A thymine-challenge test to prospectively evaluate dihydropyrimidine dehydrogenase activity for risk of severe 5-fluorouracil-induced gastrointestinal toxicity.

Purpose: Inherited dihydropyrimidine dehydrogenase (DPD) deficiency is a risk factor for severe 5-fluorouracil toxicity. We report a phenotyping approach (thymine challenge test) to prospectively determine DPD activity and the association with severe adverse events.

Methods: The primary aim of this prospective study was to determine whether a thymine challenge test could prospectively identify patients at risk of severe toxicity from treatment with 5-fluorouracil/capecitabine in combination chemotherapy schedules or monotherapy.

Functional Analysis of HSD17B3-Deficient Male Mice Reveals Roles for HSD17B7 and HSD17B12 in Testosterone Biosynthesis.

Historically, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) was thought to be the key enzyme responsible for testicular testosterone production. In humans, loss-of-function mutations in HSD17B3 impair testosterone production during prenatal life leading to impaired development of androgen-dependent tissues in 46,XY individuals. However, male mice with HSD17B3 deficiency exhibit normal testicular testosterone concentrations, normal development of reproductive organs and are fertile, suggesting that mice express other hydroxysteroid dehydrogenase enzymes capable of testicular testosterone synthesis.

Alternative splicing generates isoform diversity in .

Although the gene has a long-standing association with cancer, its mechanisms of action remain incompletely understood, acting both as a tumour suppressor in neuroendocrine tumours and as an oncogene in leukaemia. The best-characterised isoform of the encoded protein, MENIN, is the 610-amino acid MENIN isoform 2. We hypothesise that some of the complexity of biology can be attributed to a currently unappreciated contribution of different MENIN isoforms.

Compensatory mechanisms that maintain androgen production in mice lacking key androgen biosynthetic enzymes.

Testosterone and dihydrotestosterone (DHT) are essential for male development and fertility. In the canonical androgen production pathway, testosterone is produced in the testis by HSD17B3; however, adult male Hsd17b3 knockout (KO) mice continue to produce androgens and are fertile, indicating compensatory mechanisms exist. A second, alternate pathway produces DHT from precursors other than testosterone via 5α-reductase (SRD5A) activity.

Blending space and time to talk about cancer in extended reality.

We introduce a proof-of-concept extended reality (XR) environment for discussing cancer, presenting genomic information from multiple tumour sites in the context of 3D tumour models generated from CT scans. This tool enhances multidisciplinary discussions. Clinicians and cancer researchers explored its use in oncology, sharing perspectives on XR's potential for use in molecular tumour boards, clinician-patient communication, and education.

Palliative radiotherapy is effective for both well- and poorly differentiated neuroendocrine neoplasms.

Introduction: The outcomes of palliative radiation therapy (RT) for neuroendocrine neoplasms (NEN) are seldom reported. We investigated outcomes following palliative radiotherapy in a cohort of patients with NENs. We hypothesised that well-differentiated NEN will be less likely to have a clinical response than poorly differentiated NEN.

Dynamic ctDNA Mutational Complexity in Patients with Melanoma Receiving Immunotherapy.

Background: Circulating tumour DNA (ctDNA) analysis promises to improve the clinical care of people with cancer, address health inequities and guide translational research. This observational cohort study used ctDNA to follow 29 patients with advanced-stage cutaneous melanoma through multiple cycles of immunotherapy.

Method: A melanoma-specific ctDNA next-generation sequencing (NGS) panel, droplet digital polymerase chain reaction (ddPCR) and mass spectrometry analysis were used to identify ctDNA mutations in longitudinal blood plasma samples from Aotearoa New Zealand (NZ) patients receiving immunotherapy for melanoma.

Complex Patterns of Genomic Heterogeneity Identified in 42 Tumor Samples and ctDNA of a Pulmonary Atypical Carcinoid Patient.

Unlabelled: Tumor evolution underlies many challenges facing precision oncology, and improving our understanding has the potential to improve clinical care. This study represents a rare opportunity to study tumor heterogeneity and evolution in a patient with an understudied cancer type. A patient with pulmonary atypical carcinoid, a neuroendocrine tumor, metastatic to 90 sites, requested and consented to donate tissues for research.

Chromosomal Aberrations Accumulate during Metastasis of Virus-Negative Merkel Cell Carcinoma.

Merkel cell carcinoma is a rare, aggressive skin tumor initiated by polyomavirus integration or UV light DNA damage. In New Zealand, there is a propensity toward the UV-driven form (31 of 107, 29% virus positive). Using archival formalin-fixed, paraffin-embedded tissues, we report targeted DNA sequencing covering 246 cancer genes on 71 tumor tissues and 38 nonmalignant tissues from 37 individuals, with 33 of 37 being negative for the virus.

New Insights into Testosterone Biosynthesis: Novel Observations from HSD17B3 Deficient Mice.

Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the canonical androgen production pathway and is essential for normal masculinisation and testis function. Disruption to androgen production can result in disorders of sexual development (DSD).

A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function.

Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production.

Australasian Consensus Statement on the Identification, Prevention, and Management of Hormonal Crises in Patients with Neuroendocrine Neoplasms Undergoing Peptide Receptor Radionuclide Therapy.

Hormonal crises are a rare but increasingly recognized phenomenon following peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine neoplasms (NENs). Due to the paucity of published studies, approaches to the identification, prevention, and management of risk factors are inconsistent between different institutions. This consensus statement aimed to provide guidance for NEN patients undergoing PRRT.

Survival of patients with small bowel neuroendocrine neoplasms in Auckland, Aotearoa New Zealand.

Background: Small intestinal Neuroendocrine Neoplasms (SI-NENs) are the most common primary malignancy of the small bowel. The aim of this study is to define the survival of patients with an SI-NEN in Auckland, Aotearoa New Zealand (AoNZ).

Methods: A retrospective study of all patients diagnosed with a jejunal or ileal SI-NEN in the Auckland region between 2000 and 2012 was performed.

Clinical features and postoperative survival in patients with sporadic versus multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors: An international cohort study.

Background: The optimal surgical management of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 is controversial. This study sought to compare clinicopathologic characteristics and outcomes of multiple endocrine neoplasia type 1-associated and sporadic pancreatic neuroendocrine tumors from a large multi-national database.

Methods: A multi-institutional, international database of patients with surgically resected pancreatic neuroendocrine tumors was analyzed.

Circulating tumor DNA is a sensitive marker for routine monitoring of treatment response in advanced colorectal cancer.

Accurate assessment of chemotherapy response provides the means to terminate ineffective treatment, trial alternative drug regimens or schedules and reduce dose to minimize toxicity. Here, we have compared circulating tumor DNA (ctDNA) with carcinoembryonic antigen (CEA) for the cycle by cycle assessment of chemotherapy response in 30 patients with metastatic colorectal cancer. CtDNA (quantified using individualized digital droplet PCR (ddPCR) assays) and CEA levels were determined immediately prior to each chemotherapy cycle over time periods ranging from 42-548 days (average of 10 time points/patient).

Specialized Cell-Free DNA Blood Collection Tubes Can Be Repurposed for Extracellular Vesicle Isolation: A Pilot Study.

Liquid biopsies offer a minimally invasive approach to patient disease diagnosis and monitoring. However, these are highly affected by preprocessing variables with many protocols designed for downstream analysis of a single molecular biomarker. Here we investigate whether specialized blood tubes could be repurposed for the analysis of an increasingly valuable biomarker, extracellular vesicles (EVs).

Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines.

Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines.

DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis.

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation.

Tailoring a rapid autopsy protocol to explore cancer evolution: a patient collaboration.

Genomic analysis of tissues from rapid autopsy programmes has transformed our understanding of cancer. However, these programmes are not yet established in New Zealand. Our neuroendocrine tumour research group, NETwork!, received a request from a patient wishing to donate tumour tissues post-mortem.