Search Results (61)

Introduction: Hemangioblastomas (HBs) are benign, highly vascular tumors that can be found intracranially or in the spinal region, representing around 2–15% of primary intramedullary tumors. They can occur sporadically or in association with Von Hipple–Lindau (VHL) disease. Despite recent of advancement of nonsurgical treatments, complete surgical resection remains the gold standard of care for the spinal HBs. Materials and Methods: We conducted an international multicenter retrospective analysis of adult patients surgically treated for spinal HBs in four European referral centers between January 2000 and September 2024, with a minimum post-operative follow-up duration of 6 months. Patients’ sex and age at surgical intervention, clinical presentation, and duration symptoms prior to clinical diagnosis were identified. The pre- and post-operative neurological status at 1 and 6 months and at the last visit was assessed using the modified McCormick score (MCS). The extent of surgical resection was divided into gross total resection (GTR) and subtotal resection (STR). Finally, post-operative complications were inspected as well, namely cerebrospinal fluid leaks, infections, hemorrhages and post-operative spinal stability. Results: A total of 35 patients were included in the cohort, with an age median of 52 years (34.5–60) and a slight male predominance (21/35, i.e., 60%). The median follow-up period was 37.5 months (12–75). More than half were located in the cervical region, making it the most common (54.3%). Syrinxes were observed in 23 cases (72%), and HBs were more commonly intramedullary (80%). GTR was achievable in around 88% of cases. Post-operative complications were observed in nine patients (25.7%). Nearly half of patients were discharged into rehabilitations centers (48.5%). Tumor recurrence was seen in 10.3% only. At the last follow-up, an excellent overall post-operative neurological status (positive ∆ McCormick) was observed in most of patients (88%) and was found to be associated with a relatively younger age group. Tumor location and presence of syrinxes did not show any statistical significance regarding clinical outcome. In patients having benefited from intra-operative monitoring, only D-wave changes showed statistical significance regarding post-operative outcome (p < 0.05). Conclusions: A large majority of patients operated for a spinal HB demonstrated favorable outcome after surgery, with unchanged or improved neurological status. Advanced age could have an impact on the post-operative neurological outcome. Other factors such as tumor size, location, and the presence of syrinx did not seem to significantly impact the neurological outcome. Finally, the surgery of these vascular lesions with no possibility of debulking or piece-meal removal and requiring “en bloc” resection is technically demanding and should be performed by experienced teams in spine and spinal cord surgery only. Full article

von Hippel–Lindau syndrome (VHLS) is a hereditary cancer syndrome with CNS hemangioblastomas, clear cell renal carcinoma, pheochromocytoma, retinal angiomas, and a number of other manifestations. VHLS is caused by a mutation in the VHL gene and is inherited in an autosomal dominant manner. However, some cases of VHLS develop de novo, and among them, there are rare patients with a mosaic form of the disease. Genetic testing in mosaic patients is prone to false-negative results due to the low copy number of a mutant allele in DNA isolated from the blood. We describe a case of molecular genetic diagnostics of VHLS in a 39-year-old patient using various methods, including mutation analysis in asynchronous primary tumors and repeated DNA analysis from blood using NGS with high coverage for the mutant position. As a result, the patient was diagnosed with a mosaic form of VHLS caused by the variant c.481C>T (p.Arg161Ter), the proportion of which in the blood DNA was 2%. We also summarized the literature data on the mosaic form of VHLS: the severity of clinical manifestations, the features of differential diagnostics of VHLS with a negative result of routine molecular genetic VHL testing, and specific options of active surveillance and treatment for mutation carriers. Full article

Background and Objectives: Von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and can develop various cancers. Hypoxia-inducible factors 1 and 2 alphas, regulated by the VHL gene, can increase the levels of vascular endothelial growth factor, thereby activating cancer progression. Here, we demonstrated clinical and prognostic values of VHL expression in rectal cancer (RC). Materials and Methods: Von Hippel–Lindau mRNA expression was examined in 60 patients with RC. Furthermore, we evaluated survival to determine the prognostic significance of VHL mRNA expression levels in RC using the Cancer Genome Atlas (TCGA) data. Results: Lower VHL expression was correlated with the recurrence (p = 0.058) and lymphatic invasion (p = 0.078), although it was not statistically significant. In TCGA data, VHL expression level was correlated with the M stage (p = 0.044); however, it had a possible association with lymphatic invasion (p = 0.068) and N stage (p = 0.104). Survival analysis showed that lower VHL gene expression predicted poorer survival in both patients with RC and TCGA data. Conclusions: This study identified a significant correlation between VHL gene expression and RC for the first time using patient tissues and TCGA data, suggesting that the VHL gene expression level could be a potential biomarker or candidate for the treatment of RC. Further studies are required to identify the molecular pathogenesis and clinical characteristics of VHL disease in RC. Full article

Background and Objectives: Seminoma is the most common solid malignant tumour in young men. Clear-cell kidney carcinoma is the most common malignancy of the genitourinary tract. However, the synchronous occurrence of both of these tumours is rare. Case presentation: We present the case of a 36-year-old patient who presented to a medical facility at the end of 2019 with an enlarged right testicle. A unilateral orchofuniculectomy was performed, and a mass measuring 30 cm was removed. During histological examination, testicular seminoma pT2, R0, was diagnosed. An abdominal computed tomography (CT) scan showed a 6.4 cm × 6.8 cm × 6.7 cm tumour in the right kidney and a metastatic-like lesion in the right adrenal gland. A right nephrectomy and an adrenalectomy and paraaortic and paracaval lymphadenectomies were performed. A histological evaluation confirmed the presence of clear-cell renal carcinoma pT2aR0 G2, adrenal hyperplasia, and seminoma metastases in the removed lymph node. Chemotherapy with a Bleomycin, Etoposide, and Cisplatin (BEP) regimen was carried out. Three years after the last cycle of chemotherapy, a follow-up CT scan showed metastases in the left kidney, the right ischium, and the right lung. A well-differentiated clear-cell carcinoma G1 of the left kidney and metastasis of clear-cell carcinoma G2 in the right ischium were confirmed after the biopsy, and no tumour lesions were found in the lung tissue specimen. Treatment with targeted therapy with Sunitinib was started because the risk was favourable according to the Heng criteria. Genetic testing was performed, and the following genes were analysed: VHL, BAP1, CHEK2, FH, MET, MUTYH, APC, and STK11. The testing did not reveal any pathogenic or potentially pathogenic mutations or sequence changes of unknown clinical significance in the genes analysed. Conclusions: According to the authors, the occurrence of synchronous primary tumours is linked to one’s genetic predisposition. DNA sequencing of tumour tissue could provide more information on the corresponding aetiopathogenesis. Full article

Purpose: To delineate the genotype and phenotype of RH in a Chinese cohort. Methods: A group of 51 Chinese probands with RH across 76 eyes was assembled and underwent complete retinal imaging examinations. Sanger sequencing and universal primer quantitative fluorescent multiplex–polymerase chain reaction (UPQFM-PCR) were employed for mutation detection in the coding region of the Von Hippel–Lindal (VHL) gene. For frequency calculation, our series was combined with three large cohorts of East Asian descent through a literature review. Results: The Von Hippel–Lindal (VHL) syndrome was excluded in fifteen patients (median age: 32.00 years) with unilateral solitary RH. Thirty-six patients of younger ages (median: 22.00 years, p = 0.008, Mann–Whitney test) conformed to the diagnostic criteria of the VHL syndrome, and thirty-four patients were genetically confirmed. There were four novel variants identified in the VHL gene. Codons 167, 161 and 86 exhibited a mutation occurrence of more than 5% after pooling with literature data, and the large genomic deletion demonstrated a frequency of 17.65%. The RHs were classified as “extrapapillary”, “juxtapapillary” and “mixed” types in 53, 7 and 5 eyes, respectively. Almost all extrapapillary RH lesions were found in the peripheral retina. Hemangioblastomas in the central nervous system (CNS) were observed in 25 out of 31 kindreds (80.65%) with full systemic evaluation data. Conclusions: VHL-associated RH might exhibit earlier onset than non-VHL RH. Large genomic deletions were observed at a notably high frequency in the Chinese series with VHL-associated RH, which might be associated with East Asian ethnicity background. RH could potentially serve as an early indicator of CNS hemangioblastoma. Full article

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel–Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein–protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions. Full article

This review article focuses on von Hippel–Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. Genetics: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. Pathophysiology: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. Clinical Manifestations: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. Diagnosis: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. Treatment: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. Challenges: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease. Full article

Introduction: Renal cell carcinoma is one of the ten more common malignant tumors worldwide, with a high incidence and mortality rate. Kidney cancer frequently presents at an advanced stage, and it is almost invariably fatal. Much progress has been made in identifying molecular targets for therapy in the hope of improving survival rates, but still, we have no good markers for early detection or progression of the disease. Von Hippel Lindau syndrome (VHL) is an autosomal dominant cancer hereditary syndrome in which affected individuals are at risk of developing bilateral and multifocal renal cell carcinomas (RCC) as well as other tumors. These patients provide an ideal platform to investigate the potential of urinary exosomal miRNA biomarkers in the early development of ccRCC, as these patients are regularly imaged and tumors are actively monitored until the tumor reaches 3 cm before surgical excision. This allows for pre- and post-surgical urine collection and comparison to excised tumor tissues. Studying different biomarkers in urine can provide comprehensive molecular profiling available to patients and physicians and can be a great source of additional tumor genetic information. Methods: Pre- and postoperative urine samples were obtained from a cohort of VHL patients undergoing surveillance and surgical excision of ccRCCs, and exosomes were extracted. MicroRNA-Seq analysis was performed on miRNA extracted from both urine-derived exosomes and FFPE material from excised ccRCCs. Results: MicroRNA-Seq analysis highlighted a significant difference in the urinary exosome-derived miRNA expression profiles between VHL patients and normal control individuals. This included decreased expression of the miR-320 family, such as miR-320a, known to be decreased in sporadic ccRCC and suppressed by the HIF1α transcription factor activated by the loss of the VHL gene. MiR-542-5p represented a potential marker of VHL-associated ccRCC that was lowly expressed in normal control urinary exosomes, significantly increased in the preoperative urinary exosomes of tumor-bearing VHL patients, and subsequently reduced to normal levels of expression after tumor excision. In concordance with this, the expression of miR-542-5p was increased in the VHL-associated ccRCC in comparison to the normal kidney. Conclusions: This study shows the potential for miRNA profiling of exosomes from readily available biofluids to both distinguish VHL patient urine from normal control urine microRNAs and to provide biomarkers for the presence of VHL syndrome-associated ccRCC. Further validation studies are necessary to demonstrate the utility of urinary exosome-derived miRNAs as biomarkers in kidney cancer. Full article

Background: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined. Patients and Methods: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care^® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis. Results: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort. Conclusions: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1-independent mutational driver of RCC in patients with ACKD. Full article

An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: Scn1a KO mice have a high number of apoptotic neurons following seizures, but the precise mechanism underlying this remains unclear. The aim of this research was to elucidate the potential molecular mechanism of neuronal apoptosis in Scn1a KO mice by integrating proteomics and transcriptomics, with the ultimate goal of offering better neuroprotection. We found that apoptotic processes were enriched in both proteomic and transcriptomic GO analyses, and KEGG results also indicated that differential proteins and genes play a role in neurotransmission, the cell cycle, apoptosis, and neuroinflammation. Then, we examined the upstream and downstream KGML interactions of the pathways to determine the relationship between the two omics, and we found that the HIF-1 signaling pathway plays a significant role in the onset and apoptosis of epilepsy. Meanwhile, the expression of the apoptosis-related protein VHL decreased in this pathway, and the expression of p21 was upregulated. Therefore, this study suggests that VHL/HIF-1α/p21 might be involved in the apoptosis of hippocampal neurons in Scn1a KO mice. Full article

Bacterial resistance to antibiotics makes infections increasingly difficult to fight. In this context, the antimicrobial capacity of Lippia origanoides proved to be a relevant alternative. The purpose of this review is to evaluate the antibacterial activity of this essential oil against bacterial strains. This is a narrative review of the literature using the following guiding question: “Does Lippia origanoides essential oil have antimicrobial activity against bacterial strains?”. The descriptors “Lippia origanoides” and “Antimicrobial activity” were applied to the PubMed, Virtual Health Library (VHL) and Embase databases. The inclusion criteria were as follows: contain, whether in the title, abstract or body of the text, a relationship with the antibacterial activity of L. origanoides, and the possibility of accessing the full article. A total of 62 articles were found and 19 studies were chosen. A total of 13 bacteria were analyzed in the tests and the Minimum Inhibitory Concentration (MIC) was as follows: Bacillus cereus (0.62 μL/mL), Bacillus subtilis (1.25 μL/mL), Staphylococcus aureus (1.25–60 μL/mL), Chromobacterium violaceum (0.37 μL/mL), Escherichia coli (0.15–60 μL/mL), Pseudomonas aeruginosa (240 μL/mL), Salmonella cholerasuis (30 μL/mL), Salmonella thypimurium (1.25 μL/mL) and Vibrio parahaemolyticus (0.313 μL/mL). In Bifidobacterium breve and Lactobacillus acidophilus, the Minimum Bactericidal Concentration (MBC) was, respectively, 50 μL/mL and 3.135 μL/mL. In Staphylococcus epidermidis and Salmonella enteritidis, there was only MIC₅₀ (concentration to inhibit 50% of the sample), specifically, 0.37–3.0 μL/mL and 0.37 μL/mL. In total, 27.3% of articles evaluated the antibiofilm capacity of L. origanoides, and the inhibition of biofilm formation reached more than 70% in E. coli and S. aureus. Lippia origanoides essential oil revealed antimicrobial activity in all studies. Ultimately, P. aeruginosa proved to be a strain that still requires further experimentation. Full article

Introduction: Urological cancers account for a significant portion of cancer diagnoses and mortality rates worldwide. The traditional treatment options of surgery and chemoradiation can have significant morbidity and become ineffective in refractory disease. The discovery of the CRISPR system has opened up new avenues for cancer research by targeting specific genes or mutations that play a role in cancer development and progression. In this review, we summarise the current state of research on CRISPR in urology and discuss its potential for improving the diagnosis and treatment of urological cancers. Methods: A comprehensive literature search was conducted on databases including PubMed, Embase, and Cochrane Library. The keywords included CRISPR and urology OR prostate OR renal OR bladder OR testicular cancer. Results: CRISPR has been used extensively in a preclinical setting to identify and target genes in prostate cancer, including AR, NANOG, ERβ, TP53, PTEN, and PD-1. Targeting PRRX2 and PTEN has also been shown to overcome enzalutamide and docetaxel resistance in vitro. In bladder cancer, CBP, p300, hTERT, lncRNA SNGH3, SMAD7e, and FOXA1 have been targeted, with HNRNPU knockout demonstrating tumour inhibition, increased apoptosis and enhanced cisplatin sensitivity both in vitro and in vivo. Renal cancer has seen CRISPR target VHL, TWIST1, PTEN, and CD70, with the first in-human clinical trial of Anti-CD70 CAR T cell therapy showing an excellent safety profile and durable oncological results. Lastly, testicular cancer modelling has utilised CRISPR to knockout FLNA, ASH2L, HMGB4, CD24, and VIRMA, with NAE1 found to be over-expressed in cisplatin-resistant germ cell colonies. Conclusions: CRISPR is a cutting-edge technology that has been used extensively in the pre-clinical setting to identify new genetic targets, enhance drug sensitivity, and inhibit cancer progression in animal models. Although CAR T cell therapy has shown promising results in RCC, CRISPR-based therapeutics are far from mainstream, with further studies needed across all urological malignancies. Full article

O₂ is essential for the life of eukaryotic cells. The ability to sense oxygen availability and initiate a response to adapt the cell to changes in O₂ levels is a fundamental achievement of evolution. The key switch for adaptation consists of the transcription factors HIF1A, HIF2A and HIF3A. Their levels are tightly controlled by O₂ through the involvement of the oxygen-dependent prolyl hydroxylase domain-containing enzymes (PHDs/EGNLs), the von Hippel–Lindau tumour suppressor protein (pVHL) and the ubiquitin–proteasome system. Furthermore, HIF1A and HIF2A are also under the control of additional post-translational modifications (PTMs) that positively or negatively regulate the activities of these transcription factors. This review focuses mainly on two PTMs of HIF1A and HIF2A: phosphorylation and acetylation. Full article

von Hippel-Lindau (VHL) disease, due to mutations of the tumor suppressor VHL gene, is a rare hereditary syndrome with a high risk of developing clear cell renal cell carcinoma (ccRCC). We asked whether the VHL-C162F mutation interferes with proliferation, migration, healing and forming colony ability by using wild-type VHL (WT VHL) and VHL-C162F reconstituted cells. We then analyzed the in vitro impact of the sunitinib treatment on VHL-C162F cells. We showed that VHL-C162F mutations have no impact on cell morphology, colony formation and migration ability but confer a significant higher healing ability than in WT VHL cells. RNA sequencing analysis revealed that VHL-C162F mutation upregulates genes involved in hypoxia and epithelial mesenchymal transition (EMT) pathways by comparison with VHL WT cells. We next showed a decrease in healing ability in VHL-C162F cells depleting on ZHX2, an oncogenic driver of ccRCC, highlighting the potential involvement of ZHX2 in aggressiveness of the VHL-C162F cells. Moreover, we found that sunitinib treatment inhibits ZHX2 expression and induces a reduced proliferation correlating with downregulation of P-ERK. Sunitinib treatment also conferred a more mesenchymal profile to VHL-C162F cells with significant downregulation of E-cadherin and upregulation of N-cadherin, Slug and AXL. Sunitinib therapy may therefore promote disease progression in VHL-C162F patients. Full article

Exosomes are extracellular vesicles that modulate essential physiological and pathological signals. Communication between cancer cells that express the von Hippel-Lindau (VHL) tumor suppressor gene and those that do not is instrumental to distant metastasis in renal cell carcinoma (RCC). In a novel metastasis model, VHL(−) cancer cells are the metastatic driver, while VHL(+) cells receive metastatic signals from VHL(−) cells and undergo aggressive transformation. This study investigates whether exosomes could be mediating metastatic crosstalk. Exosomes isolated from paired VHL(+) and VHL(−) cancer cell lines were assessed for physical, biochemical, and biological characteristics. Compared to the VHL(+) cells, VHL(−) cells produce significantly more exosomes that augment epithelial-to-mesenchymal transition (EMT) and migration of VHL(+) cells. Using a Cre-loxP exosome reporter system, the fluorescent color conversion and migration were correlated with dose-dependent delivery of VHL(−) exosomes. VHL(−) exosomes even induced a complete cascade of distant metastasis when added to VHL(+) tumor xenografts in a duck chorioallantoic membrane (dCAM) model, while VHL(+) exosomes did not. Therefore, this study supports that exosomes from VHL(−) cells could mediate critical cell-to-cell crosstalk to promote metastasis in RCC. Full article