Prostate cancer (PCa) is a heterogeneous and prevalent neoplasm, traditionally stratified by PSA and Gleason Score. However, these biomarkers have prognostic limitations, driving the search for new molecular markers. Alterations in DNA mismatch repair (MMR) system proteins are associated with genomic instability, therapeutic resistance, and poorer clinical outcomes. Their relevance in PCa remains poorly understood, highlighting MMR status as a potential prognostic biomarker. This systematic review, following PRISMA 2020 guidelines, evaluated the relationship between MMR protein (MSH2, MSH6, MLH1, PMS2) expression and clinical-pathological outcomes in PCa. Ten studies assessing MMR protein expression in prostate adenocarcinoma samples were included. Risk of bias was assessed using the Newcastle-Ottawa Scale. Studies revealed heterogeneous MMR protein expression. Loss of MSH2 consistently correlated with poorer clinical outcomes, including biochemical recurrence, higher Gleason Scores, and perineural invasion. MSH6 was more prevalent in high-grade tumors, without clear prognostic association. Cytoplasmic MLH1 expression was linked to aggressive histological patterns; PMS2 results were conflicting. Two studies assessed Microsatellite Instability (MSI), correlating with MSH2 and PMS2. Overall, MMR protein alterations, particularly MSH2 loss, may indicate worse PCa prognosis. However, methodological heterogeneity and lack of standardization hinder definitive conclusions. Further studies, integrating MSI analyses are crucial to confirm their prognostic.

Complex karyotype (CK) in chronic lymphocytic leukemia (CLL), defined by ≥ 3 or ≥ 5 (high-CK) chromosomal aberrations, is an established adverse prognostic marker. However, different methods for counting aberrations are used in the literature and clinical trials, potentially affecting CK classification and risk stratification. We systematically compared two established counting methods: the approach by Jondreville et al., which counts one aberration per item separated by commas, and the International System for Human Cytogenomic Nomenclature (ISCN) method, which counts unbalanced aberrations involving multiple chromosomes as two aberrations. Chromosome banding analyses from 1605 CLL patients were evaluated using both counting methods. This revealed that CK classification by the two methods disagreed in 7.5% of all cases. However, both methods performed similarly in prognostic stratification of these ambiguous cases. This suggests that the method proposed by Jondreville et al. should be adopted, as it is simpler to perform and less ambiguous. Furthermore, we compared how cases were stratified if aberrations are counted across all (sub)clones (as suggested both by Jondreville et al. and the ISCN) or only in the clone with the most aberrations. In total, 3.5% of all cases were differentially classified depending on whether aberrations were counted across all clones or only in the most complex clone. Importantly, these ambiguous cases were better stratified by counting aberrations in the most complex clone only. We therefore suggest the method proposed by Jondreville et al. to determine CK status in CLL and to count aberrations only in the clone with the most aberrations.

The SMARCA4 gene encodes a key ATPase subunit of the SWI/SNF (BAF) chromatin-remodeling complex, which plays an essential role in regulating transcription and cellular differentiation. Loss-of-function alterations of SMARCA4 are common in various human cancers, including sarcomas; however, rare SMARCA4 fusion events, presumably resulting in gain of function, have also been reported. We present two pediatric soft-tissue sarcomas harboring a novel, recurrent in-frame fusion between SMARCA4 and VEZF1 (Vascular Endothelial Zinc Finger 1), a transcription factor important for vascular development and angiogenesis. The predicted fusion protein contains the N-terminal QLQ protein interaction domain of SMARCA4 and preserves most of VEZF1's C2H2 zinc-finger DNA-binding domains. Interestingly, another component of the BAF complex, SS18, has also been reported to be fused to VEZF1 in uterine sarcoma. We propose that fusion of BAF complex components to VEZF1 leads to aberrant recruitment of chromatin-remodeling activity to VEZF1 target loci, resulting in altered chromatin architecture, dysregulated VEZF1-dependent transcription, and tumorigenesis.

The clinical features and outcomes of rhabdomyosarcoma (RMS) occurring as a secondary neoplasm are unknown. We aimed to determine the prevalence of secondary RMS (sRMS) and compare patient characteristics, treatment, and overall survival (OS) between primary RMS (pRMS) and sRMS in children, adolescents, and young adults.

We queried Surveillance, Epidemiology, and End Results data for patients 0-39 years old diagnosed with RMS from 2000 to 2021. Prevalence of sRMS was reported with 95% confidence intervals (CIs). Comparisons between pRMS and sRMS were evaluated using Chi-square or Fisher's exact test for categorical variables and Mann-Whitney U tests for continuous variables. Five-year OS from time of RMS diagnosis was calculated using Kaplan-Meier analysis.

We identified 2676 patients with pRMS and 71 patients with sRMS (prevalence: 2.6%; 95% CI: 2.0%-3.3%). Patients with sRMS were older (p < 0.001) and more likely to have non-alveolar, non-embryonal histology (p < 0.001). Radiotherapy (63.6% vs. 32.4%, p < 0.001) and chemotherapy (93% vs. 77.5%, p < 0.001) were less frequently administered to patients with sRMS. Primary malignancies preceding sRMS included germ cell tumors (28.2%) and leukemia/lymphoma (23.1%). The 5-year OS in sRMS was inferior to pRMS (37% vs. 60%, p < 0.001). OS in sRMS was associated with age (p = 0.028) and site (p = 0.004).

sRMS is rare and has distinct clinical features compared to pRMS. Treatment characteristics differed, including decreased use of chemotherapy or radiotherapy, and patients with sRMS had inferior 5-year OS. While this inferior OS is likely multifactorial, decreased use of chemotherapy and radiotherapy may be contributory.

Squamous cell carcinoma is a malignant tumor that affects the skin and mucous membranes. It may present as painless superficial lesions, or as rapidly growing, exophytic masses, sometimes ulcerated, which can invade and damage surrounding tissues. It is the second most common malignant neoplasm of the skin, characterized by high clinical variability, which makes early diagnosis and timely treatment essential to improve prognosis. The aim of this case report is to evaluate the clinical efficacy, tolerability, and durability of response of electrochemotherapy in the treatment of cutaneous squamous cell carcinoma of the lip in patient with compromised general health.

We report the case of a 79-year-old male with multiple comorbidities, including chronic kidney disease, diabetes, and ischemic heart disease, who presented with a rapidly growing lesion on the lower lip. The surgical approach would entail a functional deficit of the lips and an aesthetic impairment. Due to the patient's systemic condition, a more conservative treatment was chosen, namely treating the neoplasm with electrochemotherapy.

The treatment led to controlled necrosis of the lesion and complete healing by secondary intention within three months. The patient experienced no functional impairment or recurrence during a four-year follow-up.

This case highlights the potential of electrochemotherapy as a safe and effective alternative for managing lip squamous cell carcinoma, particularly in patients who are not candidates for surgery or radiotherapy. The favorable clinical and aesthetic outcomes support its consideration in selected cases.

Retroperitoneal sarcoma (RPS) is a type of malignant tumour arising from mesenchymal tissues within the retroperitoneal space. RPSs tend to develop covertly and are often undiscovered when they have already grown significantly and invaded surrounding tissues and organs. These malignancies demonstrate high recurrence rates, present surgical challenges and exhibit limited responsiveness to radiotherapy and chemotherapy. Serum-derived molecules are known to play critical roles in tumourigenesis and tumour progression. However, the serum molecular profile of RPS patients remains unclear.

We performed multi-omics analysis of serum samples from patients with retroperitoneal dedifferentiated liposarcoma. Prolactin concentrations were quantified using Enzyme-Linked Immunosorbent Assay (ELISA). RNA-seq facilitated the identification of candidate signalling pathways, while gene expression was validated through quantitative polymerase chain reaction, immunohistochemistry and western blot analyses. Molecular mechanisms underlying transcriptional regulation were investigated through Chromatin Immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase reporter gene assays.

Integrative multi-omics profiling identified significant perturbations in galactose metabolism coupled with marked elevation of prolactin (PRL) levels in Retroperitoneal Liposarcoma (RLPS) patients. Further screening of serum prolactin levels in 100 patients with retroperitoneal tumours revealed that 90% of the cases exhibited hyperprolactinaemia in our research cohort, encompassing both malignant sarcomas and benign tumours. Studies at the clinical sample, cellular and animal levels have found that abnormally elevated prolactin in the serum can originate from sarcoma tissues. Mechanistic investigations identified SRY-box transcription factor 4 (SOX4) as a previously unrecognised transcriptional regulator of PRL. Functionally, PRL not only enhanced liposarcoma cell and fibrosarcoma cell proliferation but also conferred resistance to MDM2 inhibitors. Signalling pathway analysis revealed that PRL activates the Janus Kinase-Signal Transducer and Activator of Transcription Pathway (JAK-STAT) signalling pathway and up-regulates c-MYC expression.

This study indicates that PRL can serve as an oncogenic driver and therapeutic target. The identification of SOX4-PRL-c-MYC signalling axis provides actionable insights for developing novel therapeutic strategies against this malignancy.

Retroperitoneal sarcoma cells can secrete prolactin into the bloodstream, inducing hyperprolactinaemia, which subsequently triggers metabolic reprogramming, such as glucose metabolism. SOX4 can function as a transcription factor that facilitates PRL transcription. PRL can activate the JAK-STAT signalling pathway by binding to PRLR on sarcoma cells, leading to the up-regulation of c-MYC.

Dysregulation of transcription factors is a hallmark of lung tumorigenesis, and Sex-determining region Y-box 9 (SOX9) has emerged as a putative master regulator at the intersection of development and malignancy. Building on evidence from lung and other solid tumors, we summarize how aberrant SOX9 expression, shaped by epigenetic modification, post-translational regulation, and non-coding RNAs, drives proliferation, survival, invasion, and therapy resistance. In lung cancer, SOX9 appears to orchestrate a stem-like, plastic cell state, promoting epithelial-mesenchymal transition (EMT), metastatic dissemination, and remodeling of the tumor microenvironment (TME). These context-dependent functions position SOX9 both as an oncogenic driver and, in selected settings, as a modulator of treatment response. This review integrates current mechanistic and translational data to frame SOX9 as a clinically actionable node within key signaling circuits relevant to non-small cell and small cell lung cancer. We highlight emerging strategies that directly or indirectly target SOX9, including interference with upstream pathways, epigenetic reprogramming, and RNA-based approaches designed to modulate SOX9 expression or activity. Finally, we propose SOX9 as a dual biomarker and therapeutic handle to guide rational combination therapies aimed at overcoming drug resistance and improving patient stratification. By connecting molecular insight with unmet clinical needs, this article outlines a conceptual roadmap for SOX9-centered therapeutic approaches in lung cancer. A key novelty of this review is the integration of SOX9-centered molecular mechanisms with therapeutic resistance, biomarker potential, and emerging indirect targeting strategies in lung cancer, thereby providing a translational framework for future SOX9-guided interventions.

Accumulating evidence indicates that indirubin exerts inhibitory effects on prostate cancer (PCa) progression. However, the role and underlying mechanisms of indirubin in sensitizing PCa to docetaxel remain unclear. CCK-8 assays were initially used to determine the effect of indirubin on enhancing docetaxel sensitivity in PCa cells. Following this, the expression levels of circ-Vav3 were quantified using quantitative real-time PCR (RT-qPCR) to evaluate its potential role in docetaxel resistance. Functional experiments, including flow cytometry-based apoptosis analysis and Transwell migration/invasion assays, were conducted to assess the impact of circ-Vav3 modulation and indirubin treatment on cell viability and behavior in response to docetaxel. Rescue experiments were subsequently performed to further confirm the regulatory effect of indirubin on circ-Vav3. Additionally, xenograft tumor models in nude mice were utilized to evaluate the therapeutic efficacy of indirubin in vivo. Mechanistic interactions between circ-Vav3, miR-204-5p, and MAPK1 were further investigated using RNA pulldown assays, luciferase reporter assays, and Western blot analyses. Indirubin enhanced the sensitivity of PCa cells to docetaxel by downregulating the expression of circ-Vav3, which was found to be significantly upregulated in docetaxel-resistant PCa cells. Silencing circ-Vav3 effectively reversed this resistance, as evidenced by increased apoptosis, reduced cell migration and invasion, and decreased autophagic activity. Notably, indirubin treatment suppressed circ-Vav3 expression and thereby restored docetaxel sensitivity both in vitro and in xenograft tumor models. Mechanistically, circ-Vav3 acted as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, which led to the upregulation of the autophagy-related kinase MAPK1. Inhibition of MAPK1 effectively suppressed autophagy and re-sensitized docetaxel-resistant PCa cells, further confirming the critical regulatory role of the circ-Vav3/miR-204-5p/MAPK1 signaling axis in mediating chemoresistance. Our findings demonstrate that circ-Vav3 promotes docetaxel resistance in PCa by sponging miR-204-5p and subsequently activating MAPK1-mediated autophagy. Indirubin effectively restores chemosensitivity by targeting this regulatory pathway, offering a promising therapeutic strategy for overcoming chemoresistance in castration-resistant prostate cancer (CRPC).

Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of solid tumors; however, responses remain heterogeneous and complex to predict. In addition, a growing number of multiple ADC targets are either approved or in late-stage clinical development, such as NECTIN-4, HER2, or TROP2 for metastatic urothelial cancer. Spatial multiomics-representing next-generation methods that couple high-plex RNA sequencing and multiplex protein imaging with precise x-y-z coordinates within tissues-offer a direct way to correlate (ADC) antigen expression, cell state information, and micro-anatomical context with patient treatment outcomes. In this review, we highlight suitability and technological advancements in current spatial transcriptomics and proteomics approaches to decode modes of action and resistance to ADCs and extract biological insights, particularly in metastatic urothelial cancer-and propose an integrative framework that combines spatial readouts with machine and/or deep learning-driven analytics to stratify patients, forecast on- and off-target toxicities, and guide next-generation linker-payload designs or combination therapies.

BACKGROUND Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy with limited prognostic biomarkers and therapeutic targets. This study aims to develop a robust protein-based prognostic model and investigate the functional role of RAPTOR in HNSCC progression. MATERIAL AND METHODS Proteomic data from The Cancer Proteome Atlas and transcriptomic data from The Cancer Genome Atlas were integrated to identify prognosis-related proteins, and a multivariable Cox regression model was developed. Functional studies, including lentiviral knockdown, proliferation and invasion assays, RNA sequencing, and xenograft models, were conducted to evaluate the role of RAPTOR (encoded by the RPTOR gene). Since RAPTOR is an essential component of mTORC1 and lacks a direct inhibitor, the mTORC1 inhibitor rapamycin was used as a pharmacological surrogate to assess the therapeutic potential of targeting RAPTOR-mediated signaling. RESULTS A 7-protein prognostic model (CD45, RAPTOR, SETD2, MERIT40_pS29, HER3_pY1289, Hexokinase-I, and BETACATENIN) stratified patients into high- and low-risk groups with significantly different overall survival, and the risk score remained an independent prognostic factor. RAPTOR was markedly upregulated in HNSCC and correlated with immune infiltration. Functional assays revealed that RAPTOR silencing inhibited proliferation, migration, and invasion, suppressed PI3K/AKT/mTOR signaling and uPA expression, and upregulated both S100A8/A9 levels. Rapamycin treatment recapitulated these effects in vitro and in vivo. CONCLUSIONS This study identifies a novel protein-based prognostic model for HNSCC and demonstrates that RAPTOR promotes tumor progression through mTOR signaling and S100A8/A9-uPA regulation. Targeting RAPTOR-mediated pathways may offer new strategies for precision therapy in HNSCC.