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.

From burden to benefit: a multi-site study of the impact of allied health work-based learning placements on patient care quality.

Allied health clinical placements take place within an increasingly overstretched health care system where demand for services often exceeds availability of resources. Within this environment, student placements are often perceived as an additional burden to an already overwhelmed workforce. This study explored whether the quality of patient care was enhanced when services were re-designed using a collaborative partnership approach to more purposefully integrate students into delivery of care. Using an embedded multiple case study design, data were collected through focus groups and interviews, patient experience surveys, and secondary administrative data sources. Cases were across physiotherapy and occupational therapy in six different hospital settings. Perception of care provided by students was viewed positively by all stakeholders, including patients. Perceived health outcomes of faster improvement of health condition, improved mobility and function identified through our qualitative findings were supported by quantitative service delivery markers such as increased therapy sessions, more patients being discharged home instead of to other care facilities and reduced length of stay. Health care providers and students alike perceived improvements in service efficiencies whilst maintaining high quality care. This study has provided preliminary evidence towards improved patient care when a partnering approach is adopted whereby students are intentionally integrated into services that otherwise might not have been delivered. Furthermore, it has shifted the associated narrative from students as additional burden to students as benefit.

Impulse Control Disorders in Dopamine Agonist-Treated Hyperprolactinemia: Prevalence and Risk Factors.

CONTEXT: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain. OBJECTIVE: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls. DESIGN, SETTING AND PARTICIPANTS: Multicenter cross-sectional analysis of 113 patients and 99 healthy controls. MAIN OUTCOME MEASURES: Participants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semistructured psychological interview. RESULTS: Patients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P = .01), hypersexuality (22.1 vs 8.1%, P = .009), compulsive buying (15.9 vs 6.1%, P = .041) and punding (18.6 vs 6.1%, P = 0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P = 0.004). Independent risk factors were male sex (odds ratio [OR] 13.85), eugonadism (OR 7.85), Hardy's tumor score and psychiatric comorbidity (OR 6.86) for hypersexuality, and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study. CONCLUSIONS: DA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men.

Development and validation of a targeted gene sequencing panel for application to disparate cancers.

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour's molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

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.

Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours.

OBJECTIVE: Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. DESIGN: We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion for MEN1, CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP, CDKN1B, MEN1, PRKAR1A, SDHA, SDHB, SDHC and SDHD. RESULTS: Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1, CDKN1B or AIP. CONCLUSIONS: A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.