Abstract
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.
We report a case of central diabetes insipidus induced by the anti–PD-L1 drug avelumab. The patient was successfully managed by holding the immune checkpoint inhibitor.
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.
Abstract
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.
We described the development of PHEO in 8 pediatric MEN2B patients and found that it may develop earlier than the screening-recommended age of 11; however, it is likely clinically nonsignificant.
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest ...localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30-40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes:
,
,
,
,
,
,
,
,
,
and
; the kinase group or cluster II includes
,
,
,
and
; and the Wnt signaling group or cluster III includes
and
. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
Abstract
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.
Background Sporadic, nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) are diagnosed with increasing frequency. We compared the risk of tumor growth, metastasis, and mortality between ...patients treated versus those treated expectantly. Method A retrospective study of patients seen at our institution with sporadic NF-PNETs, with ≥12 months of follow-up. Kaplan-Meier analysis was performed. Results Between 1999 and 2014, 35 patients with an incidentally discovered nonfunctional PNET were identified. Twenty underwent resection and 15 were followed with imaging. In the operative group, 8 had NF-PNETs < 2 cm, while 12 had NF-PNETs ≥ 2 cm. In the nonoperative expectant management by serial imaging group, 10 had NF-PNETs < 2 cm while 5 had NF-PNETs ≥ 2 cm. Small NF-PNETs (<2 cm) in either the operative or nonoperative groups demonstrated no evidence of progression or metastasis (median follow-up of 27.8 months). Morbidity in the operative group was 35% with pancreatic pseudocyst the most common. Conclusion Incidentally discovered NF-PNETs < 2 cm in size can be observed safely with serial imaging.
Abstract
Purpose
Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of ...disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression.
Experimental Design
Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls). Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl).
Results
A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice.
Conclusions
Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.
This serves as a white paper by the North American Neuroendocrine Tumor Society (NANETS) on the practical considerations when providing palliative care to patients with neuroendocrine tumors in the ...context of routine disease management or hospice care. The authors involved in the development of this manuscript represent a multidisciplinary team of patient advocacy, palliative care, and hospice care practitioners, endocrinologist, and oncologists who performed a literature review and provided expert opinion on a series of questions often asked by our patients and patient caregivers affected by this disease. We hope this document serves as a starting point for oncologists, palliative care teams, hospice medical teams, insurers, drug manufacturers, caregivers, and patients to have a frank, well-informed discussion of what a patient needs to maximize the quality of life during a routine, disease-directed care as well as at the end-of-life.
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.
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.
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.
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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