Publications by authors named "Jaydira Del Rivero"

43 Publications

A blood-based polyamine signature associated with MEN1 duodenopancreatic neuroendocrine tumor progression.

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center. Houston, TX, USA.

Purpose: Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with Multiple Endocrine Neoplasia Type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor promoting roles in several cancer types. We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.

Experimental Design: Through an international collaboration between MD Anderson Cancer Center (MDACC), the National Institutes of Health (NIH), and the University Medical Center Utrecht (UMCU), plasma polyamine levels were assessed using mass spectrometry in a total of 84 patients with MEN1 (20 with distant metastatic dpNETs (cases) and 64 with either indolent dpNETs or no dpNETs (controls)). A mouse model of MEN1-pNET, Men1  fl/flPdx1-Cre  Tg, was used to test time-dependent changes in plasma polyamines associated with disease progression.

Results: A 3-marker plasma polyamine signature (3MP: n-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the three participating centers. The fixed 3MP yielded an AUC of 0.84 (95% CI: 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing cases from controls in an independent test set from MDACC. In Men1  fl/flPdx1-Cre  Tg mice, the 3MP was elevated early and remained high during disease progression.

Conclusions: Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.
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http://dx.doi.org/10.1210/clinem/dgab554DOI Listing
July 2021

Reply.

Ophthalmology 2021 Jun 18. Epub 2021 Jun 18.

National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1016/j.ophtha.2021.05.015DOI Listing
June 2021

The Immunotherapy Landscape in Adrenocortical Cancer.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.
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http://dx.doi.org/10.3390/cancers13112660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199088PMC
May 2021

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

Pancreas 2021 Apr;50(4):469-493

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001792DOI Listing
April 2021

Ataxia telangiectasia mutated germline pathogenic variant in adrenocortical carcinoma.

Cancer Genet 2021 Aug 24;256-257:21-25. Epub 2021 Mar 24.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States; Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, United States. Electronic address:

Background: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Here, we report the first case of ACC in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene.

Patients And Methods: A 56-year-old Caucasian woman with biopsy proven ACC deemed unresectable and treated with etoposide, doxorubicin and cisplatin (EDP), and mitotane presented to our institution for evaluation. The tumor specimen was examined pathologically, and genetic analyses were performed on the tumor and germline using next-generation sequencing.

Results: Pathologic evaluation revealed an 18.0 × 14.0 × 9.0 cm low-grade ACC with tumor free resection margins. Immunohistochemistry stained for inhibin, melan-A, and chromogranin. ClinOmics analysis revealed a germline pathogenic deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. Genomic analysis of the tumor showed loss of heterozygosity (LOH) of chromosome 11 on which the ATM resides.

Conclusion: ACC is an aggressive malignancy for which surgical resection currently offers the only curative option. Here we report a heterozygous loss-of-function mutation in germline DNA and LOH of ATM in tumor in an ACC patient, a classic two-hit scenario in a well-known cancer suppresser gene, suggesting a pathogenic role of the ATM gene in certain ACC cases.
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http://dx.doi.org/10.1016/j.cancergen.2021.03.003DOI Listing
August 2021

Long-term outcomes in patients with advanced adrenocortical carcinoma after image-guided locoregional ablation or embolization.

Cancer Med 2021 04 9;10(7):2259-2267. Epub 2021 Mar 9.

Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institute of Biomedical Imaging and Bioengineering and National Cancer Institute Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA.

Background: To evaluate outcomes and survival rates in patients with metastatic adrenocortical carcinoma (ACC) who were treated with image-guided locoregional treatments (IGLTs).

Purpose: To evaluate the overall survival (OS) and clinical impact of IGLT in the management of patients with advanced metastatic ACC.

Methods: Retrospective review of 39 patients treated with IGLT between 1999 and 2018 was performed. Short- and long-term efficacy of treatments were defined based upon imaging and clinical data. Subgroup survival analysis was performed on patients with metastatic disease at diagnosis (N = 17) and compared with the same stage group from the most recent National Cancer Database (NCDB) report. Statistical analysis was performed using Cox proportional hazards model.

Results: Treatments were performed at different anatomic sites including liver (N = 46), lung (N = 14), retroperitoneum (N = 5), bone (N = 4), subcutaneous (N = 2), and intracaval (N = 1). Radiofrequency, microwave, cryoablation, or a combination of two modalities (45, 18, 3, 3, respectively) were used in 69 ablation sessions. Intra-arterial procedures were performed in 12 patients in 18 treatment cycles (range 1-3 per patient). As of a 2019 analysis, 11 patients were alive with a mean follow-up of 169 months (range 63-292 months) from diagnosis. Two- and 5-year OS rates for all patients were 84.5% and 51%, respectively, and 76.5% and 59% for patients with metastatic disease at diagnosis (N = 17). This compares favorably with an NCDB report of 35% 5-year survival rate for patients with metastatic disease. Female gender and longer time from diagnosis to first IGLT were found to be predictors of prolonged survival with hazard ratios of 0.23 (p < 0.001) and 0.66 (p = 0.001), respectively.

Conclusion: IGLT may be associated with prolonged life expectancy in select patients with metastatic ACC.
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http://dx.doi.org/10.1002/cam4.3740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982621PMC
April 2021

High-Specific-Activity-I-MIBG versus Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Clin Cancer Res 2021 Jun 8;27(11):2989-2995. Epub 2021 Mar 8.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.

Targeted radionuclide therapies (TRT) using I-metaiodobenzylguanidine (I-MIBG) and peptide receptor radionuclide therapy (Lu or Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-I-MIBG therapy was approved by the FDA and both Lu-DOTATATE and I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172462PMC
June 2021

Case report of adrenocortical carcinoma associated with double germline mutations in MSH2 and RET.

Am J Med Genet A 2021 04 21;185(4):1282-1287. Epub 2021 Feb 21.

Developmental Therapeutics Branch, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.
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http://dx.doi.org/10.1002/ajmg.a.62099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986073PMC
April 2021

Case Report: Primary Hypothyroidism Associated With Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma.

Front Endocrinol (Lausanne) 2020 21;11:587065. Epub 2021 Jan 21.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Background: Lutetium 177 (Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on Lu-DOTATATE-induced thyroid dysfunction is limited.

Case Description: A 29-year-old male with  positive metastatic paraganglioma enrolled under the Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved.

Summary: We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of Lu-DOTATATE in the thyroid gland.

Conclusions: Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.
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http://dx.doi.org/10.3389/fendo.2020.587065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859638PMC
May 2021

Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland.

Lancet Oncol 2020 11;21(11):e528-e537

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.
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http://dx.doi.org/10.1016/S1470-2045(20)30332-6DOI Listing
November 2020

In Reply.

Oncologist 2021 01 23;26(1):e192-e193. Epub 2020 Nov 23.

Developmental Therapeutics Branch, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1002/onco.13589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794181PMC
January 2021

Metastatic and recurrent adrenocortical cancer is not defined by its genomic landscape.

BMC Med Genomics 2020 11 4;13(1):165. Epub 2020 Nov 4.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.

Background: Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.

Methods: We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.

Results: Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.

Conclusions: We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
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http://dx.doi.org/10.1186/s12920-020-00809-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640690PMC
November 2020

Emerging Treatments for Advanced/Metastatic Pheochromocytoma and Paraganglioma.

Curr Treat Options Oncol 2020 08 29;21(11):85. Epub 2020 Aug 29.

Developmental Therapeutics Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Opinion Statement: The incidence of metastatic pheochromocytoma (PHEO) and paraganglioma (PGL) may occur in as many as 35% of patients particularly with PGL and even more frequently in those with specific mutations. Biochemical, morphological, and molecular markers have been investigated for use in the distinction of benign from malignant PHEO/PGL. PHEO/PGL metastasizes via hematogenous or lymphatic routes and shows differences based on mutational status. The most common sites of involvement in patients that have an SDHB mutation are the bone (78%), lungs (45%), lymph nodes (36%), and liver (35%). In patients with sporadic PHEO/PGL, the most common sites of metastasis are the bones (64%), lungs (47%), lymph nodes (36%), and liver (32%). Metastases may be present at presentation or may occur later. Metastases to the liver and lungs are associated with a shorter survival. Overall, the estimated 5-year survival rates are between 34 and 74%. Currently, treatments for metastatic PHEO/PGL are essentially palliative. Surgery is potentially curative; however, tumor dissemination limits the chance for a curative resection. When surgical intervention is not amenable, the therapeutic options include radiolabeled MIBG (Azedra®-iobenguane 131 was recently FDA-approved for patients > 12 years and older with iobenguane scan positive) or systemic chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) with an overall objective response rate (ORR) of less than 40%; however, it is not clear if the administration of CVD impacts overall survival, as nearly all patients develop progressive and ultimately fatal disease. Other treatment modalities under investigation include cytoreductive techniques, novel radiopharmaceuticals, chemotherapy, radiotherapy, immunotherapy, and experimental therapies. Here we are discussing emerging treatment for advanced/metastatic PHEO/PGL.
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http://dx.doi.org/10.1007/s11864-020-00787-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456409PMC
August 2020

A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer.

Front Endocrinol (Lausanne) 2020 7;11:490. Epub 2020 Aug 7.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States.

Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.
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http://dx.doi.org/10.3389/fendo.2020.00490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427000PMC
June 2021

Incidental 68Ga-DOTATATE uptake in the pancreatic head: A case report and a unique opportunity to improve clinical care.

Medicine (Baltimore) 2020 May;99(22):e20197

Radiology and Imaging Sciences, Clinical Center.

Rationale: Neuroendocrine tumors (NETs) are neoplasms that can arise from the neuroendocrine cells distributed widely throughout the body. Majority of NETs overexpress somatostatin receptors (SSTR) on their cell surface. This biologic characteristic is exploited by SSTR-based imaging such as In octreotide scintigraphy and Ga DOTATATE positron emission tomography (PET)/computed tomography (CT), which are considered standard for initial evaluation of NETs. Although highly sensitive and specific, recent reports demonstrate a concerning incidence of "false-positive" physiologic uptake of these tracers in the pancreatic head - a common site of neuroendocrine tumor (NET) involvement. We present false positive uptake on Ga DOTATATE PET/CT along with false positive CT findings. Role of other imaging modalities is discussed.

Patient Concerns: A 78-year-old woman presented with a year-long history of diarrhea.

Diagnosis: Serum vasoactive intestinal peptide (VIP) levels were slightly elevated at 134.2 pg/mL (normal <75 pg/mL). CT showed a mildly enhancing 2.5 cm × 1.8 cm × 2.8 cm area in the pancreatic uncinate process which corresponded to focal uptake with Ga DOTATATE PET/CT. A presumptive diagnosis of pancreatic NET (vipoma) was made, and the patient was scheduled to undergo Whipple's surgery.

Interventions: She sought a second opinion and a subsequent magnetic resonance imaging (MRI) showed no lesion and the patient's surgery was deferred. Thereafter, her VIP levels spontaneously normalized. Endoscopic ultrasound (EUS) with fine needle aspiration cytology of the uncinate process showed normal pancreatic acini with no evidence of NET.

Outcomes: Patient is currently pursuing workup for alternative etiologies for chronic diarrhea.

Lessons: Conspicuous physiological uptake has been reported in the pancreatic head on 16% to 70% of Ga DOTATATE or Ga DOTANOC PET/CT scans, and 26% of the In octreotide scintigraphy scans. Image-based quantitative attempts to distinguish physiologic from pathologic uptake using SUVmax have rendered mixed results. When evaluating SSTR-based imaging uptake in the pancreatic head, patients can benefit from a higher index of suspicion of false positive uptake. Such cases require additional confirmation by MRI or EUS. Interestingly, the patient described also had mild contrast enhancement on CT, but without an MRI correlate. Because of potential morbidity and mortality related to false positive uptake, a systematic review with evidence-based recommendations for imaging may benefit patient care.
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http://dx.doi.org/10.1097/MD.0000000000020197DOI Listing
May 2020

Pulmonary Function in Patients With Multiple Endocrine Neoplasia 2B.

J Clin Endocrinol Metab 2020 09;105(9)

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Context: Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B.

Objective: This study characterized the pulmonary function of patients with MEN2B.

Design: This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health.

Results: Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of -2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035).

Conclusions: This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort.
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http://dx.doi.org/10.1210/clinem/dgaa296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365699PMC
September 2020

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

J Mol Endocrinol 2020 08;65(2):R1-R17

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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.
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http://dx.doi.org/10.1530/JME-20-0020DOI Listing
August 2020

Update on the Treatment of Medullary Thyroid Carcinoma in Patients with Multiple Endocrine Neoplasia Type 2.

Horm Metab Res 2020 Aug 16;52(8):588-597. Epub 2020 Apr 16.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine cancer that accounts for 1-2% of thyroid cancers in the United States (U.S.). While most cases are sporadic, 25% of MTC cases are hereditary. These hereditary cases occur in the setting of Multiple Endocrine Neoplasia Type 2A (MEN2A) or 2B (MEN2B) driven by mutations in the proto-oncogene. This article discusses hereditary MTC in the setting of MEN2 and the treatment options available for it. The first line treatment for this disease is typically a total thyroidectomy and tyrosine kinase inhibitors. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, have been approved for treatment of advanced MTC, but options beyond those are limited. However, several promising treatments are being studied, which are discussed in this review.
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http://dx.doi.org/10.1055/a-1145-8479DOI Listing
August 2020

Endocrine-Related Adverse Events Related to Immune Checkpoint Inhibitors: Proposed Algorithms for Management.

Oncologist 2020 04 10;25(4):290-300. Epub 2019 Oct 10.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Immune checkpoint inhibitors have proven to be effective for various advanced neoplasia. Immune-related adverse events (irAEs) as a result of increased T cell activation are unique and potentially life-threating toxicities associated with the use of immune checkpoint inhibitors. Multiple endocrine irAEs, including primary hyperthyroidism and hypothyroidism, thyroiditis, primary adrenal insufficiency, type 1 diabetes mellitus, and hypophysitis, have been reported with the use of various immune checkpoint inhibitors. In some cases, these irAEs can lead to discontinuation of treatment. Here we propose for the general oncologist algorithms for managing endocrine irAEs to aid in the clinical care of patients receiving immunotherapy. KEY POINTS: There is a relative high risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors, particularly when combination therapy is implemented. Patients treated with anti-CTLA-4 antibodies have an increased risk of hypophysitis, whereas patients treated with anti-PD-1/PD-L1 antibodies have a higher risk of primary thyroid dysfunction. Rarely, patients develop T1DM and central diabetes insipidus, and hypoparathyroidism is a rare occurrence. A growing clinical understanding of endocrine irAEs has led to effective treatment strategies with hormone replacement.
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http://dx.doi.org/10.1634/theoncologist.2018-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160393PMC
April 2020

Adrenocortical carcinoma masquerading as pheochromocytoma: a histopathologic dilemma.

Endocrinol Diabetes Metab Case Rep 2020 Jan 8;2020. Epub 2020 Jan 8.

Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center.

Summary: Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor's pathology and analysis of the patient's genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment.

Learning Points: Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC. Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis. A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor's pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.
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http://dx.doi.org/10.1530/EDM-19-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993251PMC
January 2020

Neuroendocrine Tumors-Less Well Known, Often Misunderstood, and Rapidly Growing in Incidence.

JAMA Oncol 2020 Jan;6(1):21-22

Medical Oncology and Clinical Endocrinology, Center for Cancer Research Rare Tumor Clinic, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamaoncol.2019.4568DOI Listing
January 2020

Clinical presentation and management of primary ovarian neuroendocrine tumor in multiple endocrine neoplasia type 1.

Endocrinol Diabetes Metab Case Rep 2019 Aug 20;2019. Epub 2019 Aug 20.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

Summary: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5-15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).

Learning Points: Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET. Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins. Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence. Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.
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http://dx.doi.org/10.1530/EDM-19-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709536PMC
August 2019

A Phase I Dose-Escalation Trial of BN-CV301, a Recombinant Poxviral Vaccine Targeting MUC1 and CEA with Costimulatory Molecules.

Clin Cancer Res 2019 Aug 20;25(16):4933-4944. Epub 2019 May 20.

Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: BN-CV301 is a poxviral-based vaccine comprised of recombinant (rec.) modified vaccinia Ankara (MVA-BN-CV301; prime) and rec. fowlpox (FPV-CV301; boost). Like its predecessor PANVAC, BN-CV301 contains transgenes encoding tumor-associated antigens MUC1 and CEA as well as costimulatory molecules (B7.1, ICAM-1, and LFA-3). PANVAC was reengineered to make it safer and more antigenic.

Patients And Methods: This open-label, 3+3 design, dose-escalation trial evaluated three dose levels (DL) of MVA-BN-CV301: one, two, or four subcutaneous injections of 4 × 10 infectious units (Inf.U)/0.5 mL on weeks 0 and 4. All patients received FPV-CV301 subcutaneously at 1 × 10 Inf.U/0.5 mL every 2 weeks for 4 doses, then every 4 weeks. Clinical and immune responses were evaluated.

Results: There were no dose-limiting toxicities. Twelve patients enrolled on trial [dose level (DL) 1 = 3, DL2 = 3, DL3 = 6). Most side effects were seen with the prime doses and lessened with subsequent boosters. All treatment-related adverse events were temporary, self-limiting, grade 1/2, and included injection-site reactions and flu-like symptoms. Antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most patients. Single-agent BN-CV301 produced a confirmed partial response (PR) in 1 patient and prolonged stable disease (SD) in multiple patients, most notably in -mutant gastrointestinal tumors. Furthermore, 2 patients with -mutant colorectal cancer had prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301.

Conclusions: The BN-CV301 vaccine can be safely administered to patients with advanced cancer. Further studies of the vaccine in combination with other agents are planned..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697621PMC
August 2019

Case Report of an Adrenocortical Carcinoma Associated With Germline Mutation.

J Endocr Soc 2019 Jan 12;3(1):284-290. Epub 2018 Dec 12.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, Maryland.

Adrenocortical carcinoma (ACC) is an aggressive form of cancer that originates in the cortex of the adrenal gland; the incidence of ACC is 1.5 to 2 cases per million people per year. ACCs are rare and mostly sporadic. A small proportion of ACC cases are associated with hereditary cancer syndromes. Here, we present a case of ACC with a pathogenic heterozygous germline deletion in (c.1100delC). This is, to our knowledge, the first report of a patient with ACC associated with a germline deletion.
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http://dx.doi.org/10.1210/js.2018-00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320243PMC
January 2019

Phase I/II Trial of Vandetanib and Bortezomib in Adults with Locally Advanced or Metastatic Medullary Thyroid Cancer.

Oncologist 2019 01 8;24(1):16-e14. Epub 2018 Oct 8.

Medstar Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.

Lessons Learned: Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m intravenously on days 1, 4, 8, and 11 could be administered safely.Assessing outcomes in 17 patients with medullary thyroid cancer, investigators considered the combination to be more difficult to administer than single-agent vandetanib and that achieving better outcomes was unlikely. Consequently, a planned phase II study was terminated early.

Background: The proto-oncogene RET (arranged during ransfection) has a critical role in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib (V), a multitargeted tyrosine kinase inhibitor approved for the treatment of MTC, is thought to inhibit RET in MTC. Supported by preclinical studies demonstrating that bortezomib (B) administration lowered RET mRNA and protein levels, we conducted a phase I study in advanced solid tumors of vandetanib in combination with bortezomib. The goal was to establish an RP2D (recommended phase II dose) for the combination of vandetanib plus bortezomib, a regimen envisioned as a dual strategy for targeting RET in MTC.

Methods: Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle Intrapatient dose escalation was allowed.

Results: Twenty-two patients were enrolled and received escalating mg/m bortezomib and mg vandetanib (number of patients) at initial doses of 1 and 100 (3), 1.3 and 100 (6), 1.3 and 200 (6), and 1.3 and 300 (7), respectively. Patients received a median of four cycles of bortezomib/vandetanib (range: 1-10), with 13 patients escalating to 1.3/200 and 10 to 1.3/300. G3 toxicities occurring in more than one patient included hypertension (24%), fatigue (19%), thrombocytopenia (10%), diarrhea (10%), and arthralgia (10%). There were no drug-related G4/5 toxicities. There was one dose-limiting toxicity, G3 thrombocytopenia, at bortezomib/vandetanib doses of 1.3/200 in cycle 2 that resolved without intervention. Four patients with a diagnosis of MTC (27%) had a partial response (PR).

Conclusion: The MTD of the combination was established as bortezomib, 1.3 mg/m IV days 1, 4, 8, and 11 with vandetanib 300 mg p.o. daily. RECIST responses were observed in patients with a diagnosis of MTC.
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http://dx.doi.org/10.1634/theoncologist.2018-0452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324636PMC
January 2019

Pheochromocytoma in Children and Adolescents With Multiple Endocrine Neoplasia Type 2B.

J Clin Endocrinol Metab 2019 01;104(1):7-12

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland.

Context: Multiple endocrine neoplasia type 2B (MEN2B) is characterized by early-onset medullary thyroid cancer in virtually all cases and a 50% lifetime risk of pheochromocytoma (PHEO) development. The literature on PHEO in patients with MEN2B is limited with most data being reported from adult studies that primarily address MEN2A.

Objective: The aim of the current study is to describe PHEO development in a cohort of pediatric patients with MEN2B.

Design: Retrospective chart review of patients with MEN2B evaluated at the National Institutes of Health in the period between July 2007 and February 2018.

Results: A total of 38 patients were identified (21 males and 17 females). Mean age at MEN2B diagnosis was 10.6 ± 3.9 years. Eight patients (21%) developed PHEO in the course of follow-up to date, all of whom were sporadic cases with the classic M918T RET mutation. PHEO was diagnosed based on biochemical and/or imaging screening studies in five patients, whereas three patients presented with symptoms of excess catecholamines. PHEO was diagnosed at a mean age 15.2 ± 4.6 (range, 10 to 25) years and 4.0 ± 3.3 years after MEN2B diagnosis. Only one patient was diagnosed with PHEO as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea.

Conclusion: Undiagnosed PHEO can be associated with substantial morbidity. Current American Thyroid Association guidelines recommend PHEO screening starting at age 11 for the high-/highest risk group. The youngest patient diagnosed with PHEO in our cohort was an asymptomatic 10-year-old, suggesting that PHEO development may begin before the screening-recommended age of 11, though remains clinically undetectable and thus the current screening guidelines seem appropriate.
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http://dx.doi.org/10.1210/jc.2018-00705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240163PMC
January 2019

Anti-PD-L1 Treatment Induced Central Diabetes Insipidus.

J Clin Endocrinol Metab 2018 02;103(2):365-369

Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Context: Immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti-CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade.

Case Description: We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti-PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient's symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin.

Conclusion: To our knowledge, this is the first report of central DI associated with anti-PD-L1 immunotherapy. The patient's endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality.
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http://dx.doi.org/10.1210/jc.2017-01905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800826PMC
February 2018

PARP Inhibitors: The Cornerstone of DNA Repair-Targeted Therapies.

Oncology (Williston Park) 2017 04;31(4):265-73

The activity and therapeutic licensing of poly(ADP-ribose) polymerase (PARP) inhibitors is the culmination of 50 years of research. However, the biology, mechanisms of action, adequate treatment combinations, and targeted populations for these agents need to be explored further. PARP activity is essential for the repair of single-strand DNA breaks via the base excision repair pathway. This pathway is the default repair pathway in cells with deficient high-fidelity double-strand break homologous recombination (HR) repair, such as occurs with loss of BRCA1 or BRCA2 function. Therefore, inhibition of PARP function results in cell death in HR-deficient tumors, and sensitizes tumor cells to cytotoxic agents that induce DNA damage. Applications of PARP inhibition are now being expanded beyond tumors with HR deficiency-to HR-competent tumors in which HR has been synthetically impaired through use of other agents given in combination with PARP inhibitors, or resulting from PARP inhibition in the setting of BRCA1 or BRCA2 loss.
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April 2017
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