RARE DISEASE
Hemangioblastoma
Hemangioblastoma
Hemangioblastoma
Drug discovery
0
drugs
With orphan designations
Overview
Hemangioblastomas are benign (WHO grade 1) vascular CNS tumors arising in the cerebellum (62%), spinal cord (14%), or brainstem [2][6][12]. They occur sporadically (70-80%) or as part of von Hippel-Lindau disease (VHL) [7][11]. Symptoms include headaches, ataxia, and focal neurological deficits due to mass effect or cystic components [5][16]. Diagnosis relies on MRI demonstrating enhancing nodules with flow voids [11]. Complete surgical resection remains curative for accessible tumors, while stereotactic radiosurgery and HIF-2α inhibitors (belzutifan) are used for recurrent/multiple lesions [5][13][17]. Genetic testing for VHL is recommended [10].
Categories: rare neoplastic diseases, rare neurological diseases
Research Papers
730 drug discovery papers about Hemangioblastoma, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
730 drug discovery papers about Hemangioblastoma, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-18 | Von Hippel-Lindau disease: Ocular manifestations, surveillance, systemic associations, and emerging molecular therapies.
Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary tumour predisposition syndrome affecting multiple organ systems, including the retina, central nervous system, kidneys, pancreas, adrenal glands, and inner ear. It is caused by pathogenic variants in the VHL gene, resulting in loss of functional pVHL, abnormal stabilization of hypoxia-inducible factor (HIF)-α subunits, and activation of downstream transcriptional programmes involved in angiogenesis, metabolism, cell survival, and tumour growth. Clinically, VHL is characterized by a spectrum of benign and malignant neoplasms that require lifelong surveillance and multidisciplinary management. Retinal hemangioblastomas are among the earliest manifestations and may provide the first clue to diagnosis of this multisystem disorder. Historically, management has relied on screening, surveillance, and local treatment according to lesion size, location, symptoms, and malignant potential. The emergence of HIF-2α-targeted therapy, particularly belzutifan, has begun to change this paradigm by offering a mechanism-based systemic treatment option for selected VHL-associated tumours. In this review, we summarize the ocular and systemic manifestations of VHL, its genetic and molecular basis, genotype-phenotype correlations, contemporary surveillance strategies, current local therapies, and the emerging role of HIF-2α inhibition in reshaping management.
2026-09-16 | Oral belzutifan treatment in von hippel-lindau-associated retinal hemangioblastoma: a promising approach.
Von Hippel-Lindau (VHL)-associated retinal hemangioblastomas (RHs) may cause vision-threatening exudation and hemorrhage. Conventional local therapies may be limited in advanced, recurrent, or anatomically high-risk lesions. This study evaluated ocular outcomes and observed tolerability during oral belzutifan treatment in a real-world cohort. Between January 2023 and June 2025, this retrospective observational study included five consecutive patients with genetically confirmed VHL, contributing seven eyes; each eye had at least one RH that progressed despite prior conventional local therapy. Patients received oral belzutifan 120 mg once daily. Median on-treatment follow-up (FU) was 43 weeks (IQR, 27-50); median documented cumulative belzutifan exposure was 43 weeks (range, 27-50). Data were available through January 2026. Tumor regression was quantified as the relative change in projected pixel area from baseline to last on-treatment FU. The largest baseline lesion per fundus-imaged eye was predefined for the primary analysis; all fundus-imaged lesions were assessed exploratorily. Fourteen fundus-imaged RHs were included in the projected-pixel-area analyses, and one MRI-assessed RH was reported separately. Three retinal specialists independently performed lesion measurements and exploratory overall ocular response (OOR) grading as separate assessments. Readers were masked to one another's assessments; quantitative lesion measurements were additionally masked to patient information, treatment course, and image chronology. Safety was monitored within an interdisciplinary clinical framework. In the predefined primary descriptive analysis of the largest baseline lesion per fundus-imaged eye (six eyes from four patients), all six index lesions regressed (median projected-pixel-area reduction, 58.3%; IQR, 17.2-64.7%). All four lesions in the patient-level sensitivity analysis regressed (median, 59.6%; range, 14.5-64.8%). Across all 14 fundus-imaged lesions, median regression was 57.2% (IQR, 28.5-66.9%), and 11/14 lesions (78.6%) showed > 20% regression. All three readers classified all six evaluable eyes as improved. Exudative retinal detachment resolved in three of four affected eyes. Drug-related adverse events were mostly mild to moderate and manageable. Oral belzutifan was associated with RH regression and improved exudative disease activity in this selected real-world cohort. These findings support systemic HIF-2α inhibition as a potential adjunctive therapeutic option for selected patients with progressive or anatomically high-risk ocular VHL disease. Prospective validation is required. not applicable. Not applicable.
2026-08-18 | Clinical outcomes of HIF-2α inhibition in Von Hippel-Lindau disease: a multicenter real-world study.
Management of von Hippel-Lindau (VHL) disease is challenging due to multisystem involvement and limited systemic treatment options. Belzutifan has shown promising efficacy in clinical trials; however, real-world data remain limited. We aimed to evaluate its effectiveness and safety in a real-world cohort. We conducted a retrospective study of 59 patients with VHL disease treated with belzutifan between August 2021 and January 2026. Objective response rates (ORR) for renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS HB), and pancreatic neuroendocrine tumors (pNET) were assessed by an independent radiologist. Retinal hemangioblastoma outcomes were evaluated through ophthalmology records by chart review. Median follow-up was 29 months. ORR was 27.6%, 39.6%, and 85.7% for RCC, CNS HB, and pNET, respectively. Among 13 patients with retinal hemangioblastomas (20 eyes), 17 eyes (85%) showed improvement. At data cutoff, 47 patients (79.6%) remained on treatment, while 12 (20.3%) discontinued (7 due to adverse events, 3 to disease progression, and 2 to other reasons). The most common adverse event was anemia (86.4%). Grade ≥3 adverse events occurred in 10 patients (16.9%). The procedure rate per patient-year decreased from 0.35 in the 3 years prior to treatment to 0.08 during follow-up (Incidence Rate Ratio, 0.23; 95% CI, 0.12-0.47; P < .001). Belzutifan demonstrated efficacy across VHL-associated lesions, with a favorable safety profile. Most adverse events were grade 1-2. A reduction in procedure rate was observed after treatment initiation.
2026-08-16 | [Treatment of von Hippel-Lindau Disease and Hemangioblastoma].
Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterized by the development of neoplasms in multiple organs. Hemangioblastoma is one of the most common tumors associated with VHL disease. In 2024, the "Clinical Practice Guidelines for VHL Disease" were established in Japan to provide guidance for the diagnosis, treatment, and management of VHL disease. Furthermore, in 2025, the HIF-2αinhibitor belzutifan was approved for insurance coverage in Japan for VHL-associated tumors, including hemangioblastomas. In this article, we first provide an overview of VHL disease and the "Clinical Practice Guidelines for VHL Disease," and then discuss the diagnosis and treatment of hemangioblastomas, including surgery, endovascular therapy, and radiotherapy. Finally, we review the role of the HIF-2αinhibitor belzutifan. In the future, management of VHL disease and hemangioblastomas will likely require not only individual treatment modalities, but also optimal multimodal strategies combining surgery, radiotherapy, and systemic drug therapy.
2026-08-14 | Von Hippel-Lindau Syndrome: An Updated Narrative Review for the First-Contact Clinician.
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant (AD) condition that increases the risk of developing CNS and retinal hemangioblastomas (R-Hb), as well as clear cell renal cell carcinoma (ccRCC), pheochromocytomas, pancreatic neuroendocrine tumors (pNETs), and endolymphatic sac tumors. CNS hemangioblastomas and renal cell carcinomas are among the leading causes of mortality in affected individuals. Recent therapeutic advances, particularly hypoxia-inducible factor 2 alpha (HIF-2α) inhibitors and vascular endothelial growth factor (VEGF)-targeted therapies, have yielded promising results. However, active surveillance remains the cornerstone of clinical management for reducing associated morbidity and mortality. Because VHL syndrome is multisystemic, a multidisciplinary clinical team is necessary to provide comprehensive care, including targeted pharmacotherapy and surgical resection, to prevent severe complications. This narrative review outlines the current diagnostic approach and follow-up protocols for VHL syndrome, highlighting recent therapeutic advances.
cell therapies
2026-03-19 | Comparing laminectomy and unilateral hemilaminectomy in spinal hemangioblastoma resection: A multicenter study.
This study compared laminectomy and hemilaminectomy for resection of spinal (sHBs), evaluating extent of resection, 12-month postoperative functional outcomes, perioperative complications overall, with particular attention to postoperative bleeding. This retrospective international multicenter study included 280 primary sHB patients from 13 neuro-oncological centers who underwent either laminectomy (n = 125) or hemilaminectomy (n = 155). The endpoints were the extent of resection, functional outcomes at 12 months, and postoperative bleeding requiring retreatment. Multivariable logistic regression analysis was performed to determine independent risk factors associated with these outcomes. The rate of complete resection was similar between both surgical approaches, with 86.4% in the laminectomy group and 90.3% in the hemilaminectomy group (p = 0.35). Independent predictors of incomplete resection included preoperative modified McCormick >2 (OR: 4.29, p = 0.001), combined intra- and extramedullary tumor location (OR: 2.91, p = 0.03), and cervical or thoracic tumor location (OR: 3.38, p = 0.01). Functional outcomes at 12 months did not differ significantly between the laminectomy- and hemilaminectomy-groups (p = 0.97). Postoperative bleeding was more frequently observed in tumors involving two or more spinal segments (OR: 14.6, p = 0.01). The choice of surgical approach did not impact the incidence of postoperative bleeding (p = 0.55). Laminectomy and hemilaminectomy result in comparable outcomes of sHB. Tumors affecting multiple spinal segments are associated with an increased risk of postoperative bleeding, while combined intra- and extramedullary growth, impaired preoperative functioning and non-lumbar location were associated with incomplete resection. Given the comparable outcomes, the selection of the surgical approach may be guided by surgeon preference and individual patient anatomy.
2026-01-09 | [A rare case of adrenal hemangioblastoma and literature review].
A retrospective analysis was conducted on the clinical data of a patient with adrenal hemangioblastoma (HB), pathologically confirmed at the First Medical Center of Chinese PLA General Hospital. A review of the literature relating to adrenal HB was also undertaken. The patient was a 36-year-old male in whom a right adrenal mass was incidentally detected during a physical examination. The mass measured approximately 4.7 cm×4.2 cm and had a CT attenuation value of approximately 55 HU. MRI showed an irregular mass with a slightly long T1, mixed long/short T2 signals, mildly high signal intensity on diffusion weighted imaging, and a slightly low signal on apparent diffusion coefficient. No signal drop was observed on opposed-phase imaging. Dynamic contrast-enhanced scanning revealed progressive, marked enhancement. 68Ga DOTATATE PET-CT demonstrated a slightly hypodense mass in the right adrenal gland (maximum standardized uptake value 17.3). Functional evaluation showed an elevated chromogranin A (CgA) level of 294.64 pmol/L (normal range: 64-204 pmol/L), with no other abnormalities detected. The preoperative diagnosis was pheochromocytoma, and the patient underwent surgery after adequate preoperative preparation with phenoxybenzamine hydrochloride. Immunohistochemical results-S-100 (focal weak+), melan-A (-), inhibin-α (partial+), FLI-1 (+), CK (-), Syn (partial+), CgA (-), Ki67 (2%+), CD34 (+), CD31 (+), and desmin (-)-confirmed the diagnosis of adrenal HB. Genetic testing detected no VHL gene mutation. No recurrence or metastasis was observed during more than two years of follow-up. A review of the literature revealed that this was the first reported case of adrenal HB in China. Globally, only six cases have been reported to date, four of which were clearly related to von Hippel-Lindau syndrome. Adrenal HB is exceptionally rare and lacks characteristic clinical manifestations. Significant enhancement of the solid component with flow-void vessels on MRI is considered a relatively distinctive imaging feature. Definitive diagnosis relies on pathology and immunohistochemistry. Surgical resection remains the primary treatment, and the prognosis is generally favorable.
2026-01-01 | Survival Impact of Surgery, Radiation, and Socioeconomic Factors in Spinal Hemangioblastoma: A Population-Based Study.
Spinal hemangioblastomas are rare, highly vascular benign tumors, with management typically centered on gross total resection. However, factors associated with overall survival (OS) remain poorly defined, particularly the roles of surgical extent, radiation therapy (RT), and socioeconomic variables. We aimed to evaluate clinical and demographic predictors of survival in a contemporary population-based cohort. Patients with spinal cord or cauda equina hemangioblastoma were identified from the Surveillance, Epidemiology and End Results database (1975-2022). Demographic, tumor, and treatment characteristics-including age, sex, race, income, surgical extent, and RT-were collected. Univariable and multivariable Cox proportional hazards models were used to evaluate associations with OS. Among 223 patients, older age (P<0.001) and lower household income (P=0.028) were independently associated with worse survival. Extent of resection (subtotal resection or observation vs. gross total resection) and RT were not significantly associated with OS (P=0.117). Kaplan-Meier analysis showed no survival difference by surgery (P=0.89) or between pediatric and adult patients (P=0.1), with all pediatric patients alive at last follow-up. Although RT correlated with worse survival on univariate analysis (P=0.005), this did not persist after adjustment, likely reflecting confounding by indication. Older age and lower income were associated with worse OS in patients with spinal hemangioblastoma, while neither surgical extent nor RT predicted survival. These findings suggest that subtotal resection or observation may be appropriate in select cases without compromising outcomes and emphasize the importance of addressing socioeconomic barriers in this rare, benign disease.
2025-09-25 | Role of PPV in Advanced Retinal Hemangioblastoma-A Systematic Review.
In eyes with retinal hemangioblastomas (RH), vision loss may occur despite treatment due to recurrent macular edema, macular pucker, vitreous hemorrhage, and exudative, tractional, or combined retinal detachment. Pars plana vitrectomy (PPV) plays a critical role in managing these complications. This review aims to evaluate the outcomes of PPV in patients with RH. We searched PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Google Scholar, and Web of Science (2000 to 2025) using the keywords "retinal hemangioblastoma," "capillary hemangioblastoma," "von Hippel-Lindau retina," combined with "vitrectomy," or "pars plana vitrectomy." Given the rarity of the condition, retrospective case series were included if they had ≥4 cases. Single anecdotes and non-English articles were excluded. Two independent reviewers evaluated the studies for qualitative and quantitative synthesis. Our search yielded 120 results, of which eight studies published between 2011 and 2024 met the inclusion criteria. All were retrospective case series (level IV evidence). A total of 107 eyes from 102 patients were analyzed, with sample sizes ranging from 4 to 23 eyes. Anatomic success, defined as retinal reattachment, ranged from 70% to 100% by final follow-up. However, many eyes remained in the low vision range despite anatomic success. New tumor development and proliferative vitreoretinopathy (PVR)-related complications remain key challenges in long-term management. While the evidence is limited due to study design and sample size, consistent trends across the literature suggest PPV is anatomically effective, though visual outcomes remain guarded.
2024-07-24 | Optic nerve and chiasm hemangioblastomas in von Hippel-Lindau disease: report of 12 cases and review of the literature.
Optic nerve and chiasm hemangioblastomas are rare tumors, occurring sporadically or in the context of von Hippel-Lindau (VHL) disease. They have only been portrayed in isolated case reports and small cohorts. Their natural history and therapeutic strategies are only scarcely described. To better characterize these rare tumors, we retrospectively analyzed an optic nerve and chiasm hemangioblastoma series of 12 VHL patients. By combining our own experience to a review of all known cases in literature, we intended to create treatment recommendations for optic nerve and chiasm hemangioblastomas in VHL patients. We reviewed two electronic databases in the hospitals of our senior authors, searching for VHL patients with optic nerve or chiasm hemangioblastomas. Clinical data were summarized. Tumor size and growth rate were measured on contrast enhanced MRI. Comparable data were collected by literature review of all available cases in VHL patients (Pubmed, Trip, Google and Google Scholar). Of 269 VHL patients, 12 had optic nerve or chiasm hemangioblastomas. In 10 of 12 patients, tumors were diagnosed upon annual ophthalmoscopic/MRI screening. Of 8 patients who were asymptomatic at diagnosis, 7 showed absent or very slow annual progression, without developing significant vision impairment. One patient developed moderate vision impairment. Two symptomatic patients suffered from rapid tumor growth and progressive vision impairment. Both underwent late-stage surgery, resulting in incomplete resection and progressive vision impairment. One patient presented with acute vision field loss. A watchful-waiting approach was adopted because the hemangioblastoma was ineligible for vision-sparing surgery. One patient developed progressive vision impairment after watchful waiting. In the literature we found 45 patient cases with 48 hemangioblastomas. When optic nerve and chiasm hemangioblastomas are diagnosed, we suggest annual MRI follow-up as long as patients do not develop vision impairment. If tumors grow fast, threaten the contralateral eye, or if patients develop progressive vision deficiency; surgical resection must be considered because neurological impairment is irreversible, and resection of large tumors carries a higher risk of further visual decline.
antibodies
2026-06-29 | Sandwich therapy combining photodynamic therapy and adjunctive anti-VEGF for juxtapapillary retinal capillary hemangioblastoma.
To report the outcomes of verteporfin photodynamic therapy (PDT) with adjuntive pre- and post-PDT intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections ("Sandwich PDT") for juxtapapillary retinal capillary hemangioblastoma (RCH). A retrospective case review of eyes with juxtapapillary RCH that underwent "Sandwich PDT" in a national referral center. The clinical features were evaluated with fundus photography, optical coherence tomography, and ultrasonography. Five eyes were analyzed. The median follow-up time was 42 (range, 12-77) months. Adjunctive anti-VEGFs were given 4.0 weeks (range, 1 day-12 weeks) before PDT and 6.0 weeks (3 days to 8 weeks) after PDT. One of the five eyes (20%) that had anti-VEGF injection 8 weeks before PDT developed macular exudation after PDT but resolved within 1 month. Following Sandwich PDT, tumor size regressed in 3/5 eyes (60%) and stabilized in 2/5 eyes (40%). Subretinal fluid and exudates completely resolved in the three eyes that had these features before PDT, whereas intraretinal fluid stabilized or partially responded in 4/5 (80%). Reactivation of disease activity was noted in two eyes (40%), one resolved after a second Sandwich PDT. At the last follow-up, visual acuity improved 10 ETDRS letters or more in one eye (20%), stabilized in two (40%), and worsened 10 ETDRS letters or more in two (40%). The treatment of juxtapapillary RCH remains challenging. PDT with adjunctive anti-VEGF injections achieved anatomical control, but the functional outcomes were guarded. Based on the pharmacokinetics, we propose that anti-VEGF be given 1 week before PDT for maximal coverage.
2026-06-08 | Concurrent Von Hippel-Lindau disease and enhanced S-cone syndrome leading to a distinct retinal phenotype.
Von Hippel-Lindau (VHL) disease and Enhanced S-cone syndrome (ESCS) are rare inherited disorders that independently predispose to vision-threatening retinal pathology through distinct mechanisms: VHL through hypoxia-induced activation of several angiogenic factors, which lead to the development of retinal capillary hemangioblastoma (RCH), and ESCS by disrupting photoreceptor development through NR2E3 variants. We describe the coexistence of these two conditions in a pediatric patient, confirmed by multimodal imaging, electroretinography, and genetic testing. A retrospective case report. A 13-year-old girl presented with poor vision in both eyes, mainly in dim light. Fundus examination revealed multiple small hypopigmented areas distributed nasally and temporally along the inferior arcades in both eyes, and multiple small RCHs distributed in all quadrants with superonasal exudations and macular choroidal neovascular membrane (CNVM) in the left eye. Full-field electroretinography (ff-ERG) showed nonrecordable rod responses, broadened rod-cone and cone responses, and a markedly reduced 30-Hz flicker amplitude. While the right eye was successfully managed conservatively, targeted focal laser and intravitreal anti-vascular endothelial growth factor (VEGF) therapy led to regression of neovascular lesions and visual improvement in the left eye. Whole-exome sequencing identified a heterozygous VHL c.452T > C (p.Ile151Thr) variant and a homozygous NR2E3 c.932G > A (p.Arg311Gln) variant. Both VHL disease and ESCS manifested their characteristic retinal findings of RCH, along with the typical electrophysiological features and the CNVM associated with ESCS.
2023-02-27 | Patient-specific simulation of Retinal Hemangioblastoma provides new perspectives on the role of antiangiogenic therapy
ABSTRACT Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is easily explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. However, our understanding of RH is limited by the absence of an animal model fully recapitulating the tumor. Here, we exploit a cancer mathematical model as an alternative way to explore RH development and angiogenesis. We derived our model from the agreed pathology for this tumor and compared our results with patient-specific OCTA images. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate RH pathology. Our results also suggest that angiogenesis in RH occurs suddenly when the tumor reaches a critical mass, with full capillary invasion in the order of days. These findings open a new perspective on the critical role of time in antiangiogenic therapy in RH, which has resulted ineffective. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with this mean.
2022-05-10 | Combined therapy guided by multimodal imaging of fifteen retinal capillary hemangioblastomas in a monocular Von Hippel- Lindau syndrome case report.
To report the multimodal imaging and treatment of fifteen retinal capillary hemangioblastomas (RCHs) associated with Von Hippel-Lindau syndrome in a monocular patient during a long-term following-up, which supply high-resolution exquisite SS-OCTA images (VG200; SVision Imaging, Ltd., Luoyang, China) and management experience about multiple RCHs. A 34-year-old monocular male patient complained decreased visual acuity (20/100) without pain and redness in the left eye five years ago. Von Hippel-Lindau syndrome were diagnosed with genetic testing. He, his son and daughter all carried a heterozygosity missense variant c.499C > T (p. Arg167Trp) in the Hg19 gene, a VHL gene located in Chr3:10,191,506. Fifteen RCHs were identified by the application of multimodal imaging, which including fundus photo, fundus autofluorescence (FAF), B-scan ultrasonography (US), fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA) and swept-source optical coherence tomography angiography (SS-OCTA). Transscleral cryotherapy and laser photocoagulation were performed to destroy the largest RCH with the size of 4 PD in diameter. Laser photocoagulation was conducted to seal the middle or tiny RCHs (< 1.5 PD) and their nourishing vessels. The retinal edema and exudative macular detachment were successfully relieved by intraocular injection of bevacizumab for 5 times. The RCHs in the left eye responded well to these treatments and best corrected visual acuity was 20/25 for three years. Three-month recall visits were recommended for him. For multiple retinal capillary hemangioblastomas in monocular patients, precise combined therapy guided by multimodal imaging has a profound impact on the management of new and recurrent RCHs.
2021-08-18 | Isolated juxtapapillary retinal capillary haemangioblastoma and exudative maculopathy in an elderly patient without von Hippel-Lindau syndrome: combined proton beam radiotherapy and intravitreal anti-VEGF.
A 71-year-old Caucasian man presented with an isolated juxtapapillary retinal capillary haemangioblastoma on the superior and temporal left optic disc with active exudation resulting in macular intraretinal and subretinal fluid, reduced vision, scotoma and distortion with progression over 6 weeks. He did not have von Hippel-Lindau syndrome. After proton beam radiotherapy (PBR), the tumour size remained unchanged, but did not stop the exudation. Three anti-vascular endothelial growth factor (VEGF) (ie, bevacizumab) injections at monthly intervals resulted in reduced macular oedema. Combined therapy with PBR and anti-VEGF injections sustained our patient's vision at 12 months follow-up.
gene therapies
2026-02-05 | [A Family case of von Hippel-Lindau syndrome].
Von Hippel-Lindau syndrome (FHL) is a rare autosomal dominant disease that leads to the formation of multiple organ tumor syndrome. The pathology is primarily caused by the inactivation of the VHL gene, which is located on chromosome 3 (3p25/26) and encodes ubiquitin ligase, which destroys hypoxia-induced factor-1α (HIF-1α). The genetic defect leads to the accumulation of HIF-1a protein, activating key carcinogenic pathways, and activated cytokines cause abnormal proliferation of tumor cells and oncogenesis. To date, more than 500 mutations have been registered in VHL. FHL syndrome is characterized by various tumors, including hemangioblastomas of the retina and central nervous system, pheochromocytomas, clear cell renal cell carcinoma, cystic adenoma and others. In the presented clinical description, pheochromocytoma was initially diagnosed in the patient's mother, and 2 months later in the eldest son. Subsequently, the results of a molecular genetic study made it possible to verify the diagnosis, since in the gene in exon 3 of VHL, a single nucleotide was replaced in the heterozygous state of C.500 G>A, leading to the replacement of the amino acid p.R167Q. Identification of the VHL gene mutation required genetic counseling of all family members, during which a similar mutation was identified in the younger brother. Surgical treatment is the main method of treating FHL syndrome, but advances in genetic research technologies provide new opportunities for the treatment of tumors associated with this syndrome.
2025-08-28 | Presentation, management, and clinical outcomes of von Hippel-Lindau syndrome.
von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant genetic disorder that typically leads to the development of multiple tumours in various organs. This study describes the lifetime journey of VHL patients in terms of their hospitalisation, surgery, and functional impairment, and aims to examine the local presentation patterns, treatment courses, and clinical outcomes associated with the condition. Thirty-two patients with VHL syndrome (mean age=27.9 ± 12.6 years) were retrospectively identified from five local public hospitals managed between 1 January 1993 and 30 September 2024, with a follow-up duration of 18.0 ± 10.8 years. Patient demographics, disease presentation, length of hospital stay, and treatments received were recorded and analysed. Over a total of 575.9 person-years, 17 patients (53.1%) developed renal tumours and 10 (31.3%) underwent partial or radical nephrectomy. Twenty-four patients (75.0%) underwent central nervous system (CNS) surgery for haemangioma. Eleven patients (34.4%) had phaeochromocytoma, and eight (25.0%) underwent adrenalectomy. Nine patients (28.1%) had retinal haemangioma. During the study period, 368 emergency department visits, 1209 inpatient admissions, 192 intensive care unit days, and 5635 hospitalisation days were recorded. In total, 116 surgeries were performed involving the kidneys (n=17), pancreas (n=6), adrenal glands (n=10), and CNS (n=83). Six patients required dialysis; 4373 dialysis sessions were performed. Fifteen patients died. Among the nine who died of VHL syndrome, eight had developed cerebral haemangioblastoma, three had phaeochromocytoma, and four had renal tumours. Patients with VHL syndrome often experience early-onset and recurrent diseases affecting multiple organ systems, leading to substantial morbidity and mortality. A multidisciplinary approach, along with the introduction of novel treatments, may improve disease control and clinical outcomes.
2025-07-15 | Familial risks and incidence rates for childhood nervous system tumors in Sweden
Background Childhood (< 20 years) nervous system tumors manifest in some rare cancer syndromes but how commonly they present with familial clustering between various histological types is not well known at a nation-wide level. Our aim is to enhance understanding of familial risks in childhood nervous system cancers. Methods We used the Swedish population and cancer data from years 1958–2021 to address familial risks among nervous system cancers when the case was diagnosed before age 20 years but the proband could be diagnosed at any age. Adjusted familial (relative) risks were expressed as standardized incidence ratios (SIRs). Results Familial childhood cancer cases amounted to 123 in the brain, 15 in the spinal cord and 9 in peripheral nerves. Familial risk for concordant brain cancer was about 2.0 irrespective of proband. Concordant risk of spinal cord cancer was high when mothers (17.92) or siblings were probands (24.91). High familial risk of 34.53 was recorded for hemangioblastoma, and moderate high risks were observed also for schwannoma (4.07), ependymoblastoma (3.48) and female ganglioneuroma (7.72) whereas astrocytoma risks were at the level of common cancers at other sites (1.7–2.0). Hemangioblastoma families appeared not to be related to von Hippel-Lindau syndrome because of lack of pathognomonic signs other than hemangioblastoma in the families. Conclusion In spite of the low number of childhood nervous system tumors, we observed high familial risks for, probably novel, syndromic hemangioblastoma, and schwannomas for which concordant clusters were found particularly in the spinal cord. Inquiring about a detailed family history at diagnosis of a nervous system cancer in childhood may reveal a syndromic disease due to a constitutional variant amenable to treatment.
2012-10-01 | Combined Blockade and Akt/Mtor Pathway Inhibits Growth of Human Hemangioma via Downregulation of Proliferating Cell Nuclear Antigen
Protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in the tumorigenesis and progression of multiple tumors, and has been shown to be important therapeutic targets for cancer. The present study aimed to explore the role and molecular mechanisms of AKT/mTOR pathway in human hemangioma (HA). Twenty-five cases of human HA tissues were collected. The expression of AKT, mTOR and proliferating cell nuclear antigen (PCNA) proteins was evaluated using semi-quantitative immunohistochemistry in biopsy samples in different phases of HA. AKT/mTOR pathway was blocked by recombinant small hairpin RNA adenovirus vector rAd5-AKT+mTOR (rAd5-Am), used for infecting proliferating phase HA-derived endothelial cells (HDEC). The expression of AKT, mTOR and PCNA was detected by Real-time PCR and Western blot assays. Cell proliferative activities were determined by MTT assay, and cell cycle distribution and apoptosis were analyzed by flow cytometry. As a consequence, the expression of AKT, mTOR and PCNA was significantly increased in proliferative phase HA, while that was decreased in involutive phase. Combined blockade of AKT/mTOR pathway by rAd5-Am diminished cell proliferative activities, and induced cell apoptosis and cycle arrest with the decreased expression of AKT, mTOR and PCNA in proliferative phase HDEC. In conclusion, the activity of AKT/mTOR pathway was increased in proliferative phase HA, while it was decreased in involutive phase. Combined blockade of AKT/mTOR pathway might suppress cell proliferation via down-regulation of PCNA expression, and induce apoptosis and cycle arrest in proliferative phase HDEC, suggesting that AKT/mTOR pathway might represent the important therapeutic targets for human HA.
2007-09-01 | Preferential Loss of the Nonimprinted Allele for the ZAC1 Tumor Suppressor Gene in Human Capillary Hemangioblastoma
Capillary hemangioblastomas (CHBs) are vascular, usually benign, tumors of the CNS, occurring either as a component of familial von Hippel-Lindau (VHL) disease or as a sporadic entity. Both familial and sporadic forms of VHL-associated tumors involve inactivation of the VHL gene; for CHB, 20% to 50% of sporadic cases are affected. However, other molecular alterations involved in the pathogenesis of sporadic CHBs, which represent up to 70% of CHBs, remain largely unknown. We previously identified a minimal deleted area at 6q23-24 in CHB, and the present study focused on the ZAC1 gene (6q24-25). ZAC1 is a maternally imprinted tumor suppressor gene with antiproliferative properties. We investigated loss of heterozygosity (LOH), promoter methylation, and expression status of ZAC1 in mainly sporadic cases of CHB. Our LOH analysis with 6 microsatellite markers spanning the ZAC1 gene region revealed a high frequency (6 of 10, 60%) of LOH. The promoter methylation analysis detected predominance of the methylated ZAC1 sequence in the majority (9 of 10, 90%) of the tumors. Immunohistochemistry exhibited a strongly reduced expression of ZAC1 in stromal cells of all CHBs studied. Collectively, our current results indicate that the absence of the unmethylated ZAC1 sequence was highly concurrent with ZAC1 region LOH or 6q loss and with lack of ZAC1 expression, suggesting preferential loss of the nonimprinted, expressed ZAC1 allele in CHB. This novel finding highlights the importance of ZAC1 in development of CHB, particularly in non-VHL-associated cases.
other
2025-03-14 | 442 AI for Recovering a Voice
INTRODUCTION: Patients with brain tumors commonly encounter speech impairments, and these can have a significant impact on a patient's quality of life. This study explores the potential of a novel text-to-speech application, Voice Engine, to reconstruct naturalistic, individualized voice for a patient with persistent dysarthria following brain tumor resection. METHODS: A 21-year-old female patient presented with slurred speech and facial droop due to a large posterior fossa mass. Following a sub-occipital craniectomy for resection of pathology-confirmed hemangioblastoma, the patient experienced significant, persistent dysarthria. Voice Engine was used to reconstruct the patient's voice using a 15-second audio recording from a school presentation made two years prior. The reconstructed voice was integrated into a bespoke smartphone app to facilitate text-to-speech communication. Pre- and post-app surveys were administered to assess the impact on the patient's quality of life. RESULTS: The patient reported that her voice impairment severely affected her personal esteem, relationships, and ability to perform daily activities such as ordering food, attending school, and communicating at work. Following the implementation of the Voice Engine-powered app, the patient reported significant improvements (<0.001) in the ability to perform daily activities, as well as enhanced overall well-being and agency. CONCLUSIONS: This case study highlights the potential of deep learning-based text-to-speech applications to significantly improve the quality of life for patients with persistent speech impairments following brain tumor resection. Further research is needed to explore the applicability of this approach to a larger cohort of patients with speech impairments resulting from various neurological conditions.
2025-02-27 | Unveiling a TGFBI Variant in the Retinal Capillary Hemangioblastoma, Type II Granular Corneal Dystrophy, and Von Hippel-Lindau Families: Unlocking Potential for Early Intervention and Targeted Therapy.
To identify the potential genetic factors responsible for retinal capillary hemangioblastoma (RCH) and Type II granular corneal dystrophy (GCDII), with autosomal dominant inheritance. We used whole-exome sequencing (WES) in an Iranian family to identify the possible genetic etiology of RCH and GCDII with other manifestations of von Hippel-Lindau (VHL) disease. This study included one Iranian family for WES in index patients and Sanger sequencing in all available individuals. Clinical presentations of these patients included RCH, GCD, central nervous system hemangioblastoma as well as pancreatic cyst. WES disclosed a heterozygous known pathogenic variant c.371G>A (p.R124H) in exon 4 of gene TGFBI. For the first time, our research identified the potential involvement of TGFBI: c.371G>A (p.R124H) in an Iranian family with RCH, GCDII, and other symptoms of VHL disease. In the future, TGFBI could offer a new understanding and a promising therapeutic approach for both GCDII and VHL diseases simultaneously. Before using the variant in genetic counseling, it is recommended to conduct functional analysis using appropriate animal models to understand its pathogenesis mechanism.
2024-11-27 | Reclaiming Voice with AI
Voice impairments affect millions of Americans, with personalized text-to-speech technology offering limited solutions due to the need for extensive voice banking. Here, we report the case of Alexis Bogan, a 20-year-old patient who acutely lost her voice after surgery to resect her brain stem hemangioblastoma. In a world-first application, OpenAI's Voice Engine was used to clone Ms. Bogan's voice from just 15 seconds of preexisting audio, sourced from a school project she had filmed a few years prior. This enabled her to use a personalized text-to-speech app for daily communication while rehabilitating her speech. This case was highlighted on a recent episode of the NEJM AI Grand Rounds podcast,1 framing a broader discussion on voice cloning technology. While AI is often dual use and concerns about voice cloning often center on potential misuse, such as "deepfakes" and misinformation, we argue that suppressing this technology may inflict tangible harm on patients by denying them the chance to reclaim their voice. Inspired by Ms. Bogan's journey, we urge researchers, clinicians, ethicists, policymakers, and tech companies to collaborate swiftly yet responsibly in advancing AI voice cloning in health care. By doing so, we can empower patients to recover not just their voice, but also a fundamental aspect of their identity and quality of life.
2022-04-06 | Venous congestion as a central mechanism of radiculopathies.
Compression of roots/nerves can disrupt some of their functions, but does not necessarily cause pain. This is illustrated by the frequency of nearly asymptomatic spinal stenosis or disc herniations. In fact, pain of radiculopathies (and nerve entrapments) may mostly be the consequence of intraneural oedema induced by microscopical venous stasis around roots/spinal ganglia (or nerves) not or poorly shown by imaging. This narrative review first lists arguments for a role of congestion of vasa-nervorum in the pathophysiology of radiculopathies, including those induced by disc herniation and spinal stenosis, but also other sources of overpressures in spinal venous plexuses (pregnancy, vena cava atresia and thrombosis, portal hypertension, epidural varices, arterio-venous fistula, vertebral hemangioma or hemangioblastoma). It also details sources of venous congestion around nerves outside the spine, from pelvis (May-Thurner syndrome, Nut-cracker syndrome) to buttocks (superior and inferior gluteal veins), and even thighs and legs. A better recognition of a preeminent role of venous congestion in radiculopathies, plexopathies, and nerve entrapments, should have major consequences: (i) discard the dogma that compression is mandatory to induce root/nerve suffering, since root/nerve adherences in two locations can impair blood flow in vasa-nervorum through root/nerve stretching; (ii) implementation of sensitive techniques to visualise impingement of blood flow around or within roots and nerves; (iii) better prevention of roots/nerves adherence, or arachnoiditis induced by extravascular fibrin deposition secondary to venous stasis.; (iv) optimizing treatments dampening clot formation and/or extravascular fibrin leakage in the intradural/peridural spaces, or around roots/nerves, like guided injection of tissue plasminogen activator.
2019-06-26 | Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15
Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen—transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.—Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15. FASEB J. 33, 10505–10514 (2019). www.fasebj.org
small molecules
2026-09-18 | Von Hippel-Lindau disease: Ocular manifestations, surveillance, systemic associations, and emerging molecular therapies.
Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary tumour predisposition syndrome affecting multiple organ systems, including the retina, central nervous system, kidneys, pancreas, adrenal glands, and inner ear. It is caused by pathogenic variants in the VHL gene, resulting in loss of functional pVHL, abnormal stabilization of hypoxia-inducible factor (HIF)-α subunits, and activation of downstream transcriptional programmes involved in angiogenesis, metabolism, cell survival, and tumour growth. Clinically, VHL is characterized by a spectrum of benign and malignant neoplasms that require lifelong surveillance and multidisciplinary management. Retinal hemangioblastomas are among the earliest manifestations and may provide the first clue to diagnosis of this multisystem disorder. Historically, management has relied on screening, surveillance, and local treatment according to lesion size, location, symptoms, and malignant potential. The emergence of HIF-2α-targeted therapy, particularly belzutifan, has begun to change this paradigm by offering a mechanism-based systemic treatment option for selected VHL-associated tumours. In this review, we summarize the ocular and systemic manifestations of VHL, its genetic and molecular basis, genotype-phenotype correlations, contemporary surveillance strategies, current local therapies, and the emerging role of HIF-2α inhibition in reshaping management.
2026-09-16 | Oral belzutifan treatment in von hippel-lindau-associated retinal hemangioblastoma: a promising approach.
Von Hippel-Lindau (VHL)-associated retinal hemangioblastomas (RHs) may cause vision-threatening exudation and hemorrhage. Conventional local therapies may be limited in advanced, recurrent, or anatomically high-risk lesions. This study evaluated ocular outcomes and observed tolerability during oral belzutifan treatment in a real-world cohort. Between January 2023 and June 2025, this retrospective observational study included five consecutive patients with genetically confirmed VHL, contributing seven eyes; each eye had at least one RH that progressed despite prior conventional local therapy. Patients received oral belzutifan 120 mg once daily. Median on-treatment follow-up (FU) was 43 weeks (IQR, 27-50); median documented cumulative belzutifan exposure was 43 weeks (range, 27-50). Data were available through January 2026. Tumor regression was quantified as the relative change in projected pixel area from baseline to last on-treatment FU. The largest baseline lesion per fundus-imaged eye was predefined for the primary analysis; all fundus-imaged lesions were assessed exploratorily. Fourteen fundus-imaged RHs were included in the projected-pixel-area analyses, and one MRI-assessed RH was reported separately. Three retinal specialists independently performed lesion measurements and exploratory overall ocular response (OOR) grading as separate assessments. Readers were masked to one another's assessments; quantitative lesion measurements were additionally masked to patient information, treatment course, and image chronology. Safety was monitored within an interdisciplinary clinical framework. In the predefined primary descriptive analysis of the largest baseline lesion per fundus-imaged eye (six eyes from four patients), all six index lesions regressed (median projected-pixel-area reduction, 58.3%; IQR, 17.2-64.7%). All four lesions in the patient-level sensitivity analysis regressed (median, 59.6%; range, 14.5-64.8%). Across all 14 fundus-imaged lesions, median regression was 57.2% (IQR, 28.5-66.9%), and 11/14 lesions (78.6%) showed > 20% regression. All three readers classified all six evaluable eyes as improved. Exudative retinal detachment resolved in three of four affected eyes. Drug-related adverse events were mostly mild to moderate and manageable. Oral belzutifan was associated with RH regression and improved exudative disease activity in this selected real-world cohort. These findings support systemic HIF-2α inhibition as a potential adjunctive therapeutic option for selected patients with progressive or anatomically high-risk ocular VHL disease. Prospective validation is required. not applicable. Not applicable.
2026-08-18 | Clinical outcomes of HIF-2α inhibition in Von Hippel-Lindau disease: a multicenter real-world study.
Management of von Hippel-Lindau (VHL) disease is challenging due to multisystem involvement and limited systemic treatment options. Belzutifan has shown promising efficacy in clinical trials; however, real-world data remain limited. We aimed to evaluate its effectiveness and safety in a real-world cohort. We conducted a retrospective study of 59 patients with VHL disease treated with belzutifan between August 2021 and January 2026. Objective response rates (ORR) for renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS HB), and pancreatic neuroendocrine tumors (pNET) were assessed by an independent radiologist. Retinal hemangioblastoma outcomes were evaluated through ophthalmology records by chart review. Median follow-up was 29 months. ORR was 27.6%, 39.6%, and 85.7% for RCC, CNS HB, and pNET, respectively. Among 13 patients with retinal hemangioblastomas (20 eyes), 17 eyes (85%) showed improvement. At data cutoff, 47 patients (79.6%) remained on treatment, while 12 (20.3%) discontinued (7 due to adverse events, 3 to disease progression, and 2 to other reasons). The most common adverse event was anemia (86.4%). Grade ≥3 adverse events occurred in 10 patients (16.9%). The procedure rate per patient-year decreased from 0.35 in the 3 years prior to treatment to 0.08 during follow-up (Incidence Rate Ratio, 0.23; 95% CI, 0.12-0.47; P < .001). Belzutifan demonstrated efficacy across VHL-associated lesions, with a favorable safety profile. Most adverse events were grade 1-2. A reduction in procedure rate was observed after treatment initiation.
2026-08-16 | [Treatment of von Hippel-Lindau Disease and Hemangioblastoma].
Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome characterized by the development of neoplasms in multiple organs. Hemangioblastoma is one of the most common tumors associated with VHL disease. In 2024, the "Clinical Practice Guidelines for VHL Disease" were established in Japan to provide guidance for the diagnosis, treatment, and management of VHL disease. Furthermore, in 2025, the HIF-2αinhibitor belzutifan was approved for insurance coverage in Japan for VHL-associated tumors, including hemangioblastomas. In this article, we first provide an overview of VHL disease and the "Clinical Practice Guidelines for VHL Disease," and then discuss the diagnosis and treatment of hemangioblastomas, including surgery, endovascular therapy, and radiotherapy. Finally, we review the role of the HIF-2αinhibitor belzutifan. In the future, management of VHL disease and hemangioblastomas will likely require not only individual treatment modalities, but also optimal multimodal strategies combining surgery, radiotherapy, and systemic drug therapy.
2026-08-14 | Von Hippel-Lindau Syndrome: An Updated Narrative Review for the First-Contact Clinician.
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant (AD) condition that increases the risk of developing CNS and retinal hemangioblastomas (R-Hb), as well as clear cell renal cell carcinoma (ccRCC), pheochromocytomas, pancreatic neuroendocrine tumors (pNETs), and endolymphatic sac tumors. CNS hemangioblastomas and renal cell carcinomas are among the leading causes of mortality in affected individuals. Recent therapeutic advances, particularly hypoxia-inducible factor 2 alpha (HIF-2α) inhibitors and vascular endothelial growth factor (VEGF)-targeted therapies, have yielded promising results. However, active surveillance remains the cornerstone of clinical management for reducing associated morbidity and mortality. Because VHL syndrome is multisystemic, a multidisciplinary clinical team is necessary to provide comprehensive care, including targeted pharmacotherapy and surgical resection, to prevent severe complications. This narrative review outlines the current diagnostic approach and follow-up protocols for VHL syndrome, highlighting recent therapeutic advances.
cell therapies
2026-03-19 | Comparing laminectomy and unilateral hemilaminectomy in spinal hemangioblastoma resection: A multicenter study.
This study compared laminectomy and hemilaminectomy for resection of spinal (sHBs), evaluating extent of resection, 12-month postoperative functional outcomes, perioperative complications overall, with particular attention to postoperative bleeding. This retrospective international multicenter study included 280 primary sHB patients from 13 neuro-oncological centers who underwent either laminectomy (n = 125) or hemilaminectomy (n = 155). The endpoints were the extent of resection, functional outcomes at 12 months, and postoperative bleeding requiring retreatment. Multivariable logistic regression analysis was performed to determine independent risk factors associated with these outcomes. The rate of complete resection was similar between both surgical approaches, with 86.4% in the laminectomy group and 90.3% in the hemilaminectomy group (p = 0.35). Independent predictors of incomplete resection included preoperative modified McCormick >2 (OR: 4.29, p = 0.001), combined intra- and extramedullary tumor location (OR: 2.91, p = 0.03), and cervical or thoracic tumor location (OR: 3.38, p = 0.01). Functional outcomes at 12 months did not differ significantly between the laminectomy- and hemilaminectomy-groups (p = 0.97). Postoperative bleeding was more frequently observed in tumors involving two or more spinal segments (OR: 14.6, p = 0.01). The choice of surgical approach did not impact the incidence of postoperative bleeding (p = 0.55). Laminectomy and hemilaminectomy result in comparable outcomes of sHB. Tumors affecting multiple spinal segments are associated with an increased risk of postoperative bleeding, while combined intra- and extramedullary growth, impaired preoperative functioning and non-lumbar location were associated with incomplete resection. Given the comparable outcomes, the selection of the surgical approach may be guided by surgeon preference and individual patient anatomy.
2026-01-09 | [A rare case of adrenal hemangioblastoma and literature review].
A retrospective analysis was conducted on the clinical data of a patient with adrenal hemangioblastoma (HB), pathologically confirmed at the First Medical Center of Chinese PLA General Hospital. A review of the literature relating to adrenal HB was also undertaken. The patient was a 36-year-old male in whom a right adrenal mass was incidentally detected during a physical examination. The mass measured approximately 4.7 cm×4.2 cm and had a CT attenuation value of approximately 55 HU. MRI showed an irregular mass with a slightly long T1, mixed long/short T2 signals, mildly high signal intensity on diffusion weighted imaging, and a slightly low signal on apparent diffusion coefficient. No signal drop was observed on opposed-phase imaging. Dynamic contrast-enhanced scanning revealed progressive, marked enhancement. 68Ga DOTATATE PET-CT demonstrated a slightly hypodense mass in the right adrenal gland (maximum standardized uptake value 17.3). Functional evaluation showed an elevated chromogranin A (CgA) level of 294.64 pmol/L (normal range: 64-204 pmol/L), with no other abnormalities detected. The preoperative diagnosis was pheochromocytoma, and the patient underwent surgery after adequate preoperative preparation with phenoxybenzamine hydrochloride. Immunohistochemical results-S-100 (focal weak+), melan-A (-), inhibin-α (partial+), FLI-1 (+), CK (-), Syn (partial+), CgA (-), Ki67 (2%+), CD34 (+), CD31 (+), and desmin (-)-confirmed the diagnosis of adrenal HB. Genetic testing detected no VHL gene mutation. No recurrence or metastasis was observed during more than two years of follow-up. A review of the literature revealed that this was the first reported case of adrenal HB in China. Globally, only six cases have been reported to date, four of which were clearly related to von Hippel-Lindau syndrome. Adrenal HB is exceptionally rare and lacks characteristic clinical manifestations. Significant enhancement of the solid component with flow-void vessels on MRI is considered a relatively distinctive imaging feature. Definitive diagnosis relies on pathology and immunohistochemistry. Surgical resection remains the primary treatment, and the prognosis is generally favorable.
2026-01-01 | Survival Impact of Surgery, Radiation, and Socioeconomic Factors in Spinal Hemangioblastoma: A Population-Based Study.
Spinal hemangioblastomas are rare, highly vascular benign tumors, with management typically centered on gross total resection. However, factors associated with overall survival (OS) remain poorly defined, particularly the roles of surgical extent, radiation therapy (RT), and socioeconomic variables. We aimed to evaluate clinical and demographic predictors of survival in a contemporary population-based cohort. Patients with spinal cord or cauda equina hemangioblastoma were identified from the Surveillance, Epidemiology and End Results database (1975-2022). Demographic, tumor, and treatment characteristics-including age, sex, race, income, surgical extent, and RT-were collected. Univariable and multivariable Cox proportional hazards models were used to evaluate associations with OS. Among 223 patients, older age (P<0.001) and lower household income (P=0.028) were independently associated with worse survival. Extent of resection (subtotal resection or observation vs. gross total resection) and RT were not significantly associated with OS (P=0.117). Kaplan-Meier analysis showed no survival difference by surgery (P=0.89) or between pediatric and adult patients (P=0.1), with all pediatric patients alive at last follow-up. Although RT correlated with worse survival on univariate analysis (P=0.005), this did not persist after adjustment, likely reflecting confounding by indication. Older age and lower income were associated with worse OS in patients with spinal hemangioblastoma, while neither surgical extent nor RT predicted survival. These findings suggest that subtotal resection or observation may be appropriate in select cases without compromising outcomes and emphasize the importance of addressing socioeconomic barriers in this rare, benign disease.
2025-09-25 | Role of PPV in Advanced Retinal Hemangioblastoma-A Systematic Review.
In eyes with retinal hemangioblastomas (RH), vision loss may occur despite treatment due to recurrent macular edema, macular pucker, vitreous hemorrhage, and exudative, tractional, or combined retinal detachment. Pars plana vitrectomy (PPV) plays a critical role in managing these complications. This review aims to evaluate the outcomes of PPV in patients with RH. We searched PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Google Scholar, and Web of Science (2000 to 2025) using the keywords "retinal hemangioblastoma," "capillary hemangioblastoma," "von Hippel-Lindau retina," combined with "vitrectomy," or "pars plana vitrectomy." Given the rarity of the condition, retrospective case series were included if they had ≥4 cases. Single anecdotes and non-English articles were excluded. Two independent reviewers evaluated the studies for qualitative and quantitative synthesis. Our search yielded 120 results, of which eight studies published between 2011 and 2024 met the inclusion criteria. All were retrospective case series (level IV evidence). A total of 107 eyes from 102 patients were analyzed, with sample sizes ranging from 4 to 23 eyes. Anatomic success, defined as retinal reattachment, ranged from 70% to 100% by final follow-up. However, many eyes remained in the low vision range despite anatomic success. New tumor development and proliferative vitreoretinopathy (PVR)-related complications remain key challenges in long-term management. While the evidence is limited due to study design and sample size, consistent trends across the literature suggest PPV is anatomically effective, though visual outcomes remain guarded.
2024-07-24 | Optic nerve and chiasm hemangioblastomas in von Hippel-Lindau disease: report of 12 cases and review of the literature.
Optic nerve and chiasm hemangioblastomas are rare tumors, occurring sporadically or in the context of von Hippel-Lindau (VHL) disease. They have only been portrayed in isolated case reports and small cohorts. Their natural history and therapeutic strategies are only scarcely described. To better characterize these rare tumors, we retrospectively analyzed an optic nerve and chiasm hemangioblastoma series of 12 VHL patients. By combining our own experience to a review of all known cases in literature, we intended to create treatment recommendations for optic nerve and chiasm hemangioblastomas in VHL patients. We reviewed two electronic databases in the hospitals of our senior authors, searching for VHL patients with optic nerve or chiasm hemangioblastomas. Clinical data were summarized. Tumor size and growth rate were measured on contrast enhanced MRI. Comparable data were collected by literature review of all available cases in VHL patients (Pubmed, Trip, Google and Google Scholar). Of 269 VHL patients, 12 had optic nerve or chiasm hemangioblastomas. In 10 of 12 patients, tumors were diagnosed upon annual ophthalmoscopic/MRI screening. Of 8 patients who were asymptomatic at diagnosis, 7 showed absent or very slow annual progression, without developing significant vision impairment. One patient developed moderate vision impairment. Two symptomatic patients suffered from rapid tumor growth and progressive vision impairment. Both underwent late-stage surgery, resulting in incomplete resection and progressive vision impairment. One patient presented with acute vision field loss. A watchful-waiting approach was adopted because the hemangioblastoma was ineligible for vision-sparing surgery. One patient developed progressive vision impairment after watchful waiting. In the literature we found 45 patient cases with 48 hemangioblastomas. When optic nerve and chiasm hemangioblastomas are diagnosed, we suggest annual MRI follow-up as long as patients do not develop vision impairment. If tumors grow fast, threaten the contralateral eye, or if patients develop progressive vision deficiency; surgical resection must be considered because neurological impairment is irreversible, and resection of large tumors carries a higher risk of further visual decline.
antibodies
2026-06-29 | Sandwich therapy combining photodynamic therapy and adjunctive anti-VEGF for juxtapapillary retinal capillary hemangioblastoma.
To report the outcomes of verteporfin photodynamic therapy (PDT) with adjuntive pre- and post-PDT intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections ("Sandwich PDT") for juxtapapillary retinal capillary hemangioblastoma (RCH). A retrospective case review of eyes with juxtapapillary RCH that underwent "Sandwich PDT" in a national referral center. The clinical features were evaluated with fundus photography, optical coherence tomography, and ultrasonography. Five eyes were analyzed. The median follow-up time was 42 (range, 12-77) months. Adjunctive anti-VEGFs were given 4.0 weeks (range, 1 day-12 weeks) before PDT and 6.0 weeks (3 days to 8 weeks) after PDT. One of the five eyes (20%) that had anti-VEGF injection 8 weeks before PDT developed macular exudation after PDT but resolved within 1 month. Following Sandwich PDT, tumor size regressed in 3/5 eyes (60%) and stabilized in 2/5 eyes (40%). Subretinal fluid and exudates completely resolved in the three eyes that had these features before PDT, whereas intraretinal fluid stabilized or partially responded in 4/5 (80%). Reactivation of disease activity was noted in two eyes (40%), one resolved after a second Sandwich PDT. At the last follow-up, visual acuity improved 10 ETDRS letters or more in one eye (20%), stabilized in two (40%), and worsened 10 ETDRS letters or more in two (40%). The treatment of juxtapapillary RCH remains challenging. PDT with adjunctive anti-VEGF injections achieved anatomical control, but the functional outcomes were guarded. Based on the pharmacokinetics, we propose that anti-VEGF be given 1 week before PDT for maximal coverage.
2026-06-08 | Concurrent Von Hippel-Lindau disease and enhanced S-cone syndrome leading to a distinct retinal phenotype.
Von Hippel-Lindau (VHL) disease and Enhanced S-cone syndrome (ESCS) are rare inherited disorders that independently predispose to vision-threatening retinal pathology through distinct mechanisms: VHL through hypoxia-induced activation of several angiogenic factors, which lead to the development of retinal capillary hemangioblastoma (RCH), and ESCS by disrupting photoreceptor development through NR2E3 variants. We describe the coexistence of these two conditions in a pediatric patient, confirmed by multimodal imaging, electroretinography, and genetic testing. A retrospective case report. A 13-year-old girl presented with poor vision in both eyes, mainly in dim light. Fundus examination revealed multiple small hypopigmented areas distributed nasally and temporally along the inferior arcades in both eyes, and multiple small RCHs distributed in all quadrants with superonasal exudations and macular choroidal neovascular membrane (CNVM) in the left eye. Full-field electroretinography (ff-ERG) showed nonrecordable rod responses, broadened rod-cone and cone responses, and a markedly reduced 30-Hz flicker amplitude. While the right eye was successfully managed conservatively, targeted focal laser and intravitreal anti-vascular endothelial growth factor (VEGF) therapy led to regression of neovascular lesions and visual improvement in the left eye. Whole-exome sequencing identified a heterozygous VHL c.452T > C (p.Ile151Thr) variant and a homozygous NR2E3 c.932G > A (p.Arg311Gln) variant. Both VHL disease and ESCS manifested their characteristic retinal findings of RCH, along with the typical electrophysiological features and the CNVM associated with ESCS.
2023-02-27 | Patient-specific simulation of Retinal Hemangioblastoma provides new perspectives on the role of antiangiogenic therapy
ABSTRACT Retinal Hemangioblastoma (RH) is the most frequent manifestation of the von Hippel-Lindau syndrome (VHL), a rare disease associated with the germline mutation of the von Hippel-Lindau protein (pVHL). An emblematic feature of RH is the high vascularity, which is easily explained by the overexpression of angiogenic factors (AFs) arising from the pVHL impairment. The introduction of Optical Coherence Tomography Angiography (OCTA) allowed observing this feature with exceptional detail. However, our understanding of RH is limited by the absence of an animal model fully recapitulating the tumor. Here, we exploit a cancer mathematical model as an alternative way to explore RH development and angiogenesis. We derived our model from the agreed pathology for this tumor and compared our results with patient-specific OCTA images. Our simulations closely resemble the medical images, proving the capability of our model to recapitulate RH pathology. Our results also suggest that angiogenesis in RH occurs suddenly when the tumor reaches a critical mass, with full capillary invasion in the order of days. These findings open a new perspective on the critical role of time in antiangiogenic therapy in RH, which has resulted ineffective. Indeed, it might be that when RH is diagnosed, angiogenesis is already too advanced to be effectively targeted with this mean.
2022-05-10 | Combined therapy guided by multimodal imaging of fifteen retinal capillary hemangioblastomas in a monocular Von Hippel- Lindau syndrome case report.
To report the multimodal imaging and treatment of fifteen retinal capillary hemangioblastomas (RCHs) associated with Von Hippel-Lindau syndrome in a monocular patient during a long-term following-up, which supply high-resolution exquisite SS-OCTA images (VG200; SVision Imaging, Ltd., Luoyang, China) and management experience about multiple RCHs. A 34-year-old monocular male patient complained decreased visual acuity (20/100) without pain and redness in the left eye five years ago. Von Hippel-Lindau syndrome were diagnosed with genetic testing. He, his son and daughter all carried a heterozygosity missense variant c.499C > T (p. Arg167Trp) in the Hg19 gene, a VHL gene located in Chr3:10,191,506. Fifteen RCHs were identified by the application of multimodal imaging, which including fundus photo, fundus autofluorescence (FAF), B-scan ultrasonography (US), fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA) and swept-source optical coherence tomography angiography (SS-OCTA). Transscleral cryotherapy and laser photocoagulation were performed to destroy the largest RCH with the size of 4 PD in diameter. Laser photocoagulation was conducted to seal the middle or tiny RCHs (< 1.5 PD) and their nourishing vessels. The retinal edema and exudative macular detachment were successfully relieved by intraocular injection of bevacizumab for 5 times. The RCHs in the left eye responded well to these treatments and best corrected visual acuity was 20/25 for three years. Three-month recall visits were recommended for him. For multiple retinal capillary hemangioblastomas in monocular patients, precise combined therapy guided by multimodal imaging has a profound impact on the management of new and recurrent RCHs.
2021-08-18 | Isolated juxtapapillary retinal capillary haemangioblastoma and exudative maculopathy in an elderly patient without von Hippel-Lindau syndrome: combined proton beam radiotherapy and intravitreal anti-VEGF.
A 71-year-old Caucasian man presented with an isolated juxtapapillary retinal capillary haemangioblastoma on the superior and temporal left optic disc with active exudation resulting in macular intraretinal and subretinal fluid, reduced vision, scotoma and distortion with progression over 6 weeks. He did not have von Hippel-Lindau syndrome. After proton beam radiotherapy (PBR), the tumour size remained unchanged, but did not stop the exudation. Three anti-vascular endothelial growth factor (VEGF) (ie, bevacizumab) injections at monthly intervals resulted in reduced macular oedema. Combined therapy with PBR and anti-VEGF injections sustained our patient's vision at 12 months follow-up.
gene therapies
2026-02-05 | [A Family case of von Hippel-Lindau syndrome].
Von Hippel-Lindau syndrome (FHL) is a rare autosomal dominant disease that leads to the formation of multiple organ tumor syndrome. The pathology is primarily caused by the inactivation of the VHL gene, which is located on chromosome 3 (3p25/26) and encodes ubiquitin ligase, which destroys hypoxia-induced factor-1α (HIF-1α). The genetic defect leads to the accumulation of HIF-1a protein, activating key carcinogenic pathways, and activated cytokines cause abnormal proliferation of tumor cells and oncogenesis. To date, more than 500 mutations have been registered in VHL. FHL syndrome is characterized by various tumors, including hemangioblastomas of the retina and central nervous system, pheochromocytomas, clear cell renal cell carcinoma, cystic adenoma and others. In the presented clinical description, pheochromocytoma was initially diagnosed in the patient's mother, and 2 months later in the eldest son. Subsequently, the results of a molecular genetic study made it possible to verify the diagnosis, since in the gene in exon 3 of VHL, a single nucleotide was replaced in the heterozygous state of C.500 G>A, leading to the replacement of the amino acid p.R167Q. Identification of the VHL gene mutation required genetic counseling of all family members, during which a similar mutation was identified in the younger brother. Surgical treatment is the main method of treating FHL syndrome, but advances in genetic research technologies provide new opportunities for the treatment of tumors associated with this syndrome.
2025-08-28 | Presentation, management, and clinical outcomes of von Hippel-Lindau syndrome.
von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant genetic disorder that typically leads to the development of multiple tumours in various organs. This study describes the lifetime journey of VHL patients in terms of their hospitalisation, surgery, and functional impairment, and aims to examine the local presentation patterns, treatment courses, and clinical outcomes associated with the condition. Thirty-two patients with VHL syndrome (mean age=27.9 ± 12.6 years) were retrospectively identified from five local public hospitals managed between 1 January 1993 and 30 September 2024, with a follow-up duration of 18.0 ± 10.8 years. Patient demographics, disease presentation, length of hospital stay, and treatments received were recorded and analysed. Over a total of 575.9 person-years, 17 patients (53.1%) developed renal tumours and 10 (31.3%) underwent partial or radical nephrectomy. Twenty-four patients (75.0%) underwent central nervous system (CNS) surgery for haemangioma. Eleven patients (34.4%) had phaeochromocytoma, and eight (25.0%) underwent adrenalectomy. Nine patients (28.1%) had retinal haemangioma. During the study period, 368 emergency department visits, 1209 inpatient admissions, 192 intensive care unit days, and 5635 hospitalisation days were recorded. In total, 116 surgeries were performed involving the kidneys (n=17), pancreas (n=6), adrenal glands (n=10), and CNS (n=83). Six patients required dialysis; 4373 dialysis sessions were performed. Fifteen patients died. Among the nine who died of VHL syndrome, eight had developed cerebral haemangioblastoma, three had phaeochromocytoma, and four had renal tumours. Patients with VHL syndrome often experience early-onset and recurrent diseases affecting multiple organ systems, leading to substantial morbidity and mortality. A multidisciplinary approach, along with the introduction of novel treatments, may improve disease control and clinical outcomes.
2025-07-15 | Familial risks and incidence rates for childhood nervous system tumors in Sweden
Background Childhood (< 20 years) nervous system tumors manifest in some rare cancer syndromes but how commonly they present with familial clustering between various histological types is not well known at a nation-wide level. Our aim is to enhance understanding of familial risks in childhood nervous system cancers. Methods We used the Swedish population and cancer data from years 1958–2021 to address familial risks among nervous system cancers when the case was diagnosed before age 20 years but the proband could be diagnosed at any age. Adjusted familial (relative) risks were expressed as standardized incidence ratios (SIRs). Results Familial childhood cancer cases amounted to 123 in the brain, 15 in the spinal cord and 9 in peripheral nerves. Familial risk for concordant brain cancer was about 2.0 irrespective of proband. Concordant risk of spinal cord cancer was high when mothers (17.92) or siblings were probands (24.91). High familial risk of 34.53 was recorded for hemangioblastoma, and moderate high risks were observed also for schwannoma (4.07), ependymoblastoma (3.48) and female ganglioneuroma (7.72) whereas astrocytoma risks were at the level of common cancers at other sites (1.7–2.0). Hemangioblastoma families appeared not to be related to von Hippel-Lindau syndrome because of lack of pathognomonic signs other than hemangioblastoma in the families. Conclusion In spite of the low number of childhood nervous system tumors, we observed high familial risks for, probably novel, syndromic hemangioblastoma, and schwannomas for which concordant clusters were found particularly in the spinal cord. Inquiring about a detailed family history at diagnosis of a nervous system cancer in childhood may reveal a syndromic disease due to a constitutional variant amenable to treatment.
2012-10-01 | Combined Blockade and Akt/Mtor Pathway Inhibits Growth of Human Hemangioma via Downregulation of Proliferating Cell Nuclear Antigen
Protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in the tumorigenesis and progression of multiple tumors, and has been shown to be important therapeutic targets for cancer. The present study aimed to explore the role and molecular mechanisms of AKT/mTOR pathway in human hemangioma (HA). Twenty-five cases of human HA tissues were collected. The expression of AKT, mTOR and proliferating cell nuclear antigen (PCNA) proteins was evaluated using semi-quantitative immunohistochemistry in biopsy samples in different phases of HA. AKT/mTOR pathway was blocked by recombinant small hairpin RNA adenovirus vector rAd5-AKT+mTOR (rAd5-Am), used for infecting proliferating phase HA-derived endothelial cells (HDEC). The expression of AKT, mTOR and PCNA was detected by Real-time PCR and Western blot assays. Cell proliferative activities were determined by MTT assay, and cell cycle distribution and apoptosis were analyzed by flow cytometry. As a consequence, the expression of AKT, mTOR and PCNA was significantly increased in proliferative phase HA, while that was decreased in involutive phase. Combined blockade of AKT/mTOR pathway by rAd5-Am diminished cell proliferative activities, and induced cell apoptosis and cycle arrest with the decreased expression of AKT, mTOR and PCNA in proliferative phase HDEC. In conclusion, the activity of AKT/mTOR pathway was increased in proliferative phase HA, while it was decreased in involutive phase. Combined blockade of AKT/mTOR pathway might suppress cell proliferation via down-regulation of PCNA expression, and induce apoptosis and cycle arrest in proliferative phase HDEC, suggesting that AKT/mTOR pathway might represent the important therapeutic targets for human HA.
2007-09-01 | Preferential Loss of the Nonimprinted Allele for the ZAC1 Tumor Suppressor Gene in Human Capillary Hemangioblastoma
Capillary hemangioblastomas (CHBs) are vascular, usually benign, tumors of the CNS, occurring either as a component of familial von Hippel-Lindau (VHL) disease or as a sporadic entity. Both familial and sporadic forms of VHL-associated tumors involve inactivation of the VHL gene; for CHB, 20% to 50% of sporadic cases are affected. However, other molecular alterations involved in the pathogenesis of sporadic CHBs, which represent up to 70% of CHBs, remain largely unknown. We previously identified a minimal deleted area at 6q23-24 in CHB, and the present study focused on the ZAC1 gene (6q24-25). ZAC1 is a maternally imprinted tumor suppressor gene with antiproliferative properties. We investigated loss of heterozygosity (LOH), promoter methylation, and expression status of ZAC1 in mainly sporadic cases of CHB. Our LOH analysis with 6 microsatellite markers spanning the ZAC1 gene region revealed a high frequency (6 of 10, 60%) of LOH. The promoter methylation analysis detected predominance of the methylated ZAC1 sequence in the majority (9 of 10, 90%) of the tumors. Immunohistochemistry exhibited a strongly reduced expression of ZAC1 in stromal cells of all CHBs studied. Collectively, our current results indicate that the absence of the unmethylated ZAC1 sequence was highly concurrent with ZAC1 region LOH or 6q loss and with lack of ZAC1 expression, suggesting preferential loss of the nonimprinted, expressed ZAC1 allele in CHB. This novel finding highlights the importance of ZAC1 in development of CHB, particularly in non-VHL-associated cases.
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2025-03-14 | 442 AI for Recovering a Voice
INTRODUCTION: Patients with brain tumors commonly encounter speech impairments, and these can have a significant impact on a patient's quality of life. This study explores the potential of a novel text-to-speech application, Voice Engine, to reconstruct naturalistic, individualized voice for a patient with persistent dysarthria following brain tumor resection. METHODS: A 21-year-old female patient presented with slurred speech and facial droop due to a large posterior fossa mass. Following a sub-occipital craniectomy for resection of pathology-confirmed hemangioblastoma, the patient experienced significant, persistent dysarthria. Voice Engine was used to reconstruct the patient's voice using a 15-second audio recording from a school presentation made two years prior. The reconstructed voice was integrated into a bespoke smartphone app to facilitate text-to-speech communication. Pre- and post-app surveys were administered to assess the impact on the patient's quality of life. RESULTS: The patient reported that her voice impairment severely affected her personal esteem, relationships, and ability to perform daily activities such as ordering food, attending school, and communicating at work. Following the implementation of the Voice Engine-powered app, the patient reported significant improvements (<0.001) in the ability to perform daily activities, as well as enhanced overall well-being and agency. CONCLUSIONS: This case study highlights the potential of deep learning-based text-to-speech applications to significantly improve the quality of life for patients with persistent speech impairments following brain tumor resection. Further research is needed to explore the applicability of this approach to a larger cohort of patients with speech impairments resulting from various neurological conditions.
2025-02-27 | Unveiling a TGFBI Variant in the Retinal Capillary Hemangioblastoma, Type II Granular Corneal Dystrophy, and Von Hippel-Lindau Families: Unlocking Potential for Early Intervention and Targeted Therapy.
To identify the potential genetic factors responsible for retinal capillary hemangioblastoma (RCH) and Type II granular corneal dystrophy (GCDII), with autosomal dominant inheritance. We used whole-exome sequencing (WES) in an Iranian family to identify the possible genetic etiology of RCH and GCDII with other manifestations of von Hippel-Lindau (VHL) disease. This study included one Iranian family for WES in index patients and Sanger sequencing in all available individuals. Clinical presentations of these patients included RCH, GCD, central nervous system hemangioblastoma as well as pancreatic cyst. WES disclosed a heterozygous known pathogenic variant c.371G>A (p.R124H) in exon 4 of gene TGFBI. For the first time, our research identified the potential involvement of TGFBI: c.371G>A (p.R124H) in an Iranian family with RCH, GCDII, and other symptoms of VHL disease. In the future, TGFBI could offer a new understanding and a promising therapeutic approach for both GCDII and VHL diseases simultaneously. Before using the variant in genetic counseling, it is recommended to conduct functional analysis using appropriate animal models to understand its pathogenesis mechanism.
2024-11-27 | Reclaiming Voice with AI
Voice impairments affect millions of Americans, with personalized text-to-speech technology offering limited solutions due to the need for extensive voice banking. Here, we report the case of Alexis Bogan, a 20-year-old patient who acutely lost her voice after surgery to resect her brain stem hemangioblastoma. In a world-first application, OpenAI's Voice Engine was used to clone Ms. Bogan's voice from just 15 seconds of preexisting audio, sourced from a school project she had filmed a few years prior. This enabled her to use a personalized text-to-speech app for daily communication while rehabilitating her speech. This case was highlighted on a recent episode of the NEJM AI Grand Rounds podcast,1 framing a broader discussion on voice cloning technology. While AI is often dual use and concerns about voice cloning often center on potential misuse, such as "deepfakes" and misinformation, we argue that suppressing this technology may inflict tangible harm on patients by denying them the chance to reclaim their voice. Inspired by Ms. Bogan's journey, we urge researchers, clinicians, ethicists, policymakers, and tech companies to collaborate swiftly yet responsibly in advancing AI voice cloning in health care. By doing so, we can empower patients to recover not just their voice, but also a fundamental aspect of their identity and quality of life.
2022-04-06 | Venous congestion as a central mechanism of radiculopathies.
Compression of roots/nerves can disrupt some of their functions, but does not necessarily cause pain. This is illustrated by the frequency of nearly asymptomatic spinal stenosis or disc herniations. In fact, pain of radiculopathies (and nerve entrapments) may mostly be the consequence of intraneural oedema induced by microscopical venous stasis around roots/spinal ganglia (or nerves) not or poorly shown by imaging. This narrative review first lists arguments for a role of congestion of vasa-nervorum in the pathophysiology of radiculopathies, including those induced by disc herniation and spinal stenosis, but also other sources of overpressures in spinal venous plexuses (pregnancy, vena cava atresia and thrombosis, portal hypertension, epidural varices, arterio-venous fistula, vertebral hemangioma or hemangioblastoma). It also details sources of venous congestion around nerves outside the spine, from pelvis (May-Thurner syndrome, Nut-cracker syndrome) to buttocks (superior and inferior gluteal veins), and even thighs and legs. A better recognition of a preeminent role of venous congestion in radiculopathies, plexopathies, and nerve entrapments, should have major consequences: (i) discard the dogma that compression is mandatory to induce root/nerve suffering, since root/nerve adherences in two locations can impair blood flow in vasa-nervorum through root/nerve stretching; (ii) implementation of sensitive techniques to visualise impingement of blood flow around or within roots and nerves; (iii) better prevention of roots/nerves adherence, or arachnoiditis induced by extravascular fibrin deposition secondary to venous stasis.; (iv) optimizing treatments dampening clot formation and/or extravascular fibrin leakage in the intradural/peridural spaces, or around roots/nerves, like guided injection of tissue plasminogen activator.
2019-06-26 | Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15
Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen—transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.—Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15. FASEB J. 33, 10505–10514 (2019). www.fasebj.org
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