particular predilection to invade the cavernous sinus. The objective of this systematic review was to examine the evidence regarding the molecular basis for cavernous sinus invasion in somatotropinomas. This review was conducted in accordance with the 2020 PRISMA guidelines on 13 April 2025. Inclusion criteria were reports of associations between somatotropinoma molecular changes and cavernous sinus invasion in adult patients. Title/abstract screening and full-text screening were performed, with studies assessed for risk of bias using the Newcastle-Ottawa scale. A total of 43 studies were identified, encompassing 1,824 patients (724 invasive tumours). Overall, 33 studies identified molecules that were upregulated in invasive tumours and 20 studies identified molecules that were downregulated. Few studies incorporated modern proteomic or transcriptomic techniques. Risk of bias was low with a mean Newcastle-Ottawa scale score of 7.0 (±0.6). Molecules associated with invasion were related to epithelial-mesenchymal transition (E-cadherin, ESRP1, fascin-1, and MMP-9), cellular proliferation (PTTG, AIP, TCERG1, EIF2β, E2F1, Notch 2, STAT3, ARRB1, TGFB1, SMAD3, SOX9, SGK1, MAGEA6 DLL3, EGFL7, and pEGFR), hormonal signalling (GNAS, DRD5, DRD1, sst5TMD4, SSTR2, and SSTR5), and tumour angiogenesis (VEGF and Drp1). These molecular variations present a possible explanation for the proclivity of somatotropinomas for the cavernous sinus. Identified molecules represent options for novel targeted therapies or biomarkers that could inform prognostication. Modern proteomic and transcriptomic techniques and larger somatotropinoma datasets are required to further elucidate the molecular pathways responsible for cavernous sinus invasion in somatotropinomas.

The integration of radiomics and radiogenomics in the prognostication of head and neck cancer represents a rapidly evolving field within precision oncology. This systematic review aims to appraise advanced methods in radiomics and radiogenomics concerning prognostication in head and neck cancer, with a particular focus on methodological developments and clinical applications.

BACKGROUND: Circulating 25-hydroxyvitamin D [25(OH)D] levels and genetic polymorphisms in the vitamin D receptor (VDR) have been explored as potential prognostic factors in colorectal cancer (CRC). This study aimed to investigate the association between circulating 25(OH)D levels and CRC prognostic outcomes, with a narrative evaluation of VDR polymorphisms. METHODS: We performed a systematic literature search in the Cochrane Library, PubMed, ScienceDirect, and Scopus. The primary outcomes were CRC-specific survival, overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using the random-effects model with inverse variance weighting, comparing high versus low 25(OH)D levels. Due to heterogeneity in genetic models and limited available data, VDR polymorphisms were synthesized using a narrative approach. RESULTS: Of the 61 studies included in the systematic review, 35 studies were included in the meta-analysis, which showed that higher 25(OH)D levels were associated with a lower risk of mortality, including a 26% lower CRC-specific mortality (HR 0.74; 95% CI 0.69–0.80; I2 = 0.01%), a 32% lower overall mortality (HR 0.68; 95% CI 0.64–0.72; I2 = 7.6%), and improved DFS (HR 0.71; 95% CI 0.61–0.83; I2 = 36.8%). The prognostic roles of VDR polymorphisms, particularly rs7975232 (ApaI), rs1544410 (BsmI), rs2228570 / rs10735810 (FokI), and rs731236 (TaqI) with CRC outcomes, including CRC-specific survival, OS, and DFS were reported across 18 studies. CONCLUSION: This study provides quantitative evidence supporting the potential prognostic relevance of circulating vitamin D levels in CRC. The role of VDR genetic polymorphisms remains inconclusive, warranting further investigations. TRIAL REGISTRATION: The protocol of this systematic review and meta-analysis has been registered on PROSPERO ( https://www.crd.york.ac.uk/PROSPERO/ ), with the registration number CRD42024575841.

Germline pathogenic variants (PVs) of succinate dehydrogenase subunit D (SDHD) are major genetic causes of pheochromocytomas and paragangliomas. Existing studies have reported inconsistent findings and lack a comprehensive synthesis regarding penetrance, multifocality and metastatic risk in carriers of SDHD PVs.

Although rare, ameloblastoma is a locally aggressive odontogenic tumor, with recent studies identifying the BRAF V600E mutation as its most common molecular alteration driving MAPK pathway activation. To elucidate its clinicopathological and therapeutic significance, we conducted a systematic review and meta-analysis of studies reporting both the prevalence of BRAF V600E and treatment outcomes in mutated cases. A total of 36 studies comprising 2034 patients were included, yielding a pooled mutation prevalence of 72.1% (95% CI: 67.1-76.6%), with marked enrichment in mandibular tumors (77.5%, 95% CI: 72.7-81.6%). For treatment outcomes, 12 studies involving 21 patients with BRAF V600E-mutated ameloblastoma who received targeted therapy were analyzed. Most patients demonstrated a partial or complete radiological response, suggesting promising but preliminary therapeutic efficacy. This systematic review indicates that BRAF V600E represents the predominant oncogenic driver in ameloblastoma and a promising therapeutic target. Integration of molecular testing and targeted therapy into clinical management may reduce surgical morbidity, warranting validation in prospective trials.