Approach to the patient with suspected hypotonic polyuria.

Investigation and management of hypotonic polyura is a common challenge in clinical endocrinology. The three main causes, recently renamed to arginine vasopressin deficiency (AVP-D, formerly central diabetes insipidus), AVP-resistance (AVP-R, formerly nephrogenic diabetes insipidus), and primary polydipsia (PP) require accurate diagnosis as management differs for each. This new nomenclature more accurately reflects pathophysiology, and has now been adopted by the Systemised Nomenclature of Medicine (SNOMED). Advances in diagnosis over the last few years have centered around the use of copeptin measurement. Here, we use three patient case histories to highlight the use of this approach, and to demonstrate how it can succeed where other approaches, such as the water deprivation test, sometimes fail. We discuss the overall approach to each type of patient and the strengths and limitations of diagnostic strategies, illustrating the use of the new nomenclature.

Approach to the Patient: New Era Emerges for Craniopharyngioma Management.

Papillary craniopharyngioma (PCP) and adamantinomatous craniopharyngioma (ACP) are distinct, slow-growing tumors of the suprasellar region. Their location, composition, and biology have historically evaded successful surgical radiation and medical therapy. Meanwhile compromise of critical structures either by tumor or treatments increase morbidity, impacting patient and carer quality of life. There has been a paradigm shift in the management of PCP, stemming from the discovery of BRAFV600E mutation in its tumorigenesis. Such a treatment breakthrough may soon be the case for ACP, changing the landscape of craniopharyngioma management. We use a case of ACP partially responding to ERK inhibitor therapy to demonstrate chronicity of disease progression and discuss modern management strategies highlighting the importance of access to tumor agnostic clinical trials, and future directions.

Headache in Patients with Sellar Disease: Clinicomorphological Predictors of Headache and the Outcome of Endoscopic Transsphenoidal Surgery.

Objectives Sellar pathologies are frequently found on imaging performed to investigate headache. However, both headache and incidental sellar lesions are common. Hence, this study prospectively examined headache prevalence, phenotype, and severity in patients with sellar pathologies and the impact of transsphenoidal surgery on headache. Methods Patients undergoing transsphenoidal resection of sellar lesions were consecutively recruited. At baseline, participants were defined as having headache or not and headache phenotype was characterized using validated questionnaires. Headache severity was assessed at baseline and 6 months postoperatively using the Headache Impact Test-6 (HIT-6) and Migraine Disability Assessment Score (MIDAS). Tumor characteristics were defined using radiological, histological, and endocrine factors. Primary outcomes included baseline headache prevalence and severity and headache severity change at 6 months postoperatively. Correlation between headache and radiological, histological, and endocrine characteristics was also of interest. Results Sixty participants (62% female, 47.1 ± 18.6 years) were recruited. Sixty-three percent possessed baseline headache. HIT-6 scores were higher in patients with primary headache risk factors, including younger age (R 2 = -0.417, p = 0.010), smoking history (63.31 ± 7.93 vs 54.44 ± 9.21, p = 0.0060), and family headache history (68.13 ± 7.01 vs 54.94 ± 9.11, p = 0.0030). Headaches were more common in patients with dural invasion (55.70 ± 12.14 vs 47.18 ± 10.15, p = 0.027) and sphenoid sinus invasion (58.87 ± 8.97 vs 51.29 ± 10.97, p = 0.007). Postoperative severity scores improved more with higher baseline headache severity (HIT-6: R 2 = -0.682, p < 0.001, MIDAS: R 2 = -0.880, p < 0.0010) and dural invasion (MIDAS: -53.00 ± 18.68 vs 12.00 ± 17.54, p = 0.0030). Conclusion Headaches in sellar disease are likely primary disorders triggered or exacerbated by sellar pathology. These may respond to surgery, particularly in patients with severe headache and dural invasion.

Increased Prevalence of Germline Pathogenic CHEK2 Variants in Individuals With Pituitary Adenomas.

CONTEXT: CHEK2 is a cell cycle checkpoint regulator gene with a long-established role as a clinically relevant, moderate risk breast cancer predisposition gene, with greater risk ascribed to truncating variants than missense variants. OBJECTIVE: To assess the rate and pathogenicity of CHEK2 variants amongst individuals with pituitary adenomas (PAs). METHODS: We assessed 165 individuals with PAs for CHEK2 variants. The study population comprised a primary cohort of 29 individuals who underwent germline and tumor whole-exome sequencing, and a second, independent cohort of 136 individuals who had a targeted next-generation sequencing panel performed on both germline and tumor DNA (n = 52) or germline DNA alone (n = 84). RESULTS: We identified rare, coding, nonsynonymous germline CHEK2 variants amongst 3 of 29 (10.3%) patients in our primary cohort, and in 5 of 165 (3.0%) patients overall, with affected patients having a range of PA types (prolactinoma, thyrotropinoma, somatotropinoma, and nonfunctioning PA). No somatic variants were identified. Two variants were definitive null variants (c.1100delC, c.444 + 1G > A), classified as pathogenic. Two variants were missense variants (p.Asn186His, p.Thr476Met), classified as likely pathogenic. Even when considering the null variants only, the rate of CHEK2 variants was higher in our cohort compared to national control data (1.8% vs 0.5%; P = .049). CONCLUSION: This is the first study to suggest a role for the breast cancer predisposition gene, CHEK2, in pituitary tumorigenesis, with pathogenic/likely pathogenic variants found in 3% of patients with PAs. As PAs are relatively common and typically lack classic autosomal dominant family histories, risk alleles-such as these variants found in CHEK2-might be a significant contributor to PA risk in the general population.

Pituitary tumours without distinct lineage differentiation express stem cell marker SOX2.

CONTEXT: The recent WHO 2022 Classification of pituitary tumours identified a novel group of 'plurihormonal tumours without distinct lineage differentiation (WDLD)'. By definition, these express multiple combinations of lineage commitment transcription factors, in a monomorphous population of cells. OBJECTIVES: To determine the expression of stem cell markers (SOX2, Nestin, CD133) within tumours WDLD, immature PIT-1 lineage and acidophil stem cell tumours, compared with committed cell lineage tumours. METHODS: Retrospective evaluation of surgically resected pituitary tumours from St Vincent's Hospital, Sydney. Patients were selected to cover a range of tumour types, based on transcription factor and hormone immunohistochemistry. Clinical data was collected from patient files. Radiology reports were reviewed for size and invasion. Samples were analysed by immunohistochemistry and RT-qPCR for SF-1, PIT-1, T-PIT, SOX2, Nestin and CD133. Stem cell markers were compared between tumours WDLD and those with classically "mature" types. RESULTS: On immunohistochemistry, SOX2 was positive in a higher proportion of tumours WDLD compared with those meeting WHO lineage criteria, 7/10 v 10/42 (70 v 23.4%, p = 0.005). CD133 was positive in 2/10 tumours WDLD but 0/41 meeting lineage criteria, P = 0.003. On RT-qPCR, there was no significant difference in relative expression of stem cell markers (SOX2, CD133, Nestin) between tumours with and WDLD. CONCLUSIONS: Our study is the first to biologically characterise pituitary tumours WDLD. We demonstrate that these tumours exhibit a higher expression of the stem cell marker SOX2 compared with other lineage-differentiated tumours, suggesting possible involvement of stem cells in their development.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Assessing Referrals to a Trauma and Orthopaedic Department: Evaluation of a Traffic Light System for Virtual Fracture Clinic in the Emergency Department and Urgent Care.

Background The Trauma and Orthopaedic (T&O) on-call service receives referrals from the emergency department (ED), general practice (GP) and urgent treatment centres (UTCs) and requests for inpatient reviews. The virtual fracture clinic (VFC) pathway allows ED and UTC clinicians to assess, discharge and refer when necessary. For VFC, the on-call orthopaedic consultant reviews the cases the next working day and makes an appropriate plan. This pathway consists of a traffic light system, in which practitioners can either safely discharge with written advice (green), refer to the VFC (yellow) or refer to the on-call team (red). Method The aim of this study was to assess how the VFC pathway was being utilised. All referrals to the T&O on-call team over three weeks were evaluated retrospectively. The following referrals were excluded: fractured femur, head injury, trauma calls and back pain pathway. The following data were collected: patient details, diagnosis, referral source, reason for referral, plan, double booking with VFC and appropriateness. Results A total of 191 referrals were analysed. Most referrals are from the ED (51%) and UTC (23%). Of the referrals, 39% were deemed to be inappropriate. Of the inappropriate referrals, 35% should have been referred directly to the VFC rather than the on-call team. A significant minority (7%) of inappropriate referrals were referred to the on-call team and VFC. Conclusion Education and collaboration are required with the ED and UTC to ensure the proper use of the VFC pathway. Immediate radiograph reporting may also be beneficial.

The evolution in pituitary tumour classification: a clinical perspective.

Objective: Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective. Results: In 2004, pituitary tumours were classified as 'typical' or 'atypical', based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms 'typical' and 'atypical' were omitted, though the importance of proliferative markers Ki67 and mitotic count was acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well-differentiated tumours. Whilst 'high risk' tumour types have been identified, further work is still required to improve prognostication. Conclusions: Recent WHO classifications have marked significant progress in the diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.

Predictors of pituitary tumour behaviour: an analysis from long-term follow-up in 2 tertiary centres.

OBJECTIVES: To determine the clinical utility of assessment of tumour invasion, markers of proliferation, and the French clinicopathological classification in pituitary tumour prognostication. METHODS: This is a retrospective evaluation of adult patients undergoing pituitary surgery at Oxford University and St Vincent's Hospitals, between 1989 and 2016, with at least 12 months of clinical data. Invasion was assessed radiologically, proliferative markers (Ki67, mitotic count, p53) by immunohistochemistry. Tumours were graded according to the clinicopathological classification. Intra- and interlaboratory variability of histopathology reporting was evaluated. OUTCOMES: (1) Tumour recurrence (radiological or reintervention ≥12 months postoperatively) and/or (2) "aggressive behaviour" (≥4 interventions and/or invasive tumour with recurrence/reintervention between 12 and 24 months postoperatively). RESULTS: A total of 386 patients were included, age at surgery was 56 (interquartile range [IQR] 41-67) years, 54% were male, and median follow-up was 90 months (range 44-126). Tumours were predominantly clinically nonfunctioning (252, 65%), with overall 53% invasive, and 10% that demonstrated ≥2 proliferative marker positivity. Recurrence was predicted by invasiveness (hazards ratio [HR] 1.6 [1.10-2.37], P .02), elevated mitotic count (HR 2.17 [1.21-3.89], P .01), grade (2b vs 1a HR 2.32 [1.06-5.03], P .03), and absence of gross total resection (HR 3.70 [1.72-8.00], P .01). Clinically defined aggressiveness was associated with elevated Ki67, mitotic count, and invasiveness. Ki67 reporting methodologies showed moderate correlation across laboratories (Phi 0.620), whereas p53 reporting reproducibility was poor (Phi 0.146). CONCLUSIONS: Proliferative markers, including Ki67 and mitotic count, but not p53, are important in predicting the development of aggressive pituitary tumour behaviour.

Altered Storage and Function of von Willebrand Factor in Human Cardiac Microvascular Endothelial Cells Isolated from Recipient Transplant Hearts.

The assembly of von Willebrand factor (VWF) into ordered helical tubules within endothelial Weibel-Palade bodies (WPBs) is required for the efficient deployment of the protein at sites of vascular injury. VWF trafficking and storage are sensitive to cellular and environmental stresses that are associated with heart disease and heart failure. Altered storage of VWF manifests as a change in WPB morphology from a rod shape to a rounded shape and is associated with impaired VWF deployment during secretion. In this study, we examined the morphology, ultrastructure, molecular composition and kinetics of exocytosis of WPBs in cardiac microvascular endothelial cells isolated from explanted hearts of patients with a common form of heart failure, dilated cardiomyopathy (DCM; HCMECD), or from nominally healthy donors (controls; HCMECC). Using fluorescence microscopy, WPBs in HCMECC (n = 3 donors) showed the typical rod-shaped morphology containing VWF, P-selectin and tPA. In contrast, WPBs in primary cultures of HCMECD (n = 6 donors) were predominantly rounded in shape and lacked tissue plasminogen activator (t-PA). Ultrastructural analysis of HCMECD revealed a disordered arrangement of VWF tubules in nascent WPBs emerging from the trans-Golgi network. HCMECD WPBs still recruited Rab27A, Rab3B, Myosin-Rab Interacting Protein (MyRIP) and Synaptotagmin-like protein 4a (Slp4-a) and underwent regulated exocytosis with kinetics similar to that seen in HCMECc. However, secreted extracellular VWF strings from HCMECD were significantly shorter than for endothelial cells with rod-shaped WPBs, although VWF platelet binding was similar. Our observations suggest that VWF trafficking, storage and haemostatic potential are perturbed in HCMEC from DCM hearts.

Pituitary tumours: molecular and genetic aspects.

'Pituitary tumours' is an umbrella term for various tumours originating from different regions of the hypothalamic-pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune-Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial-mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus

"What's in a name? That which we call a rose / By any other name would smell as sweet" (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

Changing the Name of Diabetes Insipidus: A Position Statement of the Working Group for Renaming Diabetes Insipidus.

Recent data show that patients with a diagnosis of diabetes insipidus (DI) are coming to harm. Here we give the rationale for a name change to arginine vasopressin deficiency and resistance for central and nephrogenic DI, respectively.

Temozolomide in aggressive pituitary tumours and pituitary carcinomas.

Survival for patients with aggressive pituitary tumours (APT) and pituitary carcinomas (PC) has significantly improved following the increasing use of temozolomide (TMZ) since the first reports of response in 2006. TMZ was established as first line chemotherapy for APT/PC in the 2018 ESE guidelines on the management of APT/PC. There is no controversy over its use as salvage therapy however there is increasing interest in exploring TMZ use earlier in the treatment algorithm for APT/PC. Overall response rates as reported in systematic reviews are around 40% but stable disease in another 25% illustrates the clinical effectiveness of TMZ. Response is higher among functional compared to non-functional tumours. Where maximal radiation thresholds have not been reached in a patient, combination radiotherapy and TMZ appears more effective. Whether combination TMZ and capecitabine (CAPTEM) offers increased benefit remains uncertain particularly given added toxicity. O6-methyl guanine DNA methyl transferase (MGMT) status is important in determining response to treatment, although examination via immunohistochemistry versus PCR-based promoter-methylation analysis remains somewhat controversial. Optimal duration of TMZ treatment has still not been determined although longer treatment courses have been associated with increased progression-free survival. Treatment options following disease progression after TMZ remain unclear but include a second course of TMZ, immunotherapy and targeted oncological agents such as bevacizumab and lapatinib as well as peptide receptor radionuclide treatment (PRRT). An experienced pituitary multidisciplinary team is essential to all management decisions in patients with APT/PC.

Changing the name of diabetes insipidus: a position statement of The Working Group for Renaming Diabetes Insipidus.

'What's in a name? That which we call a rose/By any other name would smell as sweet' (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word, and it therefore represents a convention with no intrinsic meaning. While this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rationale for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology, and pediatric endocrine societies now proposes changing the name of 'diabetes insipidus' to 'arginine vasopressin deficiency (AVP-D)' for central etiologies, and 'arginine vasopressin resistance (AVP-R)' for nephrogenic etiologies. This article provides both the historical context and the rationale for this proposed name change.

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus.

"What's in a name? That which we call a rose / By any other name would smell as sweet" (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.