Search Results (93)

Background: Post-treatment erythrocytosis (PT-E⁺)—an increase in red blood cell counts after therapy—is an uncommon but reproducible finding in a subset of Hodgkin lymphoma (HL) survivors, and its biological basis remains undefined. Methods: A targeted DNA sequencing panel of 33 genes was used at diagnosis and during follow-up in PT-E⁺ patients and HL controls who did not develop erythrocytosis (E⁻; those without increased red blood cells). Germline (inherited) and somatic (acquired) genetic variants were compared, and changes in variant frequency over time were assessed. Results: PT-E⁺ patients had a unique molecular profile. They showed inherited variants in genes that regulate oxygen sensing and red blood cell production (EPAS1, EGLN3, HIF3A, PKLR, SH2B3, and RAB4B-EGLN2). Rare, acquired mutations affecting hypoxia, HIF, and EPO pathways (EGLN1/2/3, EPAS1, HIF1A/3A, VHL, EPO, and PKLR) were also found. These changes did not appear in E⁻ controls, who instead had common clonal hematopoiesis mutations (DNMT3A, TET2, ASXL1, and JAK3). Most somatic variants in the hypoxia pathway in PT-E⁺ patients decreased or disappeared after treatment, which suggests these changes are temporary and influenced by the surrounding environment. Conclusions: PT-E⁺ is biologically different from polycythemia vera and from idiopathic or JAK2-unmutated erythrocytosis. Both inherited risk and HL-related hypoxic or inflammatory stress are present. This supports a two-hit model, in which genetically primed red blood cell pathways respond strongly to disease-related triggers. These results suggest a new way to understand erythrocytosis after HL treatment. Full article

Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN⁺) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN⁺ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-β family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN⁺ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease. Full article

Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive “smart” hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care. Full article

Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel–Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical “immune-hot yet immunosuppressed” phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy. Full article

Background and Objectives: A subset of cancer patients treated with immune checkpoint inhibitors may experience rapid tumor progression rather than therapeutic benefit, a phenomenon described as hyperprogressive disease (HPD), which is linked to poor prognosis and shortened survival. Reliable biomarkers capable of predicting HPD remain lacking. To better understand the molecular background of HPD, we analyzed promoter region methylation and somatic mutation profiles in cancer-related genes in patients with malignant melanoma (MM) and renal cell carcinoma (RCC) undergoing anti-PD-1/PD-L1 treatment. Methods: Patients diagnosed with MM or RCC and treated with anti-PD-1/PD-L1 agents between 2011 and 2020 were included, and FFPE tumor samples along with paired normal tissues were analyzed. A diagnosis of HPD was assigned to patients with RECIST 1.1-defined progressive disease who demonstrated a ≥2-fold acceleration in tumor growth kinetics after initiation of immune checkpoint inhibitor therapy. Methylation-specific real-time PCR was performed on 54 samples (15 MM tumors, 22 RCC tumors, 17 RCC-matched adjacent normal samples) to assess promoter methylation of PIK3CA, BAP1, PTEN, and TP53. Next-generation sequencing (NGS) with an 86-gene pan-cancer panel was conducted on 9 HPD samples. Results: Promoter hypermethylation involving PIK3CA, BAP1, PTEN, and TP53 was more pronounced in HPD-associated tumor samples (n = 16) than in tumors without HPD (n = 21). Within the MM cohort, PTEN and TP53 methylation levels demonstrated statistically significant differences between the two groups (p = 0.005 and p = 0.028, respectively), while no comparable associations were observed in RCC patients. NGS analysis detected missense mutations classified as pathogenic or likely pathogenic in 5 of 9 HPD patients (55.6%), involving KIT, PTEN, and VHL. Conclusions: Promoter region hypermethylation in cancer-related genes may contribute to the aggressive tumor behavior observed in HPD. The somatic variants identified in HPD patients are consistent with known oncogenic pathways. These findings support further investigation of epigenetic and genomic biomarkers for HPD risk stratification in larger, prospective cohorts. Full article

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity—lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years—the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR–natural killer (NK) cells, CAR–natural killer T (NKT) cells, and CAR–macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is a biologically heterogeneous disease. Beyond VHL inactivation, alterations in chromatin remodeling genes BAP1 and PBRM1 define distinct tumor phenotypes with prognostic implications. We sought to characterize the clinicopathological features and oncological outcomes associated with IHC-defined loss of these markers in a contemporary surgical cohort. Methods: We retrospectively analyzed 214 patients undergoing partial or radical nephrectomy for ccRCC (2010–2021). Loss of BAP1 and PBRM1 expression was assessed by automated immunohistochemistry. Tumors with retained expression were classified as wild-type and compared with those showing loss of at least one marker. Survival outcomes were evaluated using Kaplan–Meier analysis, multivariable Cox models, and Restricted Mean Survival Time (RMST). Results: IHC-defined loss was identified in 19 patients (8.9%): BAP1 in 12 (5.6%) and PBRM1 in 7 (3.3%). Tumors with IHC-defined loss showed more aggressive features, including larger size (7.7 vs. 4.7 cm; p = 0.009), higher necrosis (36.8% vs. 18.5%; p = 0.050), and more advanced stage (pT3–pT4: 47.4% vs. 16.4%; p < 0.001). Kaplan–Meier analysis demonstrated significantly worse survival outcomes in the IHC-loss group across all endpoints (p ≤ 0.011). RMST analysis at 60 months confirmed significantly worse outcomes across all endpoints (p ≤ 0.005). Conclusions: Loss of BAP1 or PBRM1 identifies a biologically aggressive ccRCC subset with worse oncological outcomes. IHC-based molecular profiling is a practical and accessible tool for risk stratification in surgically treated ccRCC. Full article

Spinal cord hemangioblastomas are rare, benign, and highly vascular tumors that occur sporadically or in association with von Hippel–Lindau disease. Despite their histological benignity, they often cause significant morbidity due to progressive neurological deficits, syrinx formation, and recurrence in the von Hippel-Lindau population. We performed a comprehensive review of the literature by searching PubMed, EMBASE, and Scopus for studies published in English on spinal cord hemangioblastomas. Eligible studies included original research, case series, and case reports with explicit clinical outcomes or management strategies for pathologically or radiographically confirmed SCHb. Gross total resection is feasible in most cases, leading to durable tumor control and favorable neurological outcomes. Preoperative embolization has been employed selectively to reduce intraoperative bleeding. Radiotherapy, particularly stereotactic radiosurgery, has shown promising local control for surgically inaccessible or recurrent lesions, while conventional external beam approaches provide less consistent results. Anti-angiogenic agents have demonstrated anecdotal benefit, and the HIF-2α inhibitor belzutifan represents the first systemic therapy approved by the FDA for VHL-associated hemangioblastomas. The management of SCHb requires an individualized, multimodal strategy. Microsurgery remains the cornerstone of treatment; radiotherapy and pharmacotherapy are valuable adjuncts for specific clinical scenarios. Further prospective studies are needed to optimize patient selection and integration of these therapies. Full article

Background/Objectives: Hemangioblastomas are rare, benign, highly vascular tumors of the central nervous system, frequently associated with von Hippel–Lindau (vHL) disease. Case Presentation: We report a 16-year-old female with vHL presenting with recurrent headaches, abdominal distension, and ocular discomfort. Imaging revealed hemangioblastomas in the fourth ventricle and retrobulbar space, alongside multiple pancreatic cysts. The patient underwent three sessions of Gamma Knife Surgery (GKS) with initial tumor regression and symptom relief. However, long-term follow-up demonstrated progressive disease, with new lesions in the cerebellum, spinal cord, and orbit, including cystic transformation. Histopathology confirmed the reticular variant of hemangioblastoma. Despite further radiosurgical and surgical recommendations, the patient and family opted for conservative management, with lesions remaining radiographically stable over nine years. Conclusions: This case demonstrates that Gamma Knife Surgery may provide temporary local disease control for selected solid hemangioblastomas in von Hippel–Lindau disease but does not alter the underlying disease course. Long-term radiographic stability should be interpreted cautiously, as hemangioblastomas exhibit saltatory growth patterns that make it difficult to distinguish treatment effect from natural tumor quiescence. These findings emphasize that radiosurgery should be regarded as a disease-control strategy rather than curative therapy, underscoring the importance of individualized management, multidisciplinary decision-making, and prolonged surveillance. Full article

The oncogenic transcription factor MYC is a key driver of the development and progression of various types of cancer, but its intrinsically disordered structure and dependence on protein–protein interactions make it a difficult therapeutic target. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that can induce the selective degradation of disease-relevant proteins. In this study, we report the synthesis and biological testing of a series of novel MYC-targeted PROTACs derived from the MYC inhibitor EN4. These ligands were conjugated to cereblon (CRBN) or von Hippel–Lindau (VHL) E3 ligase recruiters using different linker architectures and connection sites. The resulting PROTACs were synthesized in high purity and characterized analytically. Cellular evaluation in HEK293T, Panc-1 and HCT-116 cancer cells revealed only moderate reductions in cell viability. Unfortunately, none of the synthesized PROTACs showed detectable MYC degradation at biologically relevant concentrations. Testing the stability of the PROTACs in microsomes showed rapid degradation, which may be a reason for the observed inactivity in cells. These results underscore the significant challenges associated with the targeted protein degradation of intrinsically disordered transcription factors such as MYC. Further studies are necessary to identify additional causes for the lack of MYC degradation and to optimize the chemical structures accordingly. Full article

Background/Objectives: Von Hippel–Lindau (VHL) disease is a rare autosomal dominant hereditary disorder. Central nervous system hemangioblastomas are one of the most common tumor types associated with VHL disease. Although these tumors are histologically benign, delayed diagnosis and treatment may result in severe neurological dysfunction, permanent disability, and even death. However, little is known about the experiences of patients with VHL disease. The aim of this study was to gain a better understanding of the illness experiences and psychological responses of patients with VHL disease accompanied by central nervous system hemangioblastomas. Methods: A qualitative study based on a semi-structured guide was conducted. Twelve participants were recruited. Data were collected through face-to-face interviews and analyzed using the constant comparative method. Results: Four themes and their subthemes were identified: 1. powerlessness—unpredictable disease progression and uncontrollable continuity; 2. negative emotional experiences—guilt and self-blame, depression, and low self-esteem; 3. compromise—acceptance of fate, positive outlook, and sense of hope; and 4. persistent worry—worries about family members, anxiety regarding finances and employment, and uncertainty regarding the future. Conclusions: This study identified four major themes in the illness experiences of patients with VHL disease accompanied by central nervous system hemangioblastomas, which provided deep insights into the care needs of individuals with VHL disease. Healthcare providers should develop effective measures to enhance patients’ ability to maintain a good quality of life and confront the future with resilience. Full article

Background/Objectives: Advances in the genetic understanding of pheochromocytoma–paraganglioma (PPGL) have considerably refined personalized approaches to diagnosis and management. This study aims to present our institutional experience on the diagnostic characteristics, clinical course, and genetic background of patients with PPGL, in the context of the current literature. Methods: This retrospective analysis included 35 patients diagnosed with PPGL between years 2020 and 2024, all of whom underwent surgical resection and next-generation sequencing for germline mutations in major PPGL susceptibility genes. Clinical presentation, biochemical profile, pathological findings, and follow-up outcomes were compared between mutation-positive and mutation-negative cases. Results: Of the 35 patients with PPGL, germline mutations were identified in 6 patients (17%): 2 in Cluster 1A genes (SDHA, SDHB), 2 in Cluster 1B (VHL), and 2 in Cluster 2 (NF1). Consistent with existing literature, pathogenic germline variants—particularly SDHB and VHL—were identified in our cohort exclusively in patients younger than 30 years (ages 17, 20, and 25). Mutation-positive patients more frequently exhibited noradrenergic or non-secretory profiles (p = 0.01). Among the three non-secretory tumors in the cohort, two harbored genetic mutations (SDHA, NF1). Interestingly, both NF1-positive patients were normotensive—one (c.3496G > A) with a non-secretory tumor and the other (c.2329T > A) presenting at an unusually late age (63 years)—a strikingly atypical spectrum that underscores the phenotypic variability of NF1-associated PPGL. Bilateral disease was observed exclusively in VHL carriers (p = 0.03). Importantly, we identified a rare VHL c.369delG frameshift variant, not previously reported in association with PPGLs, in a patient with PPGL. No significant difference was observed between SDHB loss (p = 0.1) and proliferative indices (mitotic count, Ki-67) (p = 0.07, p = 0.6) between the two groups. During a median follow-up of 24 months (IQR: 18–36), one SDHB-positive patient had a recurrence, while no distant metastases were detected in the remaining mutation carriers. Conclusions: These findings support characteristic clinical patterns among mutation-positive PPGL and underscore the importance of systematic germline testing in all cases—irrespective of age, family history, or biochemical profile—to guide individualized management and enable cascade screening. The identification of a rare VHL c.369delG variant, previously unreported in association with PPGL, within a characteristic VHL-related clinical phenotype highlights the importance of this association. Similarly, atypical NF1 cases emphasize phenotypic variability and reinforce the importance of germline testing even in clinically silent presentations. Full article

Background: Emerging evidence suggests that lipedema may share hormonal, inflammatory, and genetic mechanisms with gynecologic diseases, particularly endometriosis. However, the extent and nature of these interrelationships remain poorly characterized, supporting the need for this scoping review. Objectives: To map and synthesize the available evidence on the clinical, pathophysiological, and epidemiological interrelationships between lipedema in women, endometriosis, and other gynecologic diseases. Methods: Searches were conducted in international and regional health databases, including MEDLINE (PubMed), CINAHL, Scopus, Embase, Web of Science, the Cochrane Library, LILACS/VHL, APA PsycInfo, SciELO, Epistemonikos, and La Referencia, as well as grey literature sources and relevant institutional websites. There were no language restrictions. The search period began in 1940, the year in which lipedema was first described by Allen and Hines. Study selection followed a two-stage process conducted independently by two reviewers, consisting of title and abstract screening followed by full-text review. Data extraction was performed using a pre-developed and peer-reviewed instrument covering participants, concept, context, study methods, and main findings. The review protocol was registered in the Open Science Framework. Results: Twenty-five studies from ten countries were included. Synthesized evidence supports the characterization of lipedema as a systemic condition with metabolic and hormonal dimensions. Key findings include symptom onset linked to reproductive milestones, a high frequency of gynecologic and endocrine comorbidities, and molecular features overlapping with steroid-dependent pathologies. These patterns reflect a recent shift from a predominantly lymphovascular paradigm toward a more integrated endocrinometabolic framework. Conclusions: The findings indicate that lipedema clusters with hormone-sensitive gynecologic and endocrine features across reproductive life stages. Full article

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect, and its complications (namely, dilatation of the thoracic ascending aorta) raise concerns regarding the proper timing of aortic surgery. The study aim is to unravel the genetic basis of BAV and its complications through a high-throughput sequencing (HTS) approach and segregation analysis if family members were available. Methods: Fifty-two Italian BAV patients were analyzed by HTS using the Illumina MiSeq platform. Targeted sequencing of 97 genes known to be or plausibly associated with connective tissue disorders or aorthopathy was performed. Thirty-five first-degree relatives of N = 10 probands underwent mutational screening for variants identified in the index cases. Results: HTS identified 194 rare (MAF < 0.01) variants in 63 genes. Regarding previously reported genes, five NOTCH1 variants in four BAV patients, four FBN1 variants in two patients and one GATA5 variant in one patient were identified. Interestingly, among further loci, the possible contribution of PDIA2, LRP1 and CAPN2 was suggested by (a) the increased prevalence of rare genetic variants, independently from their ACMG classification in the whole BAV cohort, and (b) segregation analyses of variants identified in family members. Moreover, the present data also suggest the possible contribution of rare variants to BAV complications, specifically MYLK in aortic dilatation, CAPN2 in BAV calcification and VHL and AGGF1 in valve stenosis. Conclusions: Our results underline clinical and genetic diagnosis complexity in traits considered monogenic, such as BAV, but characterized by variability in disease phenotypic expression (incomplete penetrance), as well as the contribution of different major and modifier genes to the development of complications. Full article

Von Hippel–Lindau disease-associated endolymphatic sac tumors (VHL-associated ELSTs) present diagnostic challenges due to their rarity and nonspecific symptoms. This study describes clinical, pathological and genotypic features to guide treatment. We retrospectively analyzed seven patients with VHL-associated ELSTs. The mean age of otologic symptom [hearing loss (100%) and facial nerve paralysis (85.71%)] onset was 22.43 ± 8.68 years (range: 10–33). Surgical management included trans-labyrinthine and subtotal temporal bone resection approaches. Among three patients with severe preoperative facial nerve dysfunction, two underwent great auricular nerve grafting improved to House–Brackmann grade IV, while one receiving hypoglossal–facial nerve anastomosis reached grade V. Genetic testing identified pathogenic VHL gene missense mutations in three patients. Two female patients demonstrated disease progression during pregnancy. Literature analysis revealed exon-specific patterns: Exon 1 mutations correlated with cerebellar/spinal hemangioblastomas in female patients, while Exon 3 mutations were associated with multisystem tumors. These findings support that VHL-associated ELSTs manifest early with otologic symptoms and demonstrate exon-specific phenotypic patterns. Optimal management requires complete surgical resection, genetic diagnosis, and a multidisciplinary approach to address these complex tumors and achieve favorable outcomes. Full article