scholarly journals Is there a role for biomarkers in surveillance of pancreatic neuroendocrine neoplasms in Von Hippel-Lindau’s disease?

2021 ◽  
Author(s):  
Myrthe R Naber ◽  
Saya Ahmad ◽  
Annemarie A Verrijn Stuart ◽  
Rachel H Giles ◽  
Gerlof D Valk ◽  
...  
Keyword(s):  
Early Detection ◽  
Unmet Need ◽  
Neuroendocrine Neoplasms ◽  
Surveillance Program ◽  
Autosomal Dominant Disorder ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Von Hippel Lindau ◽  
Vhl Disease

Abstract Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the development of multi-organ neoplasms. Among the manifestations of VHL are pancreatic neuroendocrine neoplasms (panNENs). In order to detect these lesions in a timely manner, patients are enrolled in a surveillance program, in accordance with the several existing VHL guidelines. However, these guidelines remain unclear about the role of biomarkers in diagnosing panNENs, despite the benefits a biomarker may offer regarding early detection of new lesions, thereby possibly limiting radiation exposure, and improving quality of life. The aim is to determine which biomarkers might be available in VHL patients and to assess what their clinical relevance in diagnosing panNENs in VHL patients is. We searched the databases of Pubmed/Medline, Embase and Web of Science to identify relevant articles. Seven studies assessing the diagnostic or prognostic value of biomarkers were included. The results from these studies were conflicting. Since no evident association between VHL-related panNENs and biomarkers was established in studies with larger study populations, currently biomarkers do not play a significant role in early detection or follow-up for panNENs in VHL patients. The absence of evidence underscores the need for specific research to address this unmet need.

Multifocal Pancreatic Neuroendocrine Neoplasms In Tuberous Sclerosis: A Rare Case

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S77-S77
Author(s):  
N C Jadhav ◽  
D L Gang
Keyword(s):  
Tuberous Sclerosis ◽  
Neurofibromatosis Type ◽  
Abdominal Ultrasound ◽  
Biologically Active ◽  
Pancreatic Tumors ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Von Hippel Lindau ◽  
Multifocal Disease

Abstract Casestudy: Pancreatic neuroendocrine neoplasms (PanNEN) are rare accounting for 2-5% of pancreatic tumors. Although mostly sporadic, 10-20% are associated with inherited syndromes, notably MEN-1, Von Hippel- Lindau disease, neurofibromatosis type 1, and tuberous sclerosis (TS). When compared to sporadic cases, PanNEN in hereditary syndromes occur at a younger age, are often multifocal, cystic, and may show characteristic microscopic patterns. TS is an autosomal dominant multi-system disorder with mutations involving TSC1 or TSC2 genes which function as tumor suppressors by inhibiting mTORC1 kinase. PanNEN is observed in 1.5-1.8% of patients with TS and no surveillance guidelines for the assessment of pancreatic lesions are established. Compared to other syndromes, PanNEN associated with TS are solitary. To our knowledge, only two cases of multifocal PanNEN in TS patients have been reported. We present a case of a 67-year-old gentleman with a history of TS also affecting two daughters. He presented to the emergency department with severe abdominal pain. Abdominal ultrasound suggested acute appendicitis and an incidental 2.0 cm solid lesion was noted in the head of the pancreas. Follow-up MRI revealed two additional non-cystic masses in the pancreatic tail. Endoscopic ultrasound-guided biopsy of a tail lesion revealed monomorphic tumor cells with stippled chromatin without cytologic atypia. Immunohistochemical staining was positive for synaptophysin and chromogranin. Ki-67 labelling index was under 1%. Diagnosis of a well-differentiated neuroendocrine tumor (G1) was made. The patient denied symptoms of the carcinoid syndrome and no biologically active hormones were detected. Gallium PET scan revealed multiple foci of radiotracer uptake throughout the pancreas in addition to those described on MRI. Although PanNEN are rare in TS, malignant behavior has been reported. This case reinforces the importance of early detection through active surveillance, especially as surgical options may be limited in multifocal disease.

Surgical management of spinal cord hemangioblastomas in patients with von Hippel—Lindau disease

2003 ◽  
Vol 98 (1) ◽  
pp. 106-116 ◽  
Author(s):  
Russell R. Lonser ◽  
Robert J. Weil ◽  
John E. Wanebo ◽  
Hetty L. Devroom ◽  
Edward H. Oldfield
Keyword(s):  
Spinal Cord ◽  
Surgical Management ◽  
Postoperative Outcome ◽  
Tumor Location ◽  
Neurological Dysfunction ◽  
Autosomal Dominant Disorder ◽  
Content Type ◽  
Von Hippel Lindau ◽  
Vhl Disease ◽  
Fine Print

Object. Von Hippel—Lindau (VHL) disease is an autosomal-dominant disorder frequently associated with hemangioblastomas of the spinal cord. Because of the slow progression, protean nature, and high frequency of multiple spinal hemangioblastomas associated with VHL disease, the surgical management of these lesions is complex. Because prior reports have not identified the factors that predict which patients with spinal cord hemangioblastomas need surgery or what outcomes of this procedure should be expected, the authors have reviewed a series of patients with VHL disease who underwent resection of spinal hemangioblastomas at a single institution to identify features that might guide surgical management of these patients. Methods. Forty-four consecutive patients with VHL disease (26 men and 18 women) who underwent 55 operations with resection of 86 spinal cord hemangioblastomas (mean age at surgery 34 years; range 20–58 years) at the National Institutes of Health were included in this study (mean clinical follow up 44 months). Patient examination, review of hospital charts, operative findings, and magnetic resonance imaging studies were used to analyze surgical management and its outcome. To evaluate the clinical course, clinical grades were assigned to patients before and after surgery. Preoperative neurological status, tumor size, and tumor location were predictive of postoperative outcome. Patients with no or minimal preoperative neurological dysfunction, with lesions smaller than 500 mm3, and with dorsal lesions were more likely to have no or minimal neurological impairment. Syrinx resolution was the result of tumor removal and was not influenced by whether the syrinx cavity was entered. Conclusions. Spinal cord hemangioblastomas can be safely removed in the majority of patients with VHL disease. Generally in these patients, hemangioblastomas of the spinal cord should be removed when they produce symptoms or signs.

scholarly journals KNOWLEDGE AND THE ROLE OF CADRES IN THE IMPLEMENTATION OF EARLY DETECTION OF TODDLERS DEVELOPMENT USING KPSP

2017 ◽  
Vol 10 (1) ◽  
pp. 22
Author(s):  
Nuryanin Yani ◽  
Ayesha H.N, Nurwening T.W.
Keyword(s):  
Early Detection ◽  
Developmental Disorders ◽  
Early Childhood Development ◽  
Childhood Development ◽  
Rank Test ◽  
Cross Sectional ◽  
Independent Variable ◽  
Relationship Of

Introduction: The development of toddlers is noteworthy considering the population size is large enough. Early detection is an important development with KPSP carried out in an effort to facilitate early detection of developmental disorders that can be given early intervention and referral early in children, in the end the quality of a child's development may be optimal. Trained cadres have the authority to monitor the development of children with KPSP Method: cross sectional analytic approach. Population health cadres in the district Lembeyan with Random sampling techniques with independent variable knowledge and skills of cadres, the role of cadres in the implementation of early detection of early childhood development using KPSP as the dependent variable. Results: Correlation between knowledge and the role of cadres in the implementation of early detection of toddlers development using KPSP analyzed using Spearman Rank test with the results of 0565, while the role and the skills to 0.485 correlation value. Conclusion: there is a relationship of knowledge to the role of cadres and there is a relationship between skill to the role of cadres in the implementation of early detection of toddler development using KPSP. It is hoped the clinic routinely provide refresher material on monitoring developments and increasing the number of screening kit (infrastructure for monitoring developments).

Endocrine Manifestations of von Hippel–Lindau Disease

2015 ◽  
Vol 139 (2) ◽  
pp. 263-268 ◽  
Author(s):  
Clarissa Cassol ◽  
Ozgur Mete
Keyword(s):  
Neuroendocrine Tumors ◽  
Autosomal Dominant ◽  
Suppressor Gene ◽  
Autosomal Dominant Disorder ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Sporadic Cases ◽  
Vhl Disease

von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by heterozygous mutations in the VHL tumor suppressor gene that is characterized by the occurrence of multiple endocrine and nonendocrine lesions. This review focuses on the endocrine manifestations of VHL disease. Pancreatic neuroendocrine proliferations (ductuloinsular complexes, islet dysplasia, endocrine microadenoma, and neuroendocrine tumors), pheochromocytomas, and extra-adrenal paragangliomas are important endocrine manifestations of VHL disease. They frequently display characteristic clinical, biochemical, and histopathologic features that, although not pathognomonic, can be helpful in suggesting VHL disease as the underlying etiology and distinguishing these tumors from sporadic cases. Recent improvements in treatment and outcomes of renal cell carcinomas have allowed pancreatic neuroendocrine tumors to emerge as a significant source of metastatic disease, making the accurate recognition and classification of these neoplasms by the pathologist of utmost importance to determine prognosis, treatment, and follow-up strategies for affected patients.

scholarly journals Pharmacological Restoration of Visual Function in a Zebrafish Model of von-Hippel Lindau Disease

2018 ◽  
Author(s):  
Rebecca Ward ◽  
Kayleigh Slater ◽  
Zaheer Ali ◽  
Alison L Reynolds ◽  
Lasse D Jensen ◽  
...  
Keyword(s):  
Visual Function ◽  
Vision Loss ◽  
Kinase Inhibitor ◽  
Multiple Organ ◽  
Loss Of Function ◽  
Autosomal Dominant Disorder ◽  
Zebrafish Model ◽  
Von Hippel Lindau ◽  
Organ Systems ◽  
Vhl Disease

AbstractVon Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterized by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality ofVhl-/-micein uterorestricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in thevhlgene represent a viable, alterative vertebrate model to investigate associated ocularloss-of-functionphenotypes. Previous studies reported neovascularization of the brain, eye and trunk together with odema in thevhl-/-zebrafish eye. In this study, we demonstratevhl-/-zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in thevhl-/-eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed invhl-/-zebrafish. We conclude that the zebrafishvhlgene contributes to the endogenous molecular barrier that prevents development of intraretinal vasculature and that sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal and choroidal vessels invhl-/-zebrafish.

scholarly journals Prevention of Cervical Cancer With Seminar and IVA Test for Productive Ages Women In Universitas Negeri Padang

2020 ◽  
Vol 3 (1) ◽  
pp. 43
Author(s):  
Elsa Yuniarti ◽  
Rahmawati Darrussyamsu ◽  
Moralita Chatri
Keyword(s):  
Cervical Cancer ◽  
Women Workers ◽  
Early Detection ◽  
Active Role ◽  
Preventive Action ◽  
Childbearing Age ◽  
Knowledge And Attitudes ◽  
Target Monitoring

Cervical cancer is one of the main problems of reproductive health in women in Indonesia. The results of a questionnaire of 100 women of productive age workers in UNP 80% had never done an IVA test and did not know about the IVA test for early detection of cervical cancer. Lack of knowledge and awareness of women workers at UNP to take preventive measures for early detection of cervical cancer, is carried out in prevention of cervical cancer with seminar and IVA test for productive ages women in Universitas Negeri Padang. Activities have been carried out in the rector's office, faculties and IVA test at the UNP polyclinic in collaboration with the Air Tawar Health Center, Padang City Health Office and the UNP Polyclinic. This activity has 3 stages namely seminar the importance of early detection of cervical cancer, IVA test and monitoring. Participants are women of childbearing age over the age of 18 who are married / widowed, not yet married but have had sexual intercourse at UNP. Seminar participants totaling 130 participants have exceeded the 30% target. Monitoring activities are carried out with questionnaires to participants through a Google form sent to participant WhatsApp. The questionnaire contained aspects of knowledge and attitudes of participants towards early detection of cervical cancer. The results obtained 88.40% knowledge aspects (very good) and 84.16% attitude (good). But the participation for IVA test is still less than 10%. With this activity increased knowledge and active role of women for preventive action with early detection of cervical cancer that aims to improve the quality of health and reduce the mortality rate of Indonesian women against cervical cancer.

VHL-RELATED NEUROENDOCRINE NEOPLASMS AND BEYOND: AN ISRAELI SPECIALIZED CENTER REAL-LIFE REPORT

2020 ◽  
Vol 26 (10) ◽  
pp. 1131-1142
Author(s):  
Auryan Szalat ◽  
Kira Oleinikov ◽  
Avital Nahmias ◽  
Vardiella Meiner ◽  
Simona Ben-Haim ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuroendocrine Tumor ◽  
Neuroendocrine Neoplasms ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Von Hippel Lindau ◽  
Mutation Carriers ◽  
Long Term Follow Up

Objective: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN). Methods: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed. Results: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed. Conclusion: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients. Abbreviations: CNS = central nervous system; HIF = hypoxia inducible factor; PGL = paraganglioma; PHD = prolyl hydroxylase; Pheo = pheochromocytoma; PNEN = pancreatic neuroendocrine neoplasms; PNET = pancreatic neuroendocrine tumor; RCC = clear cell renal cell carcinoma; VHL = Von Hippel-Lindau

scholarly journals Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease

2019 ◽  
Vol 104 (9) ◽  
pp. 3826-3834 ◽  
Author(s):  
Shahida K Flores ◽  
Ziming Cheng ◽  
Angela M Jasper ◽  
Keiko Natori ◽  
Takahiro Okamoto ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
The Cancer Genome Atlas ◽  
Exon 2 ◽  
Von Hippel Lindau ◽  
Familial Pheochromocytoma ◽  
Cancer Genome Atlas ◽  
Von Hippel Lindau Disease ◽  
Vhl Disease ◽  
Spliced Variant

Abstract Context von Hippel-Lindau (VHL) disease, comprising renal cancer, hemangioblastoma, and/or pheochromocytoma (PHEO), is caused by missense or truncating variants of the VHL tumor-suppressor gene, which is involved in degradation of hypoxia-inducible factors (HIFs). However, the role of synonymous VHL variants in the disease is unclear. Objective We evaluated a synonymous VHL variant in patients with familial PHEO or VHL disease without a detectable pathogenic VHL mutation. Design We performed genetic and transcriptional analyses of leukocytes and/or tumors from affected and unaffected individuals and evaluated VHL splicing in existing cancer databases. Results We identified a synonymous VHL variant (c.414A>G, p.Pro138Pro) as the driver event in five independent individuals/families with PHEOs or VHL syndrome. This variant promotes exon 2 skipping and hence, abolishes expression of the full-length VHL transcript. Exon 2 spans the HIF-binding domain required for HIF degradation by VHL. Accordingly, PHEOs carrying this variant display HIF hyperactivation typical of VHL loss. Moreover, other exon 2 VHL variants from the The Cancer Genome Atlas pan-cancer datasets are biased toward expression of a VHL transcript that excludes this exon, supporting a broader impact of this spliced variant. Conclusion A recurrent synonymous VHL variant (c.414A>G, p.Pro138Pro) confers susceptibility to PHEO and VHL disease through splice disruption, leading to VHL dysfunction. This finding indicates that certain synonymous VHL variants may be clinically relevant and should be considered in genetic testing and surveillance settings. The observation that other coding VHL variants can exclude exon 2 suggests that dysregulated splicing may be an underappreciated mechanism in VHL-mediated tumorigenesis.

The Role of Perioperative Systemic Therapy in Localized Pancreatic Neuroendocrine Neoplasms

2019 ◽  
Vol 110 (3-4) ◽  
pp. 234-245 ◽  
Author(s):  
Hao Xie ◽  
Junjia Liu ◽  
Siddhartha Yadav ◽  
Xavier M. Keutgen ◽  
Timothy J. Hobday ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Surgical Resection ◽  
Systemic Therapy ◽  
Pancreatic Head ◽  
Cox Proportional Hazards ◽  
Neuroendocrine Neoplasms ◽  
Original Cohort ◽  
Curative Intent ◽  
Pancreatic Neuroendocrine Neoplasms

Background: The role of perioperative systemic therapy (PST) in the management of localized pancreatic neuroendocrine neoplasms (PanNEN) is unclear. Objectives: We aimed to evaluate the benefit of PST compared to surgery alone (SA) in patients with localized PanNEN. Method: We selected patients with stages I–III PanNEN who underwent curative-intent surgical resection in National Cancer Database from 2006 to 2014. Patients who had both PST and surgical resection were matched with patients who received SA by propensity score at 1-to-1 ratio with nearest neighbor method. Results: Four thousand eight hundred and ninety-two patients were included in this study with median age of 60 years. Factors associated with significant more use of PST compared to SA included age <65 years, community medical facilities, grade 3 tumor, tumor in the pancreatic head, T34 tumor, and N1 tumor. Three hundred and one PST patients were matched with 301 SA patients. In the matched cohort, the PST group had significantly shorter overall survival (OS) compared to the SA group (median overall both not reached, p = 0.037). This finding was confirmed by multivariable Cox proportional hazards regression in the original cohort (hazard ratio [HR] 1.45, 95% CI 1.11–1.89, p = 0.006). Subgroup analyses showed that adjuvant therapy was not associated with improved OS in grades 1–2 PanNEN (HR 2.03, 95% CI 1.31–3.16, p = 0.002). Conclusions: PST stratified by grade and neoadjuvant or adjuvant therapy compared to SA was not associated with improved OS in patients with localized PanNEN. PST for localized PanNEN should be used with caution until prospective data are available.

scholarly journals Diagnostic and Interventional Role of Endoscopic Ultrasonography for the Management of Pancreatic Neuroendocrine Neoplasms

2021 ◽  
Vol 10 (12) ◽  
pp. 2638
Author(s):  
Giuseppinella Melita ◽  
Socrate Pallio ◽  
Andrea Tortora ◽  
Stefano Francesco Crinò ◽  
Antonio Macrì ◽  
...  
Keyword(s):  
Tumor Burden ◽  
Pancreatic Tumors ◽  
Proliferation Index ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Ethanol Injection ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Reduce Tumor Burden ◽  
Precise Diagnosis

Pancreatic neuroendocrine neoplasms (PanNENs) are relatively rare, but their incidence has increased significantly in the last decades. Precise diagnosis and prognostic stratification are crucial for proper patient management. Endoscopic ultrasound (EUS) is the modality of choice for diagnosis of solid pancreatic tumors, showing a higher tumor detection rate than other imaging modalities, especially for small size lesions. EUS also serves as a guide for preoperative sampling and other interventions. EUS-tissue acquisition is a safe and highly accurate technique for cyto/histological diagnosis of PanNENs with a well-demonstrated correlation between Ki-67 proliferation index values and tumor grading on EUS and surgical specimens according to the WHO 2017 classification. Furthermore, the possibility of a preoperative EUS-guided fine needle tattooing or fiducial markers placement may help the surgeon to locate small and deep tumors, thus avoiding formal pancreatic resections in favor of parenchymal-sparing surgery. Finally, locoregional ablative treatments using either ethanol injection or radiofrequency ablation have been proposed in recent studies with promising results in order to control symptoms or reduce tumor burden in selected patients unfit for surgery with functioning or non-functioning PanNENs. This article review highlights the current role of EUS in PanNENs management, focusing on the present and future applications of EUS-guided interventions.

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