Development of a person-centred digital platform for the long-term support of people living with an adult-onset genetic disease predisposition: a mixed-methods study protocol.

INTRODUCTION: Individuals at an inherited high-risk of developing adult-onset disease, such as breast cancer, are rare in the population. These individuals require lifelong clinical, psychological and reproductive assistance. After a positive germline test result, clinical genetic services provide support and care coordination. However, ongoing systematic clinical follow-up programmes are uncommon. Digital health solutions offer efficient and sustainable ways to deliver affordable and equitable care. This paper outlines the codesign and development of a digital health platform to facilitate long-term clinical and psychological care, and foster self-efficacy in individuals with a genetic disease predisposition. METHODS AND ANALYSIS: We adopt a mixed-methods approach for data gathering and analysis. Data collection is in two phases. In phase 1, 300 individuals with a high-risk genetic predisposition to adult disease will undertake an online survey to assess their use of digital health applications (apps). In phase 2, we will conduct focus groups with 40 individuals with a genetic predisposition to cardiac or cancer syndromes, and 30 clinicians from diverse specialities involved in their care. These focus groups will inform the platform's content, functionality and user interface design, as well as identify the barriers and enablers to the adoption and retention of the platform by all endusers. The focus groups will be audiorecorded and transcribed, and thematic and content data analysis will be undertaken by adopting the Unified Theory of Acceptance and Use of Technology. Descriptive statistics will be calculated from the survey data. Phase 3 will identify the core skillsets for a novel digital health coordinator role. Outcomes from phases 1 and 2 will inform development of the digital platform, which will be user-tested and optimised in phase 4. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/88892/PMCC). Results will be disseminated in academic forums, peer-reviewed publications and used to optimise clinical care.

Bilateral Knee Septic Arthritis after Prostatic Urethral Lift: A Case Report.

Introduction: Septic arthritis (SA) is a rare clinical entity that can lead to significant morbidity and mortality. Recent years have seen a rise in minimally invasive surgical therapy for the treatment of benign prostatic hyperplasia, including prostatic urethral lift. We report a case of bilateral simultaneous SA of the knees, following a prostatic urethral lift procedure. SA following a urologic procedure has not previously been reported. Case Report: A 79-year-old male presented to the Emergency Department through an ambulance with bilateral knee pain with associated fever and chills. Two weeks before presentation, he had undergone a prostatic urethral lift, cystoscopy, and Foley catheter placement. The examination was remarkable for bilateral knee effusions. Arthrocentesis was performed, and the synovial fluid analysis was consistent with a diagnosis of SA. Conclusion: This case emphasizes the need for frontline clinicians to consider SA in patients presenting with joint pain as a rare complication of prostatic instrumentation.

An International Comparison of Presentation, Outcomes and CORONET Predictive Score Performance in Patients with Cancer Presenting with COVID-19 across Different Pandemic Waves.

Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

The occurrence and associated risk factors of brain metastases in well differentiated grade 1 and 2 bronchial neuroendocrine tumours: A single centre retrospective analysis of 280 patients.

Typical and atypical bronchial carcinoid account for around 2% of all neuroendocrine neoplasms of pulmonary origin. Fewer than 5% of patients with these cancers are thought to develop brain metastases, and hence routine intracranial imaging is not currently included in staging investigations. In this study, retrospective case note analysis was performed on 280 patients diagnosed with either typical carcinoid (TC) or atypical carcinoid (AC) at a large, single-site cancer centre. None of the 219 patients with TC developed brain metastases during the course of their disease, whereas seven of the 61 AC (11.5%) were found to have intracranial spread, four of which were present at the point of diagnosis. A Cox proportional hazard model showed that a Ki-67 expression ≥18%, patient age ≥65 years and disease stage at diagnosis were all independently and significantly associated with the development of brain metastases in AC. This study has found new evidence that the incidence of brain metastases in AC is significantly higher than previously thought. Of all the variables reviewed, Ki-67 expression was most strongly associated with the development of intracranial disease in AC and could be readily translated into clinical practice. Predictive factors such as age, disease stage and Ki-67 expression could be used to identify patients at particularly increased risk of brain metastases, who would benefit from early intracranial imaging. This could allow for earlier detection and treatment of metastases, with the potential to improve clinical outcomes and patient quality of life.

TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members.

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.

Segmental duplications and their variation in a complete human genome.

Despite their importance in disease and evolution, highly identical segmental duplications (SDs) are among the last regions of the human reference genome (GRCh38) to be fully sequenced. Using a complete telomere-to-telomere human genome (T2T-CHM13), we present a comprehensive view of human SD organization. SDs account for nearly one-third of the additional sequence, increasing the genome-wide estimate from 5.4 to 7.0% [218 million base pairs (Mbp)]. An analysis of 268 human genomes shows that 91% of the previously unresolved T2T-CHM13 SD sequence (68.3 Mbp) better represents human copy number variation. Comparing long-read assemblies from human (n = 12) and nonhuman primate (n = 5) genomes, we systematically reconstruct the evolution and structural haplotype diversity of biomedically relevant and duplicated genes. This analysis reveals patterns of structural heterozygosity and evolutionary differences in SD organization between humans and other primates.

Facebook Online Support Groups for Hospice Family Caregivers of Advanced Cancer Patients: Protocol, Facilitation Skills and Promising Outcomes.

Research has demonstrated a lack of support for hospice caregivers and a higher than average level of self-reported anxiety and depression. While online support groups are gaining popularity, few protocols have been published, little research has demonstrated the skills required to facilitate, and virtually no data has explored the clinical outcomes affiliated with participation in such groups. This paper presents the preliminary experience and results of a clinical trial testing the use of online support groups designed to both educate and provide social support to caregivers of hospice cancer patients. A detailed protocol outlines educational strategies, discussion questions, and a blueprint outlining ways to engage participants. A review of field notes completed by the interventionist reveal specific facilitation skills and strategies used to engage participants. Finally, preliminary analysis of 78 participants shows the group is having a statistically significant impact on the caregiver depression.

Immune checkpoint inhibitors: a narrative review of considerations for the anaesthesiologist.

Immunotherapy has revolutionised the treatment of oncologic malignancies. Immune checkpoint inhibitors represent a new class of immunotherapy drugs. Although these drugs show promise, they are associated with immune-related adverse reactions. An increasing number of patients who undergo surgery will have had treatment with immune checkpoint inhibitors. In this narrative review article, we discuss their mechanism of action, therapeutic effects, pertinent toxicities, and address specific perioperative considerations for patients treated with immune checkpoint inhibitors.

An objective methodology capturing online commodity marketing and other harms.

Increasingly life is lived online, yet little is known about the actual nature and extent of online content that people view due to the difficulty of recording real time exposure. This includes people's exposure to harmful commodity marketing. This study aimed to develop a methodology to assess the nature and extent of exposure to, and engagement with, unhealthy commodity marketing and other public health harms online, particularly children's exposure. A convenience sample of 16 young adult participants (aged 21-29) recorded their device usage for 2 days using Zoom software. Data were coded and analysed to assess the nature and extent of marketing for alcohol, gambling, junk food and smoking products. Four focus groups were conducted with participants to explore their data collection and coding experiences, and results assessed using thematic analysis. The study found that, with some modifications, this method was feasible for gathering real-time objective data from the online world that can be analysed for a range of public health harms, including marketing of unhealthy commodities. Larger studies are recommended to build global evidence for public health action in the online world.

Population-based genetic testing of asymptomatic women for breast and ovarian cancer susceptibility.

PURPOSE: The identification of carriers of hereditary breast and ovarian cancer (HBOC) gene variants through family cancer history alone is suboptimal, and most population-based genetic testing studies have been limited to founder mutations in high-risk populations. Here, we determine the clinical utility of identifying actionable variants in a healthy cohort of women. METHODS: Germline DNA from a subset of healthy Australian women participating in the lifepool project was screened using an 11-gene custom sequencing panel. Women with clinically actionable results were invited to attend a familial cancer clinic (FCC) for post-test genetic counseling and confirmatory testing. Outcomes measured included the prevalence of pathogenic variants, and the uptake rate of genetic counseling, risk reduction surgery, and cascade testing. RESULTS: Thirty-eight of 5908 women (0.64%) carried a clinically actionable pathogenic variant. Forty-two percent of pathogenic variant carriers did not have a first-degree relative with breast or ovarian cancer and 89% pursued referral to an FCC. Forty-six percent (6/13) of eligible women pursued risk reduction surgery, and the uptake rate of cascade testing averaged 3.3 family members per index case. CONCLUSION: Within our cohort, HBOC genetic testing was well accepted, and the majority of high-risk gene carriers identified would not meet eligibility criteria for genetic testing based on their existing family history.

Pembrolizumab-induced Sarcoid-like Reactions during Treatment of Metastatic Melanoma.

Pembrolizumab is a programmed cell death protein 1, or PD-1, inhibitor therapy immunotherapy for patients with advanced melanoma. This report discusses a series of documented cases of sarcoid-like reactions associated with this therapy. Three patients with malignant melanoma developed metastatic disease and were treated with pembrolizumab immunotherapy. Subsequent imaging showed lymphadenopathy in the mediastinum and hilar regions that was confirmed to represent a sarcoid-like reaction at histologic examination. Radiologists should be aware of the association between pembrolizumab and the development of sarcoid-like reactions to avoid inaccurately ascribing these imaging findings to metastatic disease. Clinical presentation, biopsy, radiographic evidence of bilateral hilar lymphadenopathy (with paratracheal lymphadenopathy), and elevated serum angiotensin-converting enzyme levels aid in the diagnosis of sarcoid-like reactions and help avoid these reactions being mistaken for recurrent or metastatic disease.

A Systematic Review of How Young People Live with Inherited Disease: What Can We Learn for Li-Fraumeni Syndrome?

PURPOSE: Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition caused by germline TP53 mutations, confers significant cancer risks for young people (15-39 years). Yet evidence of how individuals experience this condition and the psychosocial implications are lacking. Therefore, this systematic review assessed the psychosocial implications of living with, or at risk of, an autosomal dominant condition as a young person, to draw evidence that may be analogous for young people with LFS. METHODS: We conducted a systematic search for studies published in peer-reviewed journals using Medline, CINAHL, PsycINFO, and Embase databases. Findings were synthesized and are reported thematically. RESULTS: We screened 352 articles and identified 39 studies, representing the perspectives of 765 young people. Most studies addressed hereditary breast and ovarian cancer (n = 22) and used qualitative methodologies (n = 35). Only one LFS study was identified, highlighting the distinct lack of psychosocial research describing experiences of young people with LFS. Translatable evidence showed that familial factors strongly influenced young people's experiences of genetic testing and their mutation status. Major adverse reactions to genetic test results were rare, although young people with a gene mutation experienced various psychosocial concerns at key developmental milestones, including family planning, developing romantic relationships, and making risk management decisions. CONCLUSION: Young people undergoing genetic testing for inherited disease require individualized support and recognition of previous lived experiences. We recommend that longitudinal care be made available to young people with inherited disease as they reach developmental milestones that intersect with risk management, risk perception, and family formation.

The importance of quality-of-life management in patients with advanced pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, and as such, a focus on quality of life is vital. This review will discuss various aspects of quality of life in patients with PDAC and their treatment. Pancreatic exocrine and endocrine insufficiency may result in issues related to nutrition, and pain and fatigue are other common symptoms, and may be managed with pharmaceutical or nonpharmaceutical methods. It has also been reported that low mood is a particular problem for patients with PDAC compared to patients with other cancers; however, the data supporting this is inconsistent. Data regarding improvements in quality of life in patients with PDAC receiving chemotherapy is also reviewed, which in some cases suggests a benefit to chemotherapy, particularly in the presence of a radiological response. Furthermore, the importance of early palliative care is discussed and the benefits reported including improved quality of life and mood, reduced aggressive interventions at the end of life and improved survival. Areas for future development may include increased use of quality of life as a trial outcome and the use of patient-reported outcomes to improve symptomatic care of patients, and particularly in those receiving active systemic treatment.

Health-related quality of life, anxiety, depression and impulsivity in patients with advanced gastroenteropancreatic neuroendocrine tumours.

AIM: To compare health-related quality of life (HRQoL), anxiety, depression, and impulsivity scores in patients with and without carcinoid syndrome (CS), and correlated them with serum 5-hydroxyindoleacetic acid (5-HIAA) levels. METHODS: Patients with advanced gastroenteropancreatic neuroendocrine tumours (GEPNET), with and without CS completed HRQoL QLQ-C30 and QLQ-GI.NET21, Hospital Anxiety and Depression Scale (HADS) and Barratt Impulsivity Scale (BIS) questionnaires. Two-sample Wilcoxon test was applied to assess differences in serum 5-HIAA levels, two-sample Mann-Whitney U test for HRQoL and BIS, and proportion test for HADS, between those with and without CS. RESULTS: Fifty patients were included; 25 each with and without CS. Median 5-HIAA in patients with and without CS was 367nmol/L and 86nmol/L, respectively (P = 0.003). Scores related to endocrine symptoms were significantly higher amongst patients with CS (P = 0.04) and scores for disease-related worries approached significance in the group without CS, but no other statistically-significant differences were reported between patients with and without CS in responses on QLQ-C30 or QLQ-GI.NET21. Fifteen patients (26%) scored ≥ 8/21 on anxiety scale, and 6 (12%) scored ≥ 8/21 on depression scale. There was no difference in median 5-HIAA between those scoring < or ≥ 8/21 on anxiety scale (P = 0.53). There were no statistically significant differences between groups in first or second-order factors (BIS) or total sum (P = 0.23). CONCLUSION: Excepting endocrine symptoms, there were no significant differences in HRQoL, anxiety, depression or impulsivity between patients with advanced GEPNET, with or without CS. Over one quarter of patients had high anxiety scores, unrelated to peripheral serotonin metabolism.

Gonadotrophin-releasing hormone agonist treatment for sexual offenders: A systematic review.

BACKGROUND: Sexual offending is a significant international issue causing long-term consequences for victims, perpetrators and society. AIMS: The purpose of this study was to review the existing research data assessing the efficacy of gonadotrophin-releasing hormone agonists for treating adult, male, sexual offenders. METHOD: The method of this review involved the examination of studies involving participants prescribed at least one month of a gonadotrophin-releasing hormone agonist for the purposes of reducing sexual drive related to offending. The primary outcome measures were recidivism rates and sexual functioning. Secondary outcome measures included assessment of side effects and effects on interpersonal/psychiatric functioning. Studies in the English language that were dated 1969-2015 were included. RESULTS: Twelve eligible studies (323 participants) were identified. A reduction in a variety of measures of sexual functioning and/or risk was found in all studies. Robust recidivism data was limited. Medication was rarely described as ineffectual. All studies reported side effects. Reduction in bone density and potential long-term reduction in fertility in some subjects were issues of concern. CONCLUSION: Whilst identified studies showed promising results with respect to sexual functioning, challenges in performing randomised control trials in this subject group meant that included studies were methodologically limited. This review recommends that future research must be performed before the effectiveness and tolerability of gonadotrophin-releasing hormone agonists in this population can be confirmed.

Pancreatic cancer: Are "liquid biopsies" ready for prime-time?

Pancreatic cancer is a disease that carries a poor prognosis. Accurate tissue diagnosis is required. Tumours contain a high content of stromal tissue and therefore biopsies may be inconclusive. Circulating tumour cells (CTCs) have been investigated as a potential "liquid biopsy" in several malignancies and have proven to be of prognostic value in breast, prostate and colorectal cancers. They have been detected in patients with localised and metastatic pancreatic cancer with sensitivities ranging from 38%-100% using a variety of platforms. Circulating tumour DNA (ctDNA) has also been detected in pancreas cancer with a sensitivity ranging from 26%-100% in studies across different platforms and using different genetic markers. However, there is no clear consensus on which platform is the most effective for detection, nor which genetic markers are the most useful to use. Potential roles of liquid biopsies include diagnosis, screening, guiding therapies and prognosis. The presence of CTCs or ctDNA has been shown to be of prognostic value both at diagnosis and after treatment in patients with pancreatic cancer. However, more prospective studies are required before this promising technology is ready for adoption into routine clinical practice.

Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma.

Investigation of the genetic lesions underlying classical Hodgkin lymphoma (CHL) has been challenging due to the rarity of Hodgkin and Reed-Sternberg (HRS) cells, the pathognomonic neoplastic cells of CHL. In an effort to catalog more comprehensively recurrent copy number alterations occurring during oncogenesis, we investigated somatic alterations involved in CHL using whole-genome sequencing-mediated copy number analysis of purified HRS cells. We performed low-coverage sequencing of small numbers of intact HRS cells and paired non-neoplastic B lymphocytes isolated by flow cytometric cell sorting from 19 primary cases, as well as two commonly used HRS-derived cell lines (KM-H2 and L1236). We found that HRS cells contain strikingly fewer copy number abnormalities than CHL cell lines. A subset of cases displayed nonintegral chromosomal copy number states, suggesting internal heterogeneity within the HRS cell population. Recurrent somatic copy number alterations involving known factors in CHL pathogenesis were identified (REL, the PD-1 pathway, and TNFAIP3). In eight cases (42%) we observed recurrent copy number loss of chr1:2,352,236-4,574,271, a region containing the candidate tumor suppressor TNFRSF14. Using flow cytometry, we demonstrated reduced TNFRSF14 expression in HRS cells from 5 of 22 additional cases (23%) and in two of three CHL cell lines. These studies suggest that TNFRSF14 dysregulation may contribute to the pathobiology of CHL in a subset of cases.

Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous, autosomal-recessive disorder, characterized by oto-sino-pulmonary disease and situs abnormalities. PCD-causing mutations have been identified in 20 genes, but collectively they account for only ∼65% of all PCDs. To identify mutations in additional genes that cause PCD, we performed exome sequencing on three unrelated probands with ciliary outer and inner dynein arm (ODA+IDA) defects. Mutations in SPAG1 were identified in one family with three affected siblings. Further screening of SPAG1 in 98 unrelated affected individuals (62 with ODA+IDA defects, 35 with ODA defects, 1 without available ciliary ultrastructure) revealed biallelic loss-of-function mutations in 11 additional individuals (including one sib-pair). All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities. Additionally, all individuals with mutations who had defined ciliary ultrastructure had ODA+IDA defects. SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms. Zebrafish morpholino studies of spag1 produced cilia-related phenotypes previously reported for PCD-causing mutations in genes encoding cytoplasmic proteins. Together, these results demonstrate that mutations in SPAG1 cause PCD with ciliary ODA+IDA defects and that exome sequencing is useful to identify genetic causes of heterogeneous recessive disorders.

The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line.

The HeLa cell line was established in 1951 from cervical cancer cells taken from a patient, Henrietta Lacks. This was the first successful attempt to immortalize human-derived cells in vitro. The robust growth and unrestricted distribution of HeLa cells resulted in its broad adoption--both intentionally and through widespread cross-contamination--and for the past 60 years it has served a role analogous to that of a model organism. The cumulative impact of the HeLa cell line on research is demonstrated by its occurrence in more than 74,000 PubMed abstracts (approximately 0.3%). The genomic architecture of HeLa remains largely unexplored beyond its karyotype, partly because like many cancers, its extensive aneuploidy renders such analyses challenging. We carried out haplotype-resolved whole-genome sequencing of the HeLa CCL-2 strain, examined point- and indel-mutation variations, mapped copy-number variations and loss of heterozygosity regions, and phased variants across full chromosome arms. We also investigated variation and copy-number profiles for HeLa S3 and eight additional strains. We find that HeLa is relatively stable in terms of point variation, with few new mutations accumulating after early passaging. Haplotype resolution facilitated reconstruction of an amplified, highly rearranged region of chromosome 8q24.21 at which integration of the human papilloma virus type 18 (HPV-18) genome occurred and that is likely to be the event that initiated tumorigenesis. We combined these maps with RNA-seq and ENCODE Project data sets to phase the HeLa epigenome. This revealed strong, haplotype-specific activation of the proto-oncogene MYC by the integrated HPV-18 genome approximately 500 kilobases upstream, and enabled global analyses of the relationship between gene dosage and expression. These data provide an extensively phased, high-quality reference genome for past and future experiments relying on HeLa, and demonstrate the value of haplotype resolution for characterizing cancer genomes and epigenomes.