Search Results (416)

Background: Sarcomas are rare, aggressive malignancies with limited therapeutic options in advanced stages. This is the first real-world study in the MENA region evaluating the clinical utility of Next-Generation Sequencing (NGS) in guiding sarcoma treatment and improving outcomes. Methods: We retrospectively reviewed sarcoma patients who underwent NGS at a major referral center (2021–2024), comparing clinical and molecular outcomes between those who received NGS-based treatment adjustments (NBTA) and those who did not. Results: Seventy-eight patients were included (60% male; median age 44 years). Soft tissue sarcomas accounted for 70.5% of cases (n = 55), while bone sarcomas represented 29.5% (n = 23). Prior to NGS, 64.1% of patients had received a median of one line of systemic therapy. NGS was performed late in the disease course in 73% of cases. At least one mutation was detected in 87% (median 3 mutations). Targetable alterations were identified in 33% at the time of testing, rising to 42% with updated genomic knowledge and therapeutic advances. Overall, 20.5% received NBTA. Among non-NBTA patients, 67% had no actionable targets, 17% had no detectable mutations, and 16% were ineligible due to cost, limited access, or clinical deterioration. Tumor Mutational Burden was low in 79%, intermediate in 19%, and high in 2%, and all tumors were microsatellite stable. Patients receiving NBTA had a longer median Progression-Free Survival (9 vs. 2 months; p = 0.023). Median Overall Survival was longer in the NBTA group (74 vs. 48 months), though not statistically significant (p = 0.207). Genomic alterations were subtype-specific: EWSR1 rearrangements (Ewing and Desmoplastic small round cell tumors), CDK4 and MDM2 amplifications (Liposarcoma and Osteosarcoma), TP53 and RB1 mutations (Leiomyosarcoma), CDKN2A/B deletions (Undifferentiated Pleomorphic Sarcoma and Chondrosarcoma), and SS18 rearrangements (Synovial Sarcoma). Conclusions: Genomics-guided therapy in sarcoma is feasible and impactful. Expanding timely access to molecular profiling is essential for advancing precision oncology in the MENA region. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

Background/Objectives: Targeted gene sequencing (TGS) for Comprehensive Genomic Profiling (CGP) use in sarcomas has recently increased in clinical practice. We report on TGS real-world data over a period of 3 years (2022–2025) at the IRCCS Istituto Ortopedico Rizzoli, with the aim of identifying potential actionable targets and providing therapeutic indications for advanced sarcoma patients. Methods: We analyzed 22 advanced sarcoma patients by using the VariantPlex Pan Solid Tumor kit panel, including 185 genes. In nine cases, saliva samples for germinal DNA analysis were available. Sequencing was performed on the NextSeq-500 Platform and analyzed with Archer Analysis software. The Cancer Genome Interpreter and OncoKB Database tools were used to find potential actionable targets. Results: We found the most frequent genetic variants, including missense, deletion, duplication, and delins, in the NOTCH4, AR, BARD1, MUC16, and ROS1 genes. Copy Number alterations affected the CDKN2A, CDKN2B, TP53, RHOA, MYC, CCND3, and DDR2 genes mainly in osteosarcoma samples. In four patients, longitudinal analyses of subsequent lesions showed the maintenance of most genomic alterations and enrichment in missense or splice variants in PMS2, SMARCA4, ARID1A, AKT1, BMPR1A, and PTEN, indicating the occurrence of tumor evolution. Germline variants subtraction identified the specific somatic tumor mutations. Advantages and disadvantages of our approach were considered in order to refine the analysis setting and better select possible actionable targets. Conclusions: Early access to genomic analyses, routine germline assessment, and broad gene panels would help in identifying possible targeted drugs with sufficient evidence of activity beneficial to each patient. In the clinical management of advanced sarcoma patients, when analyzing cost-effectiveness and sustainability, the role of the Molecular Tumor Board in the governance of the complexity introduced by mutational oncology should be considered. Full article

Background: Oncological treatment remains a major clinical challenge. Despite therapeutic advances and the diversity of available approaches, many tumors continue to exhibit limited responsiveness to chemotherapy. In this context, nutrition has emerged as a promising complementary strategy to support cancer therapy. In particular, interventions based on nutritional deprivation have gained prominence due to their ability to modulate tumor metabolism, inducing alterations that may increase the sensitivity of cancer cells to conventional treatments. Accordingly, the present study aimed to evaluate the safety and efficacy of caloric restriction combined with chemotherapy in a Sarcoma-180 model, investigating its effects on immunological and hematological parameters, antioxidant activity, oxidative stress, and tumor and liver morphology, as well as DNA damage. Methods: Mice bearing Sarcoma-180 were randomly assigned to four groups: Ad Libitum (AL), Ad Libitum + Doxorubicin (ALDOX), Caloric Restriction (CR), and Caloric Restriction + Doxorubicin (CRDOX). Assessment included tumor weight and volume, food and caloric intake, hematotoxicity, lipid metabolism, oxidative stress and antioxidant markers, genotoxicity, morphological alterations in the tumor and liver, and overall survival. Results: The data obtained demonstrate that caloric restriction combined with doxorubicin is both safe and feasible, as it preserves body weight and does not induce metabolic disturbances. Importantly, this combined strategy produced a marked reduction in tumor volume and mass while also mitigating the hematotoxicity typically associated with doxorubicin. In peripheral blood, the regimen decreased chemotherapy-induced DNA damage, supporting a systemic protective effect. Consistently, the combination reduced oxidative stress markers (NOx and MDA) and enhanced antioxidant activity within the tumor. Histological analyses further confirmed these outcomes, showing tumor cell death with features compatible with apoptosis and reduced local invasion. Together, these data indicate that caloric restriction enhances the antitumor efficacy of doxorubicin while simultaneously improving treatment tolerance. Conclusions: This study demonstrates that caloric restriction, combined with doxorubicin, is safe, well-tolerated, and enhances the antitumor response in the Sarcoma-180 model. Full article

Background/Objectives: Synovial sarcoma (SS) is a malignant soft tissue neoplasm with good outcomes in adolescents with localized tumors, but poor outcomes in older adults and in advanced or metastatic cases. Targeting cancer metabolism, such as glutamine metabolism, is a promising therapeutic strategy. In this study, we investigated glutamine dependency in SS and assessed the therapeutic potential of inhibiting the glutamine transporter ASCT2 using V9302. Methods: Immunohistochemistry (IHC) was used to evaluate ASCT2 expression in SS and liposarcoma (LPS) specimen. The effects of glutamine deprivation and V9302 were examined in a SS cell line (HS-SY-II), patient-derived SS cells (SSH1), and a normal cell line (HEK293). Cell viability, apoptosis, and protein expression were assessed using the CCK-8 assay, flow cytometry, and Western blotting, respectively. The therapeutic efficacy of V9302 was evaluated in a xenograft model using IHC. Results: ASCT2 expression was elevated in SS tumor tissues compared with adjacent normal tissues and LPS specimens. Both the HS-SY-II cell line and SSH1 cells exhibited strong glutamine dependency for proliferation. V9302 selectively reduced HS-SY-II cell viability by suppressing the AKT/mTOR signaling pathway and inducing apoptosis via caspase-3 activation, with minimal effects on control cells. In vivo, V9302 administration significantly inhibited tumor growth without inducing systemic toxicity, and IHC of the treated tumors confirmed the suppression of the mTOR pathway and induction of apoptosis. Conclusions: Our findings suggest that SS is a glutamine-dependent malignancy and validate ASCT2 as a promising therapeutic target. The ASCT2 inhibitor V9302 demonstrated therapeutic efficacy both in vitro and in vivo, supporting its potential as a therapeutic agent for SS. Full article

Background: Uterine malignancies frequently metastasize to the lungs. Pulmonary metastasectomy has demonstrated survival benefits in some malignancies; however, its efficacy for uterine malignancies remains unclear. Methods: We retrospectively analyzed 38 patients who underwent pulmonary metastasectomy for uterine malignancies at the Kanagawa Cancer Center between 2010 and 2020. The primary endpoint was recurrence-free survival (RFS) after pulmonary resection. Results: The median patient age was 63 years. The primary sites were the cervical uteri (n = 22) and corpus uteri (n = 16). The FIGO stages at the time of treatment for the primary tumor were I, II, III, IV, and unknown in 20, 7, 9, 1, and 1 patient, respectively. The median disease-free interval (DFI), defined as the interval between primary treatment and first recurrence, was 26.5 months. Most patients had single metastasis (n = 32). The procedures for metastasectomy included lobectomy, segmentectomy, and wedge resection (n = 15, 8, and 15, respectively), and two cases resulted in microscopically incomplete resection. The median follow-up period after pulmonary metastasectomy was 57 months, with 16 patients experiencing recurrence after pulmonary metastasectomy (5-year RFS rate: 55.6%). Univariate analysis identified FIGO stage ≥ III, DFI < 12 months, presence of synchronous extrapulmonary recurrence, and uterine sarcoma as poor prognostic factors. No prognostic differences were found between cervical and corpus uteri cancers. Conclusions: Pulmonary metastasectomy may confer prognostic benefits in patients with uterine malignancies. Careful consideration is warranted for patients with advanced-stage primary tumors, early recurrence after primary treatment, synchronous extrapulmonary recurrence, and uterine sarcoma. Full article

Background/Objectives: Primary cardiac sarcomas are rare and aggressive tumors. Management is often guided by evidence from other sarcoma types due to limited disease-specific data. This study aimed to analyze the clinical characteristics, pathology, treatment, and outcomes of primary cardiac sarcomas at a national referral center in Spain. Methods: We conducted a retrospective, observational, single-center study from February 2017 to December 2024. Patient data were collected from medical records, and a descriptive analysis was performed. Results: Twelve patients were identified (58% female; median age 43 years, range 13–76). Dyspnea was the most common symptom (8/12, 67%), and the right atrium was the most frequent tumor site (6/12, 50%). Angiosarcoma was the predominant histologic subtype (6/12, 50%). Seven patients had localized disease at diagnosis. Surgery was performed in six patients, with complete (R0) resection in two. Two patients received adjuvant chemotherapy, one underwent cardiac transplantation, and one received sequential chemo- and radiotherapy. All patients experienced tumor recurrence, with a median recurrence-free survival of 5 months (95% CI, 1.5–8.6). Median overall survival for localized disease was 22 months (95% CI, 16–28). Five patients were metastatic at diagnosis, and 11 of 12 developed metastases. Median progression-free survival for first-line therapy was 5.9 months (95% CI, 1.8–9.9), and median overall survival for advanced disease was 12 months (95% CI, 10–13.6). Conclusions: Complete surgical resection was rarely achieved, and recurrence was universal. Outcomes remained poor even for localized disease, highlighting the limited efficacy of current therapies and the need for improved multimodal treatment strategies. Full article

Background: Ewing sarcoma (ES) is a highly aggressive malignant tumor that predominantly affects children and young adults. Despite advances in multimodal therapy, relapse and refractory disease remain the leading causes of treatment failure. High-dose chemotherapy followed by autologous stem cell transplantation (HDCT-ASCT) has been proposed as a consolidation strategy for high-risk or relapsed ES; however, its clinical value remains controversial. Methods: We retrospectively analyzed 46 consecutive patients with locally advanced or metastatic ES who underwent HDCT-ASCT after at least one prior systemic therapy line. Clinical, pathological, and transplant-related variables were evaluated for associations with overall survival (OS), post-transplant OS (OS-2), and progression-free survival (PFS). Survival was estimated using the Kaplan–Meier method, and prognostic factors were assessed by Cox proportional hazards modeling. Results: The median age at diagnosis was 23 years (range: 14–55). Median OS from diagnosis was 42 months, while post-transplant OS-2 and PFS were 8 and 5 months, respectively. Younger patients (≤23 years) had significantly longer OS (50 vs. 34 months; p = 0.027). Liver metastasis predicted inferior OS (HR = 5.411; p = 0.006), whereas lung metastasis was associated with shorter OS-2 (HR = 2.672; p = 0.025) and PFS (HR = 6.037; p = 0.016). Treatment-related mortality was low (2.1%), though hematologic toxicity was universal. Overall, HDCT-ASCT provided transient disease control, with modest benefit confined to younger, chemosensitive, and medically fit patients. Conclusions: In this real-world cohort, HDCT-ASCT was feasible and safe but offered limited survival advantage in heavily pretreated Ewing sarcoma. Prognosis was primarily influenced by age and metastatic distribution, particularly hepatic and pulmonary involvement. These findings support a risk-adapted, biology-driven approach reserving HDCT-ASCT for selected patients and highlight the need for post-transplant maintenance strategies integrating targeted or immunotherapeutic modalities. Full article

Background/Objectives: Soft tissue sarcomas (STS) remain a therapeutic challenge due to their limited response to radiation and conventional chemotherapies. While recent advances in immunotherapy have improved outcomes in several cancers, these strategies have been largely disappointing in STS patients. Naturally occurring STS in dogs have been suggested as a spontaneous, immunocompetent model of human STS, but further characterization of its tumor immune microenvironment is needed to validate its relevance. This study aimed to identify the shared immune-related components of canine and human STS and to determine how these factors influence the tumor biology, progression, and prognosis. Results: Data from 75 dogs with STS was analyzed. In addition, we characterized the tumor immune microenvironment using immunohistochemistry and compared gene expression between canine and human STS. Progression-free survival and time to metastasis was significantly longer in castrated males in comparison to females. In addition, dogs with appendicular tumors had better progression- and recurrence-free survival, whereas tumor recurrence following surgical excision was associated with a shorter time to metastasis. Immunohistochemistry revealed infiltration of CD204⁺ cells in most of the tumors examined, and disease-free intervals were shorter in dogs with tumors exhibiting FOXP3⁺ cell infiltration. Gene expression profiling demonstrated similarities between canine STS and human undifferentiated pleomorphic sarcomas, with MYC dysregulation emerging as a poor prognostic indicator for dogs. Conclusions: The comparative analysis between the human and canine STS microenvironment offers a valuable insight into the clinical behavior and immune landscape of canine STS, underscoring its potential as a relevant preclinical model for the translation and development of future immunotherapies. Full article

The high failure rate of anticancer drugs in clinical trials highlights the need for preclinical models that accurately reproduce the structural, biochemical, and mechanical complexity of human tumors. Conventional two-dimensional cultures and animal models often lack the physiological complexity required to predict clinical outcomes, driving the development of three-dimensional systems that better emulate the tumor microenvironment. Among these, microfluidic-based spheroid models have emerged as powerful tools for cancer research and drug screening. By integrating 3D spheroids with microfluidics, these platforms allow precise control of nutrient flow, oxygen gradients, shear stress, and interstitial pressure, while supporting co-culture with stromal, immune, and endothelial cells. Such systems enable the investigation of drug response, angiogenesis, metastasis, and immune interactions under dynamic and physiologically relevant conditions. This review summarizes recent advances in microfluidic spheroid models for cancer, covering both carcinomas and sarcomas, with an emphasis on device design, biomaterial integration, and translational validation. Key challenges remain, including technical complexity, scalability constraints, and the absence of standardized protocols. Overall, the merger of microfluidic technology with 3D spheroid culture provides a promising pathway toward predictive, ethical, and personalized preclinical testing, bridging the gap between in vitro modeling and clinical oncology. Full article

Malignant peripheral nerve sheath tumors (MPNSTs) are one of the most difficult sarcomas to treat. Due to the rarity of MPNSTs, many of the therapeutic approaches used are from treatment guidelines for soft tissue sarcoma. Besides surgery, little success has been achieved using these therapies. Traditional chemotherapy and radiation therapy regimens designed to treat sarcoma have unclear efficacy when used to treat MPNSTs. Targeted therapeutics that succeeded in other sarcomas failed to produce positive results in MPNSTs. Moreover, investigational agents that have shown efficacy in preclinical models have produced disappointing outcomes in clinical trials. While therapeutic options for patients with MPNST have remained relatively stagnant, dramatic improvements in therapeutic outcomes of other rare sarcomas have been made. This difference in success is likely caused by the complex heterogeneity of MPNSTs that hinders drug development, although many MPNSTs are associated with neurofibromatosis type 1 (NF1), a genetic disorder resulting from mutations in the NF1 gene that encodes the negative RAS regulator neurofibromin. The development of new agents for MPNST treatment has shifted away from solely targeting RAS pathway gene products to stimulating the immune system and manipulating other MPNST driver mutations such as CDKN2A/B, SUZ12, EED, and TP53. This review presents recent advances in the treatment of sarcomas and the future of drug development targeting MPNSTs. Full article

Atypical Teratoid/Rhabdoid Tumor (AT/RT) is a highly aggressive neoplasm of the central nervous system (CNS), most commonly affecting infants and young children. Originally recognized as a distinct entity following cytogenetic identification of monosomy 22 in renal Rhabdoid Tumors, AT/RT now encompasses CNS tumors characterized by SMARCB1 (INI-1) or SMARCA4 (BRG-1) alterations within the SWI/SNF chromatin-remodeling complex. The integration of immunohistochemical markers with advanced molecular diagnostics—including next-generation sequencing, DNA methylation profiling, and gene enrichment analyses—has facilitated robust tumor classification and the identification of three molecular subgroups: TYR, SHH, and MYC. Despite its distinctive histopathologic features, AT/RT remains diagnostically challenging in adolescent and adult populations due to age-related bias and potential morphologic heterogeneity. Differential considerations, including epithelioid sarcoma, poorly differentiated chordoma, CRINET, choroid plexus carcinoma, and rare composite tumors, further complicate the diagnostic landscape. A comprehensive, multimodal diagnostic approach combining histologic, immunophenotypic, and molecular data is essential to accurately identify AT/RT and guide clinical management, particularly in diagnostically ambiguous or atypical cases. Full article

Kaposi’s sarcoma (KS), an AIDS-defining illness, is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). A member of the human herpesvirus family, designated as human herpesvirus 8 (HHV-8), KSHV is also linked to other oncogenic manifestations such as primary effusion lymphoma (PEL). The current dearth of available compounds against KSHV necessitates development of effective antiviral treatments. As with other herpesviruses, KSHV can result in both lytic and latent infections. KSHV pathogenesis and the development of KS have been associated with the expression of KSHV genes and transcripts during viral infections. The transcriptome of KSHV heavily intersects with regulatory pathways and mechanisms involved with a multitude of diseases in humans. Circular RNAs (circRNAs) have recently been discovered to be expressed by KSHV. Research endeavors on KSHV circRNAs have focused on the roles they play throughout latent and lytic infection. Understanding the specific functions and interactions of KSHV circRNAs with the viral and host transcriptomes, as well as how they are identified and analyzed, will be the primary focus of this review. Overall, recent advances in KSHV circRNA research have deepened our understanding of the KSHV transcriptome and pathogenesis and are paving the way for the development of circRNA-based antiviral therapies. Full article

Human Immunodeficiency Virus (HIV) infection is associated with a wide spectrum of urological manifestations, reflecting both the direct effects of viral infection and the indirect consequences of immunosuppression, opportunistic infections, malignancies and long-term combined antiretroviral therapy (cART). This narrative review provides a contemporary, multifaceted overview of the clinical and pathological presentations of urological conditions in people living with HIV (PLWHIV), based on articles published between 1989 and 2025. Conditions discussed include HIV-associated nephropathy (HIVAN), opportunistic genitourinary infections, malignancies such as Kaposi sarcoma and lymphoma, as well as non-infectious complications such as HIV-associated nephropathy and erectile dysfunction (ED). The review highlights the evolving epidemiology of these conditions in the cART era, with a noted decline in opportunistic infections but a rising burden of chronic kidney disease and malignancies, largely due to improved survival and ageing of the HIV-positive population. Pathological insights are explored and discussed, including mechanisms of HIV-associated renal injury, such as direct viral infection of renal epithelial cells and genetic predispositions linked to Apolipoprotein L1 (APOL1) variants. In addition, psychosocial factors, including anxiety, stress, stigma, and alcohol use, are discussed, as they may contribute to late presentation to clinical urology services. The review also considers the challenges faced in low and middle-income countries, the impact of HIV on urological services, and the important role of palliative care in advanced disease. Ultimately, this review underscores the need for early recognition, comprehensive diagnostic and surgical evaluation, and integrated social, psychological, and palliative management strategies tailored to the unique needs of PLWHIV. A deeper understanding of the interplay between HIV, cART, psychosocial determinants, and urological health is essential for improving patient outcomes and guiding future research in this evolving field. Full article

Low-complexity domains (LCDs) are protein regions characterized by a simple amino acid composition and low sequence complexity, as they are typically composed of repeats or a limited set of a few amino acids. Historically dismissed as “garbage sequences”, these regions are now acknowledged as critical functional elements. This review systematically explores the structural characteristics, biological functions, pathological roles, and research methodologies associated with LCDs. Structurally, LCDs are marked by intrinsic disorder and conformational dynamics, with their amino acid composition (e.g., G/Y-rich, Q-rich, S/R-rich, P-rich) dictating structural tendencies (e.g., β-sheet formation, phase separation ability). Functionally, LCDs mediate protein–protein interactions, drive liquid–liquid phase separation (LLPS) to form biomolecular condensates, and play roles in signal transduction, transcriptional regulation, cytoskeletal organization, and nuclear pore transportation. Pathologically, LCD dysfunction—such as aberrant phase separation or aggregation—is implicated in neurodegenerative diseases (e.g., ALS, AD), cancer (e.g., Ewing sarcoma), and prion diseases. We also summarize the methodological advances in LCD research, including biochemical (CD, NMR), structural (cryo-EM, HDX-MS), cellular (fluorescence microscopy), and computational (MD simulations, AI prediction) approaches. Finally, we highlight current challenges (e.g., structural heterogeneity, causal ambiguity of phase separation) and future directions (e.g., single-molecule techniques, AI-driven LCD design, targeted therapies). This review provides a comprehensive perspective on LCDs, illuminating their pivotal roles in cellular physiology and disease, and offering insights for future research and therapeutic development. Full article