Von Hippel-Lindau Research Articles

G-Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy.

Fragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper-expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small-molecule inhibitor for FMRP so far. In this study, we developed the first FMRP-targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP-targeting G-quadruplex RNA (sc1) to a von Hippel-Lindau (VHL)-targeting ligand peptide (named as sc1-VHLL). Sc1-VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro-inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1-VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor-bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1-VHLL based treatment remarkably inhibited the tumor growth.

The Interplay between von Hippel-Lindau Tumor Suppressor Gene, Lon Protease, ROS Accumulation, and Inflammation in Clear Cell Renal Cell Carcinoma.

This study explores the role of the von Hippel-Lindau (VHL) tumor suppressor gene and Lon protease in the development of clear cell renal carcinoma (ccRCC) through mechanisms involving inflammation and reactive oxygen species (ROS) accumulation in kidney cells. By examining the impact of VHL on the early stages of kidney cancer development, this research highlights the contributions of inflammation and ROS, as well as the involvement of Lon protease. The findings reveal increased Lon expression and ROS levels in VHL-knockdown HK-2 cells, along with elevated phospho-c-Jun N-terminal kinase (JNK) levels, emphasizing the complex interplay between VHL, Lon protease, inflammation, and ROS in kidney cell models. These insights point to potential therapeutic pathways for ccRCC.

Genotype-phenotype correlation of ocular von Hippel-Lindau disease in Koreans.

This scientific report aims to investigate the genotype-phenotype correlations of retinal hemangioblastoma (RH) in von Hippel-Lindau (VHL) disease. The study included 77 patients with genetically confirmed VHL disease who visited an ophthalmology clinic for the evaluation of RH. The presence, location, and size of RH were evaluated, Patients were categorized into three groups based on variants: HIF-1α binding site missense (HM), non-HIF-1α binding site missense (nHM), and truncating (TR) mutations. Fifty-six patients (72.7%) had RH in either eye, and 24 had bilateral RH. Sixteen patients (20.8%) had juxtapapillary RH in either eye. Nine patients had RH ≥ 2.0 disc diameters in size. VHL c.208G>A variant was the most frequent single mutation. Compared with patients having nHM mutations (15 patients) in VHL gene, patients with HM mutations (33 patients) or TR mutations (26 patients) presented a greater number of eyes affected (p = 0.007 and 0.004, respectively), a greater number of RH (p = 0.012 and 0.003, respectively), and more frequent presentation of large RH ≥ 2.0 disc diameters (p = 0.012, and 0.013, respectively). In conclusion, this study provides a deeper understanding of the genetic spectrum of VHL disease in Korean VHL disease and highlights the importance of the location of missense mutations regarding the risk of RH.

8789 Unraveling Von Hippel Lindau Syndrome: A Comprehensive Analysis of Clinical Manifestations, Age-Related Variations, and Tumor Prevalence in a Specialized Endocrine Center

Abstract Disclosure: K.K. Pasam: None. Y. Gupta: None. A. Goyal: None. N. Tandon: None. Introduction: This study presents a thorough examination of Von Hippel Lindau (VHL) syndromes, focusing on the clinical spectrum and genetic mutations in our population. Methods: The study, conducted at the Department of Endocrinology and Metabolism from 2016 to 2022. Objectives included studying the spectrum of diseases in index patients and asymptomatic family members. Results: In our study, we identified 19 index cases and 12 asymptomatic cases identified on screening. The analysis of 31 VHL patients revealed a mean age of presentation of 24.2±11.1 years. Pancreatic cysts were the most common manifestation in 61% followed by pheochromocytoma in 54%, cerebellar hemangioblastomas in 45%, retinal angiomas in 39% and renal cell carcinoma in 35%. 16% of patients presented with nonfunctioning pancreatic neuroendocrine tumors, and one case featured an endolymphatic sac tumor.Pheochromocytomas in VHL syndrome presented at a remarkably young age, with an average of 23.1±11.4 years. Bilateral pheochromocytomas were observed in 14 (82%) and hormonal evaluation revealed urinary noradrenaline, normetanephrines, and plasma normetanephrine elevations of 5, 6, and 7-fold, respectively.The median size of pheochromocytomas in VHL syndrome was 5.4 cm. Metastatic pheochromocytoma was observed in one patient. Genetic analysis was available for 9 patients with most common mutation in exon 3 of chromosome 3. Discussion:The average age of VHL syndrome presentation in our cohort is younger than in other Indian studies. Males in our study were 45%, deviating from the absence of gender preponderance associated with VHL. Disparities in age of diagnosis and tumor prevalence compared with other international cohorts highlight potential regional and ethnic variations. Multiple pancreatic cysts in our study, with a prevalence of 61%, lower than the South Indian study's 71%. Literature comparisons indicate pancreatic cyst prevalence ranging from 42% to 51.6%. Cerebellar hemangioblastomas and retinal angiomas, typical VHL lesions, displayed prevalence rates of 45% and 39%, respectively.Pheochromocytoma, the second most common tumor in our cohort (54%), exhibited variations in prevalence compared to international studies. Higher rates reported by Fagundes et al. and Dwivedi et al. from Brazil might be attributed to recruitment biases from endocrine centers.The average age of VHL-associated pheochromocytoma presentation in our study contrasts with MEN2, emphasizing the unique features of VHL. Our study, reporting a 16% prevalence of PNETs, aligns with Binderup et al. The mean age of presentation for VHL-associated PNETs (20.8 ± 3.63 years) contrasts with Western literature, suggesting potential ethnic differences. Conclusion: Our study contributes to a nuanced understanding of VHL syndrome, shedding light on age-related variations, gender distribution, and tumor prevalence. Presentation: 6/2/2024

8789 Unraveling Von Hippel Lindau Syndrome: A Comprehensive Analysis Of Clinical Manifestations, Age-Related Variations, And Tumor Prevalence In A Specialized Endocrine Center

Abstract Disclosure: K.K. Pasam: None. Y. Gupta: None. A. Goyal: None. N. Tandon: None. Introduction: This study presents a thorough examination of Von Hippel Lindau (VHL) syndromes, focusing on the clinical spectrum and genetic mutations in our population. Methods: The study, conducted at the Department of Endocrinology and Metabolism from 2016 to 2022. Objectives included studying the spectrum of diseases in index patients and asymptomatic family members. Results: In our study, we identified 19 index cases and 12 asymptomatic cases identified on screening. The analysis of 31 VHL patients revealed a mean age of presentation of 24.2±11.1 years. Pancreatic cysts were the most common manifestation in 61% followed by pheochromocytoma in 54%, cerebellar hemangioblastomas in 45%, retinal angiomas in 39% and renal cell carcinoma in 35%. 16% of patients presented with nonfunctioning pancreatic neuroendocrine tumors, and one case featured an endolymphatic sac tumor.Pheochromocytomas in VHL syndrome presented at a remarkably young age, with an average of 23.1±11.4 years. Bilateral pheochromocytomas were observed in 14 (82%) and hormonal evaluation revealed urinary noradrenaline, normetanephrines, and plasma normetanephrine elevations of 5, 6, and 7-fold, respectively.The median size of pheochromocytomas in VHL syndrome was 5.4 cm. Metastatic pheochromocytoma was observed in one patient. Genetic analysis was available for 9 patients with most common mutation in exon 3 of chromosome 3. Discussion:The average age of VHL syndrome presentation in our cohort is younger than in other Indian studies. Males in our study were 45%, deviating from the absence of gender preponderance associated with VHL. Disparities in age of diagnosis and tumor prevalence compared with other international cohorts highlight potential regional and ethnic variations. Multiple pancreatic cysts in our study, with a prevalence of 61%, lower than the South Indian study's 71%. Literature comparisons indicate pancreatic cyst prevalence ranging from 42% to 51.6%. Cerebellar hemangioblastomas and retinal angiomas, typical VHL lesions, displayed prevalence rates of 45% and 39%, respectively.Pheochromocytoma, the second most common tumor in our cohort (54%), exhibited variations in prevalence compared to international studies. Higher rates reported by Fagundes et al. and Dwivedi et al. from Brazil might be attributed to recruitment biases from endocrine centers.The average age of VHL-associated pheochromocytoma presentation in our study contrasts with MEN2, emphasizing the unique features of VHL. Our study, reporting a 16% prevalence of PNETs, aligns with Binderup et al. The mean age of presentation for VHL-associated PNETs (20.8 ± 3.63 years) contrasts with Western literature, suggesting potential ethnic differences. Conclusion: Our study contributes to a nuanced understanding of VHL syndrome, shedding light on age-related variations, gender distribution, and tumor prevalence. Presentation: 6/2/2024

8623 Atypical VHL Genetic Variant Causing Paraganglioma

Abstract Disclosure: G. Mangu: None. J.J. Faria Briceno: None. R. Yatavelli: None. Abstract: Pheochromocytomas and paragangliomas (PPGLs) are rare chromaffin cell tumors that originate from the adrenal medulla and extra-adrenal paraganglia respectively. Previous studies have shown that incidental PPGLs are seen in older patients with mild symptoms. They have lower levels of plasma catecholamines and lower incidence of malignancy than patients with nonincidental PPGLs. We report a case of an incidental paraganglioma in a young female with atypical pathogenic variant in the VHL gene which is known to cause familial erythrocytosis but NOT VHL syndrome or PPGL. Case Presentation: A 33-year-old African American female with no significant medical history presented to the emergency room with the chief complaint of right lower quadrant pain for 2 days, which started with her menstruation. The vitals were BP 128/67, pulse 67 and physical examination was unremarkable. CT showed a 4.0 x 3.0 cm heterogenous enhancing left adrenal mass and MRI with adrenal protocol revealed 3.4 x 3.1 cm mass consistent with pheochromocytoma. Labs revealed elevated plasma nor metanephrines and 24-hour urine normetanephrines were 1020 mcg. She was asymptomatic without hypertension, palpitations, or chest pain. She underwent laparoscopic left adrenalectomy after appropriate alpha blockade. The pathology report showed left periadrenal paraganglioma with immunohistochemistry staining significant for Carbonic anhydrase IX (CAIX) membranous expression which is mostly seen in paragangliomas associated with von Hippel-Lindau syndrome. Clinically, she did not have any stigmata for hereditary PPGL syndrome. Her genetic testing revealed a pathogenic heterozygous variant in the VHL gene, Exon 3, c.598C.T (pArg200Trp), which is a missense variant expected to disrupt VHL protein function. Although she has a germline mutation in VHL, it is not the garden variant which is associated with classic VHL syndrome. It has been reported to cause autosomal recessive erythrocytosis but not PPGL. Conclusion: The pathogenic heterozygous variant in VHL gene, Exon 3, c.598C.T (pArg200Trp) is known to cause autosomal recessive familial erythrocytosis type 2 in the Chuvash population, termed as Chuvash Polycythemia. Our patient did not have polycythemia but had iron deficiency anemia from menorrhagia. Several studies have reported that this variant does not cause VHL syndrome, however it has been reported in a single family with VHL syndrome but WITHOUT pheochromocytoma. To our knowledge, incidental adrenergic paraganglioma associated with this mutation has not been reported in the literature. Presentation: 6/3/2024

8338 A Case Series of 3 Patients with Unusual Miliary Lung Metastases in Paraganglioma: Diagnostic Workup, Treatment Challenges and Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G>T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C>G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively.Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

8338 A Case Series Of 3 Patients With Unusual Miliary Lung Metastases In Paraganglioma: Diagnostic Workup, Treatment Challenges And Outcomes

Abstract Disclosure: K.M. Charles: None. M.A. Nazari: None. A. Jha: None. A. Derkyi: None. S. Talvacchio: None. M.J. Kuo: None. M. Patel: None. T. Prodanov: None. A.S. Alzahrani: None. A. Chen: None. J. Glod: None. J. Del Rivero: None. A.M. Gharib: None. K. Pacak: None. Background: Pheochromocytomas (PCCs) and paragangliomas (PGLs, together PPGLs) are uncommon neuroendocrine tumors originating from adrenal medulla chromaffin cells and sympathetic/parasympathetic ganglia. Metastatic disease occurs in a subset of PPGLs, ranging from 5% to 30% depending on the underlying genetic factors. Metastases are typically found in the bone, lung, lymph nodes, or liver. Historically, there have been no reported cases of PPGL with miliary pattern of pulmonary metastases. Methods: Three patients were identified with pulmonary metastases. All patients were evaluated between 2016 and 2023, and all developed extensive pulmonary metastatic disease. The evaluation process involved reviewing their medical history, laboratory results, and potential therapeutic approaches. Each patient underwent surgical intervention for the primary tumor and received systemic therapies once metastatic spread was detected. Results: We present three patients with either germline succinate dehydrogenase subunit D (SDHD) or von Hippel-Lindau (VHL) pathogenic variants who developed this rare condition. Patient 1: a 14-year-old female with right PCC and a recurrent left neck PGL carrying VHL type 2 pathogenic variant: VHL c.250G>T (p.Val84Leu) and received various chemotherapies with an unfavorable response. Patient 2: a 23-year-old female with a left jugular PGL carrying SDHD pathogenic variant: SDHD c.124_127delinsA TA (p.Glu42Ilefs*44). Patient 3: a 26-year-old female with a right PCC carrying a germline VHL type 2 pathogenic variant: VHL c.439C>G (p.Leu147Val). The latter two patients experienced disease stabilization through chemotherapy and systemic targeted radiotherapy, respectively. Discussion/Conclusion: This case series is unique as it highlights the rare occurrence of miliary spread of pulmonary metastases resulting from PCC or PGL. It also provides insight into prospective treatments options and outcomes for clinicians administering care within this population of patients. Though it is not clear at this time, this case series may represent a new subset of PPGL that have different genomic features and require a different therapeutic approach. Presentation: 6/1/2024

6891 Exclusive Normetanephrine Secreting Pheochromocytoma In A Young Male

Abstract Disclosure: E. Askar: None. H. Moran: None. IntroductionPheochromocytomas and paragangliomas arise from chromaffin cells and produce excessive catecholamines. Hypertension is their primary clinical symptom. they differ in their catecholamine secretory phenotype; paragangliomas typically secrete norepinephrine, while pheochromocytomas typically secrete epinephrine. Here, we present a case 21-year-old male with pheochromocytoma with elevated norepinephrine but normal epinephrine levels.Case presentationA 21 -year-old male with no past medical history presented with episodes of palpitations, sweating, and elevated blood pressure. He also reported abdominal pain. On admission, his blood pressure was 143/92 mmHg, pulse was 71/min, respiration was 16/min, and oxygen saturation was 100% in room air. The rest of physical exam was not significant. His electrolyte panel was normal. Computed tomography (CT) abdomen and pelvis with contrast was performed and showed a right adrenal mass measuring 4.9 x 4.0 x 6.5 cm which is predominantly hypoattenuating (approximately 30 Hounsfield units) with thick nodular rim of enhancement. Hormonal workup showed normal serum testosterone, DHEA-S, AM cortisol, ACTH, aldosterone, plasma metanephrine, and urine metanephrine, but profoundly high plasma normetanephrine 3641.6 (0.0-210.1) pg/mL. His 24-hour urinary normetanephrine was elevated at 14874 (80-440) ug/24hr, confirming a pheochromocytoma. The high norepinephrine level in the setting of normal epinephrine raised suspicion for Von Hippel Lindau (VHL). He was started on alpha and beta blockage and had laparoscopic removal of the right adrenal gland. The pathology report confirmed the diagnosis of pheochromocytoma confined to right adrenal. The patient was then referred for genetic testing. Conclusion: Pheochromocytoma can be a part of familial disorders, although being sporadic in nature most of the time. As demonstrated in our case, the hallmark of pheochromocytoma associated with VHL is nearly exclusive normetanephrine secretion and a high ratio of normetanephrine to metanephrine. Confirmation and testing of genes aid in proper monitoring and follow-up. The preferred course of treatment is radical resection. Presentation: 6/2/2024

7109 "My Stomach hurts": A Rare Case of Adrenal Cortical Carcinoma

Abstract Disclosure: R.C. Attah: None. I. Sirisena: None. Pheochromocytoma/Paragangliomas are rare neurogenic tumors that arise from chromaffin cells present in the adrenal medulla or extra-adrenal paraganglia, these cells produce catecholamines. Typically, these tumors are discovered as incidentalomas. They can be hereditary as seen in genetic syndromes like multiple endocrine neoplasia type 2A or 2B, neurofibromatosis type 1 or Von Hippel Lindau syndrome but can occur sporadically. Patients typically present with hormonal hypersecretion signs or symptoms like abdominal pain, episodic headaches, sweating, hypertension and tachycardia, but some patients are asymptomatic. Patient is a 37-year-old female with past medical history of hypertension, type 2 diabetes mellitus and fatty liver who presented to the ED with abdominal pain for a few weeks. On arrival, her vitals were BP 205/124, HR 102, RR 14 and SpO2 100% on room air. CT abdomen was obtained which showed a 7.6 x 4.7 x 5.7 cm mass replacing left adrenal gland with small left retroperitoneal hemorrhage worrisome for adrenal cortical carcinoma, metastatic disease or pheochromocytoma. Hormonal workup revealed elevated 24-hr urine cortisol 124.2mcg (ref 4.0-50.0mcg/24h), normal aldosterone/renin ratio 10.63ng/dL (ref <30ng/dl), failed low dose dexamethasone suppression test with post-dex AM cortisol 7.20ug/dL (ref <1.8ug/dL), slightly elevated serum total catecholamine 1256pg/mL (242-1125 pg/mL), norepinephrine 1155pg/mL (ref 217-1109 pg/mL), total metanephrine and normetanephrine 341pg/mL (reg <205 pg/mL), normetanephrine 244.1 (ref <210.1pg/mL), elevated 24-hr urine normetanephrine 700ug/L (ref 131-612ug/L), metanephrine 136ug/L (ref 36-209ug/L) and DHEA-s level 285ug/dl (ref 23-266ug/dL). Due to elevation in cortisol, adrenal cortical carcinoma was suspected as these tumors are frequently associated with cortisol secretion. However, pheochromocytoma with co-secretion of ACTH could not be excluded. She was started on doxazosin for alpha blockade and eventually started on beta blockade with Metoprolol. She underwent a left adrenalectomy and was started on steroid taper post-op due to concern of cortisol co-secretion. Surgical pathology was positive for Left adrenal malignant pheochromocytoma and ganglioneuroma. Genetic panel was negative with no mutation identified in the 54 gene Hereditary paraganglioma-pheochromocytoma panel. This patient had a large adrenal tumor (>4cm mass) but mildly elevated catecholamines which could have led to misdiagnosis as her catecholamine levels were less than 2-3x ULN which is unusual for pheochromocytomas. Roughly 25% of people with pheochromocytoma are undiagnosed throughout their lifespan. This condition can be life-threatening, hence early diagnosis and intervention can be lifesaving. Prognosis of malignant pheochromocytoma is dependent on tumor size, presence of SDHB gene mutation or visceral metastases. Presentation: 6/1/2024

Hypoxia regulate developmental coronary angiogenesis potentially through VEGF-R2- and SOX17-mediated signaling.

The development of coronary vessels in embryonic mouse heart involves various progenitor populations, including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is known to regulate coronary growth from the SV, whereas VEGF-A/VEGF-R2 signaling controls growth from the endocardium. Previous studies suggest hypoxia might regulate coronary growth, but its specific downstream pathways are unclear. In this study, we further investigated the role of hypoxia and have identified SOX17- and VEGF-R2-mediated signaling as the potential downstream pathways in its regulation of developmental coronary angiogenesis. HIF-1α stabilization by knocking out von Hippel Lindau (VHL) protein in the myocardium (cKO) disrupted normal coronary angiogenesis in embryonic mouse hearts, resembling patterns of accelerated coronary growth. VEGF-R2 expression was increased in coronary endothelial cells under hypoxia in vitro and in VHL cKO hearts in vivo. Similarly, SOX17 expression was increased in the VHL cKO hearts, while its knockout in the endocardium disrupted normal coronary growth. These findings provide further evidence that hypoxia regulates developmental coronary growth potentially through VEGF-R2 and SOX17 pathways, shedding light on mechanisms of coronary vessel development.

Unique properties of clinical manifestation and magnetic resonance imaging for differential diagnosis of optic nerve hemangioblastoma.

To investigate the unique properties of clinical manifestation and radiological imaging for differential diagnosis of optic nerve hemangioblastoma (ONH) from adult optic nerve glioma (ONG) prior to surgical resection. ONH and adult ONG patients were recruited from 2012 to 2022. A total of seven ONH patients (8 eyes) and 23 adult ONG patients (24 eyes) were assessed. The median onset age of ONH patients was older than that of adult ONG patients (p = 0.007). There were 42.9% (3/7) of ONH patients closely associated with the diagnosis of Von Hippel-Lindau (VHL) syndrome. Notably in Magnetic Resonance Imaging (MRI), the retrobulbar hemangioblastomas in all ONH patients were primarily intraorbital (100%, 8/8), canalicular (87.5%, 7/8), and anterior intracranial (12.5%, 1/8), especially concentrated in the orbital apex, with little posterior optic pathway involvement. Nearly all affected parts of optic nerve in the ONH group (75.0%, 6/8) presented with circumscribed cystic-solid components, characterized by cystic lesions (peritumoral oedema) anteriorly and solid tumours posteriorly, with significant heterogeneous enhancement. Adult ONG lesions prior to extend from the anterior portion to the whole length of the optic nerve, with relatively innocent enlargement in the postcontrast study. Optic nerve tumours in those with older ages at diagnosis (>30 years) or those diagnosed with VHL syndrome are more likely to be indicative of ONH. In the absence of associated VHL syndrome, a distinguishing MRI feature is the concentration of tumours in the orbital apex, characterized by circumscribed cystic-solid components and heterogeneous enhancement of the solid portion.

Application of carbonic anhydrase IX in sporadic hemangioblastoma of the central nervous system and hemangioblastoma associated with von Hippel-Lindau disease.

This research aims to examine the expression of carbonic anhydrase IX (CAIX) protein in hemangioblastoma of the central nervous system and its potential application in pathological diagnosis and differential diagnosis. Immunohistochemistry was used to identify the expression of CAIX and the α-inhibin protein. The sensitivity and specificity of CAIX and α-inhibin for identifying hemangioblastoma of the central nervous system were compared. In addition, 86 patients with meningiomas were gathered to detect CAIX protein expression. Hemangioblastoma and angiomatous, microcystic the two subtypes of meningiomas, were compared for CAIX and EMA protein expression. In hemangioblastoma, there were significant differences in the median positive percentage and staining intensity of CAIX and α-inhibin (p < 0.05). There was no discernible difference in the expression of the CAIX protein between sporadic hemangioblastoma of the central nervous system and those linked to von Hippel‒Lindau disease. In comparison to angiomatous and microcystic meningiomas, the positive rate of CAIX in hemangioblastomas was substantially greater (p < 0.001). The expression of EMA in microcystic meningioma (6/6) and angiomatous meningioma (17/17) was significantly different from hemangioblastoma (0/30) (p < 0.0001). Hemangioblastoma might be diagnosed with high specificity and sensitivity through CAIX immunohistochemistry. The combination of CAIX with EMA is useful for the diagnosis and differential diagnosis of hemangioblastoma.

Penfluridol inhibits melanoma growth and metastasis through enhancing von Hippel‒Lindau tumor suppressor-mediated cancerous inhibitor of protein phosphatase 2A (CIP2A) degradation.

Melanoma's high metastatic potential, especially to the brain, poses significant challenges to patient survival. The blood‒brain barrier (BBB) is a major obstacle to the effective treatment of melanoma brain metastases. We screened antipsychotic drugs capable of crossing the BBB and identified penfluridol (PF) as the most active candidate. PF reduced melanoma cell viability and induced apoptosis. In animal models, PF effectively inhibited melanoma growth and metastasis to the lung and brain. Using immunoprecipitation combined with high-resolution mass spectrometry, and other techniques such as drug affinity responsive target stability, we identified CIP2A as a direct binding protein of PF. CIP2A is highly expressed in melanoma and its metastases, and is linked to poor prognosis. PF can restore Protein Phosphatase 2A activity by promoting CIP2A degradation, thereby inhibiting several key oncogenic pathways, including AKT and c-Myc. Additionally, von Hippel‒Lindau (VHL) is the endogenous E3 ligase for CIP2A, and PF enhances the interaction between VHL and CIP2A, promoting the ubiquitin‒proteasome degradation of CIP2A, thereby inhibiting melanoma growth and metastasis. Overall, this study not only suggests PF's potential in treating melanoma and its brain metastases but also highlights CIP2A degradation as a therapeutic strategy for melanoma.

Imaging of pancreatic serous cystadenoma and common imitators.

Pancreatic cystic neoplasms are lesions comprised of cystic components that show different biological behaviors, epidemiology, clinical manifestations, imaging features, and malignant potential and management. Benign cystic neoplasms include serous cystic neoplasms (SCAs). Other pancreatic cystic lesions have malignant potential, such as intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. SCAs can be divided into microcystic (classic appearance), honeycomb, oligocystic/macrocystic, and solid patterns based on imaging appearance. They are usually solitary but may be multiple in von Hippel-Lindau disease, which may depict disseminated involvement. The variable appearances of SCAs can mimic other types of pancreatic cystic lesions, and cross-sectional imaging plays an important role in their differential diagnosis. Endoscopic ultrasonography has helped in improving diagnostic accuracy of pancreatic cystic lesions by guiding tissue sampling (biopsy) or cyst fluid analysis. Immunohistochemistry and newer techniques such as radiomics have shown improved performance for preoperatively discriminating SCAs and their mimickers.

Non-Markovian Dynamic Models Identify Non-Canonical KRAS-VHL Encounter Complex Conformations for Novel PROTAC Design.

Targeted protein degradation (TPD) is emerging as a promising therapeutic approach for cancer and other diseases, with an increasing number of programs demonstrating its efficacy in human clinical trials. One notable method for TPD is Proteolysis Targeting Chimeras (PROTACs) that selectively degrade a protein of interest (POI) through E3-ligase induced ubiquitination followed by proteasomal degradation. PROTACs utilize a warhead-linker-ligand architecture to bring the POI (bound to the warhead) and the E3 ligase (bound to the ligand) into proximity. The resulting non-native protein-protein interactions (PPIs) formed between the POI and E3 ligase lead to the formation of a stable ternary complex, enhancing cooperativity for TPD. A significant challenge in PROTAC design is the screening of the linkers to induce favorable non-native PPIs between POI and E3 ligase. Here, we present a physics-based computational protocol to predict noncanonical and metastable PPI interfaces between an E3 ligase and a given POI, aiding in the design of linkers to stabilize the ternary complex and enhance degradation. Specifically, we build the non-Markovian dynamic model using the Integrative Generalized Master equation (IGME) method from ∼1.5 ms all-atom molecular dynamics simulations of linker-less encounter complex, to systematically explore the inherent PPIs between the oncogene homologue protein and the von Hippel-Lindau E3 ligase. Our protocol revealed six metastable states each containing a different PPI interface. We selected three of these metastable states containing promising PPIs for linker design. Our selection criterion included thermodynamic and kinetic stabilities of PPIs and the accessibility between the solvent-exposed sites on the warheads and E3 ligand. One selected PPIs closely matches a recent cocrystal PPI interface structure induced by an experimentally designed PROTAC with potent degradation efficacy. We anticipate that our protocol has significant potential for widespread application in predicting metastable POI-ligase interfaces that can enable rational design of PROTACs.

Hereditary Pheochromocytoma as a Main Manifestation of von Hippel Lindau Disease (vHL) in Childhood – A Long-term Follow-up of 5 Patients with vHL from One Family

Hereditary Pheochromocytoma as a Main Manifestation of von Hippel Lindau Disease (vHL) in Childhood – A Long-term Follow-up of 5 Patients with vHL from One Family

Surgical Treatment of Craniocervical Junction Tumors: Neurosurgery Department Experience of “Hôpital Principal De Dakar”

Introduction: Craniocervical tumors are uncommon but represent a medical emergency for diagnosis and treatment. Their approaches require of course surgical expertise in addition to adapted technical platform. In light of the limited resources available in our practice, we consequently made the decision to share our experience with the surgical treatment of this pathology. Patients and method: We performed a retrospective analysis on eight observations of patients treated in the neurosurgery department of “Hôpital Principal de Dakar” between July 2015 and December 2022 for progressive tumor spinal cord compression at the craniocervical junction. Results: We observed a 10% frequency, a mean age of 39.25 years, and extremes between 8 and 62 years. There was a 0.6 sex ratio. The most common risk factor was type I neurofibromatosis, and one case of Von Hippel-Lindau disease. All of our patients had pyramidal syndrome. Overall, there were 2 tumors with posterolateral extradural site and 4 tumors with extramedullary intradural location, including 2 posterolateral and 2 anterolateral. The location was intramedullary and cerebella-medullary in one case each. The posteromedial occipitocervical approach, which was employed on six patients, was the most utilized method. Five patients had total tumor resection, whereas three had partial resection. Two of our patients had postoperative complications: a worsening of motor deficit and a death following dependence on mechanical ventilation. We only received four histological confirmations for the anatomopathological samples. Our patients&amp;apos; evolution was positive over an average follow-up of 21 months, with neurological improvement and walking autonomy. Conclusion: Tumors affecting the craniocervical junction are still treated surgically. Despite the need for improvement in our working conditions, our results appear to be satisfactory.

Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study

The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7-40·1). In approach 1, 22 of 50 patients (44% [95% CI 30-59]) had an objective response. In approach 2, 19 of 25 patients (76% [55-91] had an objective response. 23 (46%) of 50 patients had a grade 3-5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.

Selective Degradation of MLK3 by a Novel CEP1347-VHL-02 PROTAC Compound Limits the Oncogenic Potential of TNBC.

Triple-negative breast cancer (TNBC) is associated with poor prognosis because of the lack of effective therapies. Mixed-lineage protein kinase 3 (MLK3) is a protein that is often upregulated in TNBC and involved in driving the tumorigenic potential of cancer cells. Here, we present a selective MLK3 degrader, CEP1347-VHL-02, based on the pan-MLK inhibitor CEP1347 and a ligand for E3 ligase von Hippel-Lindau (VHL) by employing proteolysis-targeting chimera (PROTAC) technology. Our compound effectively targeted MLK3 for degradation via the ubiquitin-proteasome system in several cell line models but did not degrade other MLK family members. Furthermore, we showed that CEP1347-VHL-02 robustly degraded MLK3 and inhibited its oncogenic activity in TNBC, measured as a reduction of clonogenic and migratory potential, cell cycle arrest, and the induction of apoptosis in MDA-MB-468 cells. In conclusion, we present CEP1347-VHL-02 as a novel MLK3 degrader that may be a promising new strategy to target MLK3 in TNBC.