This study evaluates the natural history of von Hippel–Lindau disease–associated pancreatic lesions to determine the factors associated with pancreatic neuroendocrine tumor phenotype and prognosis.

/pdf/association-of-vhl-genotype-with-pancreatic-neuroendocrine-1h1nr75mwc.pdf

Association of VHL Genotype With Pancreatic Neuroendocrine Tumor Phenotype in Patients With von Hippel-Lindau Disease.

Von Hippel-Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.

Management recommendations for pancreatic manifestations of von Hippel-Lindau disease.

Endocrine neoplasms comprise a variety of benign and malignant tumors that arise from the endocrine glands or other neuroendocrine tissues, such as the paraganglia. Most childhood endocrine tumors, typified by papillary thyroid carcinoma, are sporadic and not attributable to an identifiable germline mutation, whereas others, epitomized by catecholamine-producing tumors and medullary thyroid carcinoma, are familial and occur within the context of a broader hereditary tumor syndrome. In familial endocrine neoplasms, the mode of inheritance is autosomal dominant and mutations are primarily inactivating mutations causing loss of function in a tumor suppressor gene. Advances in genetic testing and research have led to the ongoing discovery of novel tumor-susceptibility genes, in addition to a better understanding of the underlying pathophysiology of these unique disorders. Knowledge regarding genotype-phenotype relationships continues to evolve, as has clinical practice regarding the age of performing predictive genetic testing, screening for endocrine tumors in an asymptomatic carrier, and the timing of therapeutic intervention. Given the rapidly changing field, it is beneficial for patients with an endocrine tumor to be evaluated in programs with known multidisciplinary expertise. In addition, the results of genetic testing and formal genetic counseling should be fully incorporated into treatment planning and long-term follow-up. This chapter reviews the pathophysiology, diagnosis, and management of pediatric endocrine tumors and the most common genetic syndromes associated with their diagnosis.

Pheochromocytoma/Paraganglioma, Medullary Thyroid Carcinoma, and Hereditary Endocrine Neoplasia Syndromes

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) comprise a heterogenous and diverse group of neoplasms arising from a common neuroendocrine cell origin. The majority of these tumors occur sporadically while ~20% manifest within the context of hereditary syndromes. Germline MEN1 mutations cause a syndrome with an increased susceptibility to multifocal primary GEP NETs. In addition, somatic MEN1 mutations also occur in these sporadic lesions. MEN1 alterations are the most frequent somatic mutation found in pancreatic neuroendocrine tumors. In this review, we explore the implication of the loss of the MEN1-encoded protein menin as a key pathogenic driver in subsets of GEP NETs with downstream consequences including upregulation of the oncogenic receptor c-MET (hepatocyte growth factor receptor). Furthermore, the review will summarize the data related to the clinical presentation, therapeutic standards, and outcomes of these tumors in both sporadic and germline MEN1 mutation-associated contexts. Finally, we present the data on c-MET expression in GEP NETs, clinical trials using c-MET inhibitors and provide an overview of the molecular mechanisms by which c-MET inhibition in these lesions represents a potential precision-medicine targeted approach.

/pdf/c-met-inhibition-novel-treatment-for-sporadic-and-men1-2nnfpxjn8q.pdf

c-MET inhibition: novel treatment for sporadic and MEN1-associated GEP NETs

Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.

/pdf/phakomatoses-and-endocrine-gland-tumors-noteworthy-and-not-40bht6xwws.pdf

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations

Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.

https://pubs.rsna.org/doi/pdf/10.1148/radiol.2018180687

Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors.

Small animals, such as mice, are used in radiopharmaceutical biodistribution studies and innumerous others preclinical investigations involving ionizing radiation. Longitudinal preclinical studies with five or more image procedures, involving radiopharmaceuticals injection and/or X-radiation, are not uncommon. However, a suitable dosimetric evaluation is not always available and, sometimes, absorbed doses in animal organs or tissues and their influence in experimental results were not appropriately taken into account. Accurate calculation of absorbed doses in mice organs are needed to evaluate potential radiobiological effects that may interfere with in vivo experiments. In this work, we perform a preliminary 16α-[18F]-fluoro-17β-estradiol (18F-FES) radiation dosimetry estimates for female mice. The obtained animal dosimetric results can be useful for evaluating animal doses during the design of longitudinal preclinical studies.

/pdf/18f-fes-radiation-dosimetry-preliminary-estimates-for-4qkt5fjz.pdf

18F-FES radiation dosimetry preliminary estimates for preclinical studies based on voxelized phantom

Small animals, such as mice, have been used in experiments involving ionizing radiation. New preclinical experimental methods often include extensive imaging (MicroCT and/or PET/SPECT) that can result in absorbed dose values considerably high. In addition, assays with theranosticsradiopharmaceuticals administered in small animals have been used to determine the main potential adverse effects and the therapeutic efficacy. For all these mentioned cases, the precise quantification of absorbed doses and the determination of energy deposition patterns are of fundamental importance to qualify or exclude potential radiobiological effects that may interfere with in vivo experiment results. Thus, the development and improvement of mouse phantoms is essential for good small animal dosimetry. In 2021, our group segmented and implemented a female C57BL mouse phantom, called FM_BRA, in the MCNP. The objective of this work was to review the segmentation of the FM_BRA computational model and to identify and segment new organs for an improved version of this phantom. Three different researchers segmented different organs of the model. The masses of the segmented organs were compared with those of the first version. Information on mass or volume of organs from different mouse strains, and more specifically from the C57BL strain, was also obtained from the literature for comparison and to aid in segmentation. The mice image representing a female mouse of the C57BL strain weighing 26 g were kindly provided by the Turku Center for Disease and were manually segmented. The software GIMP® 2.10 was used to select and segment each organ/tissue. The IMAIOS-VET Anatomy website was used as an anatomical basis for the identification of organs/tissues. The IMAGEJ® software was applied to assemble the segmented images into a 3D stack and to convert the segmented images into binary files. The volumes of the segmented organs were measured with a C++ in house program. Corresponding human tissue densities provided in ICRP 110 were used to calculate organ mass from the calculated volumes. Data were compared with literature reports. The number of segmented organs increased from 20 in the old model to 33 in the new models. The masses of the organs segmented in this work, by the different researchers, showed agreement in most cases. However, organs such as the small intestines, bones and trachea still deserve a new round of reviewing.

https://ojs.brazilianjournals.com.br/ojs/index.php/BRJD/article/download/59411/43005

Improvement of the female mouse computational model developed at CDTN

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Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors.

18F-FES radiation dosimetry preliminary estimates for preclinical studies based on voxelized phantom

Improvement of the female mouse computational model developed at CDTN