Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis.

PURPOSE: Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset. METHODS: We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH. RESULTS: Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1-3 or in cortisol before cycles 1-4. CONCLUSIONS: TSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

MEN4, the MEN1 Mimicker: A Case Series of three Phenotypically Heterogenous Patients With Unique CDKN1B Mutations.

CONTEXT: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. OBJECTIVE: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. DESIGN/METHODS: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. SETTING: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. OUTCOME: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry. RESULTS: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G > A, p.Trp60*; c.475G > A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). CONCLUSIONS: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4.

Emergency management of paediatric status epilepticus in Australia and New Zealand: practice patterns in the context of clinical practice guidelines.

AIMS: To establish current acute seizure management through a review of clinical practice guidelines (CPGs) and reported physician management in the 11 largest paediatric emergency departments in Australia (n= 9) and New Zealand (n= 2) within the Paediatric Research in Emergency Departments International Collaborative (PREDICT) network, and to compare this with Advanced Paediatric Life Support (APLS) guidelines and existing evidence. METHODS: (i) Review of CPGs for acute seizure management at PREDICT sites. (ii) A standardised anonymous survey of senior emergency doctors at PREDICT sites investigating management of status epilepticus (SE). RESULTS: Ten sites used seven different seizure CPGs. One site had no seizure CPG. First line management was with benzodiazepines (10 sites). Second line and subsequent management included phenytoin (10), phenobarbitone (10), thiopentone (9), paraldehyde (6) and midazolam infusion (5). Of 83 available consultants, 78 (94%) responded. First line management of SE without intravenous (IV) access included diazepam per rectum (PR) (49%), and midazolam intramuscular (41%) and via the buccal route (9%). First line management of SE with IV access included midazolam IV (50%) and diazepam IV (44%). The second line agent was phenytoin (88%); third line agents were phenobarbitone (33%), thiopentone and intubation (32%), paraldehyde PR (22%) and midazolam infusion (6%). Fourth line agents were thiopentone and intubation (60%), phenobarbitone (16%), midazolam infusion (13%) and paraldehyde (9%). CONCLUSIONS: Initial seizure management by CPG recommendations and reported physician practice was broadly similar across PREDICT sites and consistent with APLS guidelines. Practice was variable for second/third line SE management. Areas of controversy would benefit from multi-centred trials.

Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases.

Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

Emergency department management of gastro-enteritis in Australia and New Zealand.

OBJECTIVE: Comparison of clinical practice guideline (CPG) recommendations and reported physician management of gastro-enteritis at Paediatric Research in Emergency Departments International Collaborative (PREDICT) network sites as a baseline for further randomised controlled trials. METHODS: Two part survey comprising: (i) review of CPGs from PREDICT sites for gastro-enteritis; and (ii) survey of senior emergency department physicians regarding the management of gastro-enteritis. RESULTS: All 11 PREDICT sites participated. Nine CPGs were available with three sites using a common CPG. For moderate dehydration, eight CPGs advocated nasogastric (NG) rehydration in preference to intravenous (IV) rehydration. The IV route was reserved for severe dehydration or failed NG rehydration. In the second component of the survey, 78 of 83 (94%) physicians responded. In moderate dehydration, 82% of respondents used NG rehydration. In severe dehydration, 86% used IV fluids; 12% used NG and 3% an initial IV bolus followed by NG fluid. Serum electrolytes were measured universally with IV fluid use and by 22% using NG rehydration. The IV fluid bolus was with normal saline (86%). Fifty-four per cent used anti-emetics 'rarely' or 'sometimes'. The commonest agents were ondansetron (60%) and metoclopramide (29%). CONCLUSIONS: CPG recommendations and physician practice for the management of gastro-enteritis were similar across PREDICT sites with a focus on NG for moderate dehydration and IV for severe dehydration. A variety of fluids and administration rates were used. Anti-emetics were used infrequently. The efficacy and safety of newer anti-emetics should be explored in collaborative studies. Collaborative development of new CPGs should be considered to simplify fluid regimens.

Croup management in Australia and New Zealand: a PREDICT study of physician practice and clinical practice guidelines.

OBJECTIVE: Comparison of clinical practice guideline (CPG) recommendations and reported physician management of croup at PREDICT (Paediatric Research in Emergency Departments International Collaborative) sites as baseline for planned randomized controlled trials. METHODS: Review of CPGs for croup from PREDICT sites and survey of specialist pediatric emergency physicians regarding croup management. PREDICT sites included 8 tertiary pediatric hospitals and 3 large mixed emergency departments in Australia and New Zealand. RESULTS: Nine of the 11 sites had a CPG for croup. Response rate was 94% (78/83). Adrenaline was recommended for moderate croup (3%), severe croup (52%), and life-threatening croup by (100%). Steroid therapy was recommended for mild croup (45%), for moderate croup (97%), for severe croup (97%), and for life-threatening croup (96%). Steroid choice was oral dexamethasone (60%) and oral prednisolone (38%). In severe croup, 77% used intravenous/intramuscular dexamethasone, 10% used intravenous/intramuscular methylprednisolone, and 8% used nebulized budesonide. Commonest dosage regimens were 0.15 mg/kg dexamethasone or 1 mg/kg prednisolone. A standard volume dosage regimen for nebulized adrenaline was used by 54%, whereas 39% used a weight-based formula. Clinical practice guidelines recommended 5 mg (11%) or 10 mg (33%) for standard volume dosing, and all CPGs using weight-based dosing recommend 0.5 mg/kg with maximum doses ranging from 5 to 15 mg. CONCLUSIONS: Croup management at PREDICT emergency departments is similar, based on oral steroids and nebulized adrenaline. The steroid and adrenaline regimens used by respondents and their CPGs were not consistent. This reflects limitations of available evidence for management of this common disease, highlighting the need for definitive trials, particularly in the management of mild croup.

Bronchiolitis management in pediatric emergency departments in Australia and New Zealand: a PREDICT study.

OBJECTIVES: Bronchiolitis is the most frequent reason for admission in infants. We set out to compare clinical practice guideline (CPG) recommendations and physician management of bronchiolitis at Paediatric Research in Emergency Departments International Collaborative (PREDICT) sites in Australia and New Zealand as a baseline for prospective trials. METHODS: (i) Review of bronchiolitis CPGs from PREDICT sites. (ii) Survey of senior pediatric emergency physicians at PREDICT sites to determine management strategies in bronchiolitis. RESULTS: All 11 PREDICT sites participated. Ten sites used a specific bronchiolitis CPG. beta-agonists were not recommended unless the child was older or asthma was suspected. Eight sites did not and 2 sites only recommended corticosteroids for older infants in whom asthma was likely. For rehydration, 7 sites recommended intravenous (i.v.) fluids exclusively or in the acute phase, with 3 recommending nasogastric (n.g.) fluids in the recovery phase or for difficult vascular access. Two sites recommended n.g. fluids for moderate and i.v. fluids for severe bronchiolitis. Physician response rate was 78/83 (94%). No medications were used for mild (94%) or moderate (83%) bronchiolitis. Inhaled beta-agonists were used by 5% for moderate and 18% for severe bronchiolitis. Steroids were not used by any physicians for mild or moderate and was used by only 3% for severe bronchiolitis. The preferred mode of rehydration was i.v. in 45%, n.g. in 49%, and either one depending on disease severity in 6%. CONCLUSIONS: Management of bronchiolitis was similar across PREDICT sites. Practice is equally split between i.v. and n.g. rehydration. This reflects a lack of evidence which should be addressed through a multicenter comparative trial.

How useful is urinary-free cortisol in the clinic?

Measurement of 24-h urine-free cortisol is frequently employed as a first-line screening and disease-monitoring test in Cushing's syndrome (CS). The quest for 'cortisol specificity' has seen the emergence of mass spectrometry (MS) based assays, particularly liquid chromatography/tandem mass spectrometry. In contrast to traditional immunoassays, liquid chromatography/tandem mass spectrometry 'free cortisol' measurement is less susceptible to 'interference' from cortisol precursors and metabolites. However, detection of these conjugates is important in mild CS and therefore, missed by MS if cortisol alone is measured. MS assays nevertheless are capable of measuring broad steroid profiles, including the potential to distinguish benign from malignant adrenal-based CS and detection of exogenous glucocorticoids. Until this is routine practice, we recommend against abandoning immunoassays measurement of urine-free cortisol.

Evaluation of Blood Glucose Meter Efficacy in an Antenatal Diabetes Clinic.

BACKGROUND: The optimal treatment of diabetes in pregnancy requires accurate measurement of blood glucose levels, in order to minimize adverse outcomes for both mother and neonate. Self-monitoring of blood glucose is routinely used to measure glycemic control and to assess whether treatment targets are being met; however, the accuracy of blood glucose meters in pregnancy is unclear. MATERIALS AND METHODS: Pregnant women with gestational, type 1, or type 2 diabetes mellitus were eligible to participate. Nonfasting capillary blood glucose levels were measured in duplicate using the BGStar(®) (Sanofi, Sydney, Australia) and FreeStyle Lite(®) (Abbott, Sydney) blood glucose meters. Venous blood samples were collected and analyzed for plasma glucose, hematocrit, and glycated hemoglobin. Capillary blood glucose was compared with plasma glucose and further assessed according to International Organization for Standardization (ISO) 15197:2013 standards. RESULTS: One hundred ten women were recruited, providing 96 samples suitable for analysis. The mean ± SD laboratory plasma glucose level was 4.6 ± 1.4 mmol/L; the BGStar and FreeStyle Lite capillary blood glucose values were 5.3 ± 1.4 mmol/L and 5.0 ± 1.3 mmol/L, respectively. Both meters showed a positive bias (0.42 mmol/L for the FreeStyle Lite and 0.65 mmol/L for the BGStar). Furthermore, neither meter fulfilled the ISO 15197:2013 standards, and there was a nonsignificant improvement in meter performance at blood glucose levels of ≤4.2 mmol/L. Hematocrit did not affect the results of either blood glucose meter. Clarke Error Grid analysis demonstrated that approximately 70% of the results of both meters would lead to appropriate clinical action. CONCLUSIONS: The BGStar and FreeStyle Lite blood glucose meters did not meet ISO 15197:2013 recommendations for blood glucose monitoring systems when assessed in a population of women with diabetes in pregnancy. Clinicians should consider this difference in blood glucose readings when making diabetes-related treatment decisions.