21 Jul 2023

Updates from the NIH Clinical Center in Bethesda, Maryland

• Lynn Bliss R.N., Craig Cochran R.N. and Smita Jha M.D., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health  

  The NIH Clinical Center has an ongoing Natural History Study of Parathyroid Disorders, including Multiple Endocrine Neoplasia(s) Type 1 (MEN1) beginning in 1977, which continues in an updated form as Protocol #000344 (ClinicalTrials.gov Identifier #NCT04969926). NIH is one of the few centers across the world that facilitates the conduct of long-term studies of rare diseases and is an ideal place to conduct clinical research on these disorders. To date, we have evaluated approximately 2200 patients under the study, of which 400 patients from 175 families have MEN1. The genetic cause of MEN1 was discovered through this study in 1997 (1). This letter is an update describing some recent findings from the study, which were made possible through your participation. 

  • Thymic neuroendocrine tumors (NETs), or thymic carcinoids, are uncommon in patients with MEN1 but are a major cause of mortality in patients with these tumors. An improved understanding of the mechanism that results in these tumors is needed to identify potential therapeutic targets. We identified a 4.8% prevalence of thymic tumors in our cohort of patients with MEN1 (14 of 294 patients). DNA and RNA-sequencing of the available thymic tumors confirmed the loss of both copies of the MEN1 gene, confirming that these tumors are related to the genetic mutations found in MEN1, and identified molecular targets that can lead to better surveillance and treatment of these tumors. The findings were published in Endocrine-Related Cancer in 2021 (2). 
  • We recently reported that patients with MEN1 experience a two-fold increase in the incidence of venous thromboembolism relative to the general population. This increased risk is comparable to the risk known to be associated with certain cancer types like prostate, breast, or colon cancer. While confirmation of these findings from other centers that see patients with MEN1 is needed before a change in practice can be recommended, we encourage physicians to consider thromboembolic disorders in the differential diagnosis for potential presentations in patients with MEN1. Patients should be educated on the symptoms of deep venous thrombosis, which include pain or tenderness, swelling and warmth, or discoloration in the affected area, typically in the lower leg or calf. Common symptoms of a pulmonary embolus include unexplained shortness of breath, chest discomfort or pain, cough, and loss of consciousness. Findings from this study were published in Journal of Clinical Endocrinology and Metabolism (3).
  • Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with MEN1, and metastatic dpNET is the primary cause of disease-related mortality. There is a need to identify blood-based biomarkers which would allow us to identify patients with MEN1 who are at high risk of developing metastatic dpNET. Through an international collaboration between the University of Texas MD Anderson Cancer Center, National Institutes of Health, and University Medical Center Utrecht in the Netherlands, 20 patients with metastatic dpNETs and 64 with either local dpNETs or no dpNETs (controls) were identified. We found that a three-marker blood-based polyamine signature distinguished patients with metastatic dpNETs from controls in this pilot study with 66.7% sensitivity and 95% specificity. These findings were further validated in a mouse model of MEN1 indicating potential utility in monitoring patients with MEN1. Further validation work is required before this tool can be used in routine clinical practice. The findings were published in the Journal of Clinical Endocrinology and Metabolism (4).
  • More recently, in a study to evaluate the long-term outcomes of parathyroid autografts during repeat parathyroidectomies, which consisted predominantly of patients with MEN1 with a median follow-up of 10 years, we found that 49% of these grafts were fully functional and 11% partially functional at last follow-up. These outcomes favored immediate placement of grafts over delayed placement. Among the patients in whom the graft attained full functionality, an overwhelming 83% experienced post-graft recurrence of primary hyperparathyroidism. Median time to post-graft recurrence was 8 years, with a 4–15-year range, but was significantly shorter in patients with graft-related recurrence. In these cases, positive localization findings on sestamibi (parathyroid) scans and ultrasound of the neck and forearm were accurate 67% and 75% of the time as confirmed by “surgical cure” of hyperparathyroidism. The parathyroid hormone (PTH) gradient between the arm with the graft and the opposite arm was significantly higher in graft-related recurrences. These findings highlight the challenges associated with accurately localizing the source of excess PTH in patients with post-graft recurrence and underscore the importance of obtaining bilateral PTH levels in patients who have forearm grafts. Further details about these findings can be found in the Journal of Endocrine Society (5). 

  We express our gratitude to Dr. Jenny Blau for her services as the Principal Investigator of the study from January 2018-May 2020. On that note, we want to take the opportunity to introduce some new members on the team. Dr. Smita Jha completed her Endocrinology training at the Inter-Institute Endocrinology Training Program, National Institutes of Health, Bethesda, Maryland with prior experience in study of genetic diseases. She has served as the Principal Investigator of the study since October 2020. Ms. Lynn Bliss joined our team in early 2022 as a Research Nurse. She has been working alongside Mr. Craig Cochran, also a Research Nurse, to understand the medical needs of our patients and how these needs can be best addressed in the context of our research goals. Ms. Della Cox continues to serve as Patient Care Coordinator for our team. Ms. Anisha Ninan is a Nurse Practitioner who started working with our team in early 2022. Mr. James Welch continues to support the study as a genetic counselor. And as in the past, Drs. Lee Weinstein and Bill Simonds continue to provide input into this ongoing study and advise the team. In addition to this primary team, we collaborate with a multidisciplinary team of experts, such as gastroenterologists led by Dr. Stephen Wank, endocrine surgeons led by Dr. Naris Nilubol and oncologists led by Dr. Jaydira del Rivero.

  We continue to recruit patients for our Natural History Study. Natural History Studies allow scientists to follow a large population of patients over time. Participants can continue to receive standard of care treatment from their local doctors during the period of enrollment in the study. Knowledge gained from Natural History Studies informs the design of any interventional study that may be pursued to investigate a new diagnostic tool or therapy for the disease. The information generated over time from Natural History Studies allows scientists to:

  • recognize the natural disease course and its rate of progression
  • understand the cause of disease-related morbidity or mortality
  • identify disease outcome(s) or its surrogates
  • study any correlation of genetic change to clinical features, and
  • identify predictive biomarkers such as clinical, laboratory, or imaging features that can predict disease severity. 

  Individuals must have a personal or family history of a parathyroid-related disorder such as MEN1 and be willing to undergo genetic testing to participate in our study. For us to evaluate if you are eligible for the study, we request a complete packet of your medical reports including laboratory tests (blood and urine), reports and images (preferably as a CD) of prior imaging studies performed, operative and pathology reports, and genetic testing results, if performed. If deemed eligible for the study, the current average wait time for an appointment is 4-6 months. Participants may be seen as an outpatient or inpatient at the NIH Clinical Center in Bethesda, Maryland, for an evaluation. All reports including lab results, radiology results, physician notes, and more are available online through the NIH Patient Portal (https://clinicalcenter.nih.gov/followmyhealth) to provide patients with access to medical information regarding care received at the NIH Clinical Center. These reports can be shared by the patients with their local physicians. All testing and follow-up care at the NIH Clinical Center is free of charge. We strongly encourage all participants to have a local doctor who is familiar with their medical history and with whom we can work to optimize care. Patients are not required under the study to follow up but may choose to do all or some of their follow-ups at the NIH Clinical Center. Alternatively, patients may choose to send us their records and images performed at an outside hospital and see us for a televisit. Since blood and tissue samples are so critical in advancing our knowledge of the disease, patients should consider having their MEN1-related surgeries performed at the NIH Clinical Center. Alternatively, patients may request that their tumor tissue removed during surgery be released to the NIH Clinical Center for research. In each of these cases described above, it is important that patients fully comprehend the scope of our study and provide written informed consent in advance. For more information about the study, please contact our research nurse Lynn Bliss, R.N. at BoneMineralclinic@niddk.nih.gov. 

  We gratefully acknowledge the enthusiastic participation of the patients and their relatives, who make it possible for us to study Multiple Endocrine Neoplasia(s) and develop new diagnostic and treatment approaches. We are working towards initiating new studies of potential interest and value to the patient community. Stay tuned!

  References 

  1. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404-407.
  2. Mandl A, Welch JM, Kapoor G, Parekh VI, Schrump DS, Ripley RT, Walter MF, Del Rivero J, Jha S, Simonds WF, Jensen RT, Weinstein LS, Blau JE, Agarwal SK. Two distinct classes of thymic tumors in patients with MEN1 show LOH at the MEN1 locus. Endocr Relat Cancer. 2021;28(11):L15-L19.
  3. Lee ME, Ortega-Sustache YM, Agarwal SK, Tepede A, Welch J, Mandl A, Bansal R, Tirosh A, Piaggi P, Cochran C, Simonds WF, Weinstein LS, Blau JE. Patients With MEN1 Are at an Increased Risk for Venous Thromboembolism. J Clin Endocrinol Metab. 2021;106(2):e460-e468.
  4. Fahrmann JF, Wasylishen AR, Pieterman CRC, Irajizad E, Vykoukal J, Murage E, Wu R, Dennison JB, Krishna H, Peterson CB, Lozano G, Zhao H, Do KA, Halperin DM, Agarwal SK, Blau JE, Del Rivero J, Nilubol N, Walter MF, Welch JM, Weinstein LS, Vriens MR, van Leeuwaarde RS, van Treijen MJC, Valk GD, Perrier ND, Hanash SM. A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression. J Clin Endocrinol Metab. 2021;106(12):e4969-e4980.
  5. Chuki E, Graf A, Ninan A, Tora R, Abijo T, Bliss L, Nilubol N, Weinstein LS, Agarwal SK, Simonds WF, Jha S. Long-Term Outcomes of Parathyroid Autografts in Primary Hyperparathyroidism. Journal of the Endocrine Society. 2023;7(5).

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