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Hyponatraemia is a common electrolyte abnormality seen in a wide range of oncological and haematological malignancies and confers poor performance status, prolonged hospital admission and reduced overall survival, in patients with cancer. Syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia in malignancy and is characterised by clinical euvolaemia, low plasma osmolality and concentrated urine, with normal renal, adrenal and thyroid function. Causes of SIAD include ectopic production of vasopressin (AVP) from an underlying tumour, cancer treatments, nausea and pain. Cortisol deficiency is an important differential in the assessment of hyponatraemia, as it has an identical biochemical pattern to SIAD and is easily treatable. This is particularly relevant with the increasing use of immune checkpoint inhibitors, which can cause hypophysitis and adrenalitis, leading to cortisol deficiency. Guidelines on the management of acute, symptomatic hyponatraemia recommend 100 mL bolus of 3% saline with careful monitoring of the serum sodium to prevent overcorrection. In cases of chronic hyponatraemia, fluid restriction is recommended as first-line treatment; however, this is frequently not feasible in patients with cancer and has been shown to have limited efficacy. Vasopressin-2 receptor antagonists (vaptans) may be preferable, as they effectively increase sodium levels in SIAD and do not require fluid restriction. Active management of hyponatraemia is increasingly recognised as an important component of oncological management; correction of hyponatraemia is associated with shorter hospital stay and prolonged survival. The awareness of the impact of hyponatraemia and the positive benefits of active restoration of normonatraemia remain challenging in oncology.
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Department of Medicine, University College Dublin, Dublin, Ireland
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Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA
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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors arising from the adrenal medulla and extra-adrenal ganglia, respectively. Approximately 15–25% of PCC/PGL can become metastatic. Up to 30–40% of patients with PCC/PGL have a germline pathogenic variant in a known susceptibility gene for PCC/PGL; therefore, all patients with PCC/PGL should undergo clinical genetic testing. Most of the susceptibility genes are associated with variable penetrance for PCC/PGL and are associated with different syndromes, which include susceptibility for other tumors and conditions. The objective of this review is to provide an overview of the germline susceptibility genes for PCC/PGL, the associated clinical syndromes, and recommended surveillance.
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Summary
Short synacthen tests (SST) are frequently used for assessing adrenocorticotropin hormone (ACTH) deficiency. In this study, we present the case of a 53-year-old man receiving immunotherapy for metastatic melanoma, who subsequently developed immune checkpoint inhibitor (ICI)-induced hypothyroidism and was investigated for the presence of ICI-induced hypocortisolaemia on different occasions. Despite two reassuring SSTs, he subsequently developed clinical and biochemical evidence of ACTH deficiency. The ACTH on local measurement was not conclusive in keeping with ICI-related ACTH deficiency but when repeated using an alternative assay confirmed the diagnosis. The case illustrates the evolution of ACTH deficiency and exposes the potential pitfalls of screening strategies. Two important lessons may be gleaned from this case: (i) SSTs can be normal in early cases of secondary adrenal insufficiency, for example, hypophysitis due to adrenal reserve and (ii) when there is mismatch between the clinical and biochemical presentation, the ACTH should be repeated using a different assay.
Learning points
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Short synacthen tests, useful for ruling out adrenalitis and primary adrenal failure, may be normal in early adrenocorticotrophic hormone deficiency and secondary adrenal failure due to residual adrenal reserve.
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If clinical suspicion of adrenal insufficiency persists despite an initial satisfactory SST, it is important to recognise the need for re-assessment of cortisol levels.
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Insulin tolerance test remains a useful tool in the investigation of secondary adrenal insufficiency.
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Levothyroxine replacement may accelerate the metabolism of cortisol in cases of concurrent hypothyroidism and hypoadrenalism, and therefore, glucocorticoid replacement must precede levothyroxine treatment, to avoid adrenal crisis.
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The prevalence of immunotherapy-related endocrinopathies is likely to increase with increasing use of ICI and it is crucial that clinicians are alert to their subtle symptoms.
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Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
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Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
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Department of Medicine, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota, USA
Prostate Cancer Foundation, Santa Monica, California, USA
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Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
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The androgen receptor (AR) signaling pathway regulates the progression of prostate cancer (PC). Metastatic castration-resistant prostate cancer (mCRPC) patients generally receive AR-targeted therapies (ART) or androgen-deprivation therapies (ADT) with the initial response; however, resistance is inevitably observed. Prior studies have shown activity and upregulation of a family of androgen production, uptake, and conversion – APUC genes – based on genomic analyses of patient germlines. Genetic variants of some APUC genes, such as the conversion gene, HSD3B1, predict response to second-generation androgen-targeted therapies. Studies have begun to elucidate the overall role of APUC genes, each with unique actionable enzymatic activity, in mCRPC patient outcomes. The current role and knowledge of the genetic and genomic features of APUC genes in advanced prostate cancer and beyond are discussed in this review. These studies inform of how interpreting behavior of APUC genes through genomic tools will impact the treatment of advanced prostate cancer.
Siteman Cancer Center, St Louis, Missouri, USA
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Siteman Cancer Center, St Louis, Missouri, USA
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Summary
Downregulation of tumor suppression genes by DNA hypermethylation has been proposed as a potential cause of neuroendocrine neoplasm (NEN) formation. In this report, we present a patient simultaneously diagnosed with acute myeloid leukemia (AML) and a metastatic nonfunctioning pancreatic NEN. Because of the two competing diagnoses, he was treated with lanreotide, venetoclax and a long course of the hypomethylating agent decitabine. The AML responded to venetoclax and decitabine treatment while the PanNEN stabilized on lanreotide. Over multiple months of treatment, the PanNEN showed gradual tumor response, consistent with decitabine treatment effect, and the patient remained without disease progression for both malignancies. We believe that some PanNENs can benefit from treatment with hypomethylating agents such as decitabine. To support this, we review the relevant literature and suggest a mechanism for the efficacy of decitabine in our case.
Learning points
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Neuroendocrine neoplasms are associated with an increased risk of second primary cancers.
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Epigenetic changes such as hypermethylation and inhibition of tumor suppressor genes might explain the development and behavior of certain NENs.
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The use of hypomethylating agents such as decitabine might have a role in the treatment of PanNENs. Future studies are needed to confirm that.
South Australian Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia
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The current treatment paradigm for prolactinomas involves dopamine agonist (DA) therapy as the first-line treatment, with surgical resection reserved for cases where there is DA failure due to resistance or intolerance. This review highlights how DA therapy can be optimised to overcome its increasingly recognised pitfalls, whilst also addressing the potential for expanding the use of surgery in the management of prolactinomas. The first part of the review discusses the limitations of DA therapy, namely: DA resistance; common DA side effects; and the rare but serious DA-induced risks of cardiac valvulopathy, impulse control disorders, psychosis, CSF rhinorrhoea and tumour fibrosis. The second part of the review explores the role of surgery in prolactinoma management with reference to its current second-line position and recent calls for surgery to be considered as an alternative first-line treatment alongside DA therapy. Randomised trials comparing medical vs surgical therapy for prolactinomas are currently underway. Pending these results, a low surgical threshold approach is herein proposed, whereby DA therapy remains the default treatment for prolactinomas unless there are specific triggers to consider surgery, including concern regarding DA side effects or risks in vulnerable patients, persistent and bothersome DA side effects, emergence of any serious risks of DA therapy, expected need for long-term DA therapy, as well as the traditional indications for surgery. This approach should optimise the use of DA therapy for those who will most benefit from it, whilst instituting surgery early in others in order to minimise the cumulative burden of prolonged DA therapy.
St Vincent’s Hospital Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
Garvan Institute of Medical Research, Sydney, Australia
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St Vincent’s Hospital Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
Garvan Institute of Medical Research, Sydney, Australia
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Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
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Faculty of Medicine, Notre Dame University, Sydney, Australia
Institute of Academic Surgery, Royal Prince Alfred Hospital, Sydney, Australia
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St Vincent’s Hospital Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, Australia
Faculty of Medicine, Notre Dame University, Sydney, Australia
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Department of Otolaryngology Head and Neck Surgery, University of Alabama Birmingham, Birmingham, Alabama, USA
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Garvan Institute of Medical Research, Sydney, Australia
Department of Endocrinology, St Vincent’s Hospital, Sydney, Australia
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Objective
Transsphenoidal surgery (TSS) is the first-line treatment for Cushing’s disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing’s disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission.
Methods
Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing’s disease at a tertiary centre (1990–2019). Remission was defined as MSeC <138 nmol/L by 6 weeks postoperatively. Recurrence was defined as elevated 24-h urine free cortisol, lack of suppression after dexamethasone or elevated midnight salivary cortisol.
Results
In this study, 42 patients (age 47 ± 13 years, 83% female) were assessed with 55 ± 56 months of follow-up. Remission occurred after 77% of primary (n = 30) and 42% of revision operations (n = 12). After primary surgery, remission was associated with lower MSeC nadir (26 ± 36 nmol/L vs 347 ± 220 nmol/L, P < 0.01) and lower adrenocorticotropin nadir (2 ± 3 pmol/L vs 6 ± 3 pmol/L, P = 0.01). Sustained remission 5 years after surgery was predicted by MSeC <92 nmol/L within 2 weeks postoperatively (sensitivity 100% and specificity 100%). After revision surgery, remission was predicted by lower MSeC nadir (70 ± 45 nmol/L vs 408 ± 305 nmol/L, P = 0.03), smaller tumour diameter (3 ± 2 mm vs 15 ± 13 mm, P = 0.05) and absence of cavernous sinus invasion (0% vs 71%, P = 0.03). Recurrence after primary and revision surgery occurred in 17% and 20% of patients respectively.
Conclusions
Lower postoperative MSeC nadir strongly predicted remission after both primary and revision surgery. Following primary surgery, an MSeC <92 nmol/L within 2 weeks predicted sustained remission at 5 years. MSeC nadir was the most important prognostic marker following TSS for Cushing’s disease.
Search for other papers by Sara Coelho in
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Research Center, Portuguese Oncology Institute of Porto, EPE, Porto, Portugal
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School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal
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Objectives
Therapeutic options for pancreatic neuroendocrine neoplasia (Pan-NEN) have increased over the last decade. We aim to understand the evolution of the prognosis of patients with diagnosis of Pan-NEN within a 12-year period, considering the implementation of new treatments.
Methods
This study is a retrospective cohort study of patients diagnosed with Pan-NENs between 2006 and 2017. Survival outcome estimates were calculated by Kaplan–Meier method. The impact of baseline clinicopathological characteristics on survival was explored with the use of Cox proportional hazard model.
Results
Of the 97 patients, 77 (79.9%) had well-differentiated neuroendocrine tumor (NET) according to WHO 2010 classification, and 52 (53.6%) had localized or locoregional disease. There were no differences between clinicopathological characteristics and survival outcomes when comparing patients diagnosed between 2006–2011 and 2012–2017. Neuroendocrine carcinoma – HR 2.76, 95% CI 1.17–6.55 – and stages III and IV at diagnosis were independent poor prognostic factors – HR 6.02, 95% CI 2.22–16.33 and HR 6.93, 95% CI 2.94–16.32, respectively.
Conclusions
The new therapeutic approaches did not induce better survival outcomes on Pan-NEN in recent years. This is possibly due to the indolent nature of NET grades 1 and 2, even metastatic, allowing patients to be submitted to new target therapies along their disease course.
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Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy
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Adrenocorticotropic hormone (ACTH)-secreting pituitary tumors mainly express somatostatin receptor 5 (SSTR5) since SSTR2 is downregulated by the elevated levels of glucocorticoids that characterize patients with Cushing’s disease (CD). SSTR5 is the molecular target of pasireotide, the only approved pituitary tumor-targeted drug for the treatment of CD. However, the molecular mechanisms that regulate SSTR5 are still poorly investigated. This review summarizes the experimental evidence supporting the role of the cytoskeleton actin-binding protein filamin A (FLNA) in the regulation of SSTR5 expression and signal transduction in corticotroph tumors. Moreover, the correlations between the presence of somatic USP8 mutations and the expression of SSTR5 will be reviewed. An involvement of glucocorticoid-mediated β-arrestins modulation in regulating SSTRs expression and function in ACTH-secreting tumors will also be discussed.
