Optimising oncology drug expenditure in Ireland.

A combination of improvements in patient survival, increasing treatment duration, and the development of more expensive agents has led to a doubling of per-capita spending on cancer medicines in Ireland (2008-2018). Despite this, access to new drugs is poor in comparison to other EU countries. We examine methods to optimise oncology drug spending to facilitate access to newer anticancer agents. Key targets for spending optimisation (biosimilar use, clinical trials and expanded access programs, waste reduction, avoidance of futile treatment, and altered drug scheduling) were identified through an exploratory analysis. A structured literature search was performed, with a focus on articles relevant to the Irish Healthcare system, supplemented by reports from statutory bodies. At the present time, EMA-approved agents are available once approved by the NCPE. Optimising drug costs occurs through guideline-based practice and biosimilar integration, the latter provides €80 million in cost savings annually. Access to novel therapies can occur via over 50 clinical trials and 28 currently available expanded access programmes. Additional strategies include reversion to weight-based immunotherapy dosing, potentially saving €400,000 per year in our centre alone, vial sharing, and optimisation of treatment schedules. A variety of techniques are being employed by oncologists to optimise costs and increase access to innovation for patients. Use of biosimilars, drug wastage, and prescribing at end of life should be audited as key performance indicators, which may lead to reflective practice on treatment planning. Such measures could further optimise oncology drug expenditure nationally facilitating approval of new agents.

"The third wing of the plane": Fathers' perceptions of their role in the treatment process for daughters with eating disorders.

Eating disorders are complex mental health conditions exacerbated by high mortality rates. International and national guidelines recommend family involvement in the treatment process, recognising the family as an important source of support to young people. Research suggests fathers engage less in the process compared to mothers. In studies exploring parental perspectives, most samples consisted of mothers, with fathers minimally represented. Few studies explore family involvement from the perspective of fathers. This study aimed to explore the experiences of fathers regarding their involvement in the treatment process. Qualitative descriptive methods were used, involving focus group interviews of seven fathers. Interviews were assisted by a semi-structured interview guide. A qualitative content analysis approach was used to analyse the data regarding paternal experiences of engagement in the treatment process. Fathers understood the importance of the whole family working together but viewed mothers as taking a more central role in the treatment process, with fathers more at the periphery. Gender emerged as an influencing factor in paternal involvement, with mothers primarily taking on responsibility for the child with the eating disorder and fathers providing secondary support. Healthcare providers need to be aware of the contribution of gendered roles within the family system and consider this when working with families within the treatment process. Consequently, mental health nurses have an important role in encouraging fathers to become actively involved in the treatment process.

Salvage Therapy With Selpercatinib for RET-Rearranged NSCLC With Pralsetinib-Related Pneumonitis and Leptomeningeal Disease: A Case Report.

Selpercatinib and pralsetinib are RET inhibitors with substantial activity in advanced RET-rearranged NSCLC. We present a case of pralsetinib-related pneumonitis and leptomeningeal and brain metastases progression during treatment suspension for pneumonitis. During recovery, selpercatinib administration led to rapid neurologic response and complete intracranial response and allowed pneumonitis resolution. This case supports the safety of selpercatinib in patients with pneumonitis on pralsetinib and highlights its marked efficacy in leptomeningeal disease.

Updates in Management of Malignant Pleural Mesothelioma.

OPINION STATEMENT: Malignant pleural mesothelioma (MPM) is an aggressive asbestos-associated thoracic malignancy that is usually incurable. As demonstrated in the landmark MARS2 trial, surgical resection does not improve survival outcomes and its role in managing MPM is limited. Whilst platinum-pemetrexed chemotherapy in combination with bevacizumab was the standard first-line approach for unresectable disease, landmark phase 3 trials have now established the role of immune checkpoint inhibitors (CPIs) in the upfront management of unresectable disease: either nivolumab-ipilimumab or carboplatin-pemetrexed-pembrolizumab. Patient selection for optimal strategy remains an ongoing question. For relapsed disease novel genomic-based therapies targeting a range of aberrations including losses of the tumour suppressor genes BAP1, CDKN2A and NF2, are being evaluated. Nonetheless, the future of MPM therapeutics holds promise. Here we overview current treatment strategies in the management of MPM.

Minimal Residual Disease Monitoring in Radically Treated Non-Small Cell Lung Cancer: Challenges and Future Directions.

Circulating tumor DNA (ctDNA) analysis can identify patients with residual disease before it is clinically or radiologically evident. Minimal residual disease (MRD) is an advancing area in the management of radically treated solid tumors. Which MRD assay is optimum and when it should be used is still not defined. Whilst promising, the clinical utility of this technology to guide patient care is still investigational in non-small cell lung cancer (NSCLC) and has not entered routine care. Once technically and clinically optimized, MRD may be utilized to personalize adjuvant therapy, detect disease relapse earlier and improve cure rates. In this review, we discuss the current status of MRD monitoring in NSCLC by summarizing frequently used MRD assays and their associated evidence in NSCLC. We discuss the potential applications of these technologies and the challenge of demonstrating MRD clinical utility in trials.

Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review.

A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.

Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC. METHODS: cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results. RESULTS: Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001). CONCLUSIONS: cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.

'Meet Me Where I Am': Mental health service users' perspectives on the desirable qualities of a mental health nurse.

Nurses play a central role in the delivery of quality mental health services. Desired qualities of a mental health nurse, in particular therapeutic relationships, have been described in the literature, primarily reflecting the nursing paradigm. Service users' perspectives must be more fully understood to reflect contemporary mental health policy and to recognize their position at the centre of mental health service delivery and to directly influence and contribute their perspectives and experiences to mental health nursing education. A qualitative exploratory research project was undertaken to inform and enhance understanding of what service users see as the desired qualities of a mental health nurse. The project was co-produced by service users as experts by experience, and mental health nurse academics to ensure the service user perspective was privileged. This international project conducted in Europe and Australia included a series of focus groups with service users (n = 50). Data were analysed thematically. Being with me was a major theme identified and reflected the sub-themes: respect towards service users as persons; empathy, compassion and effective communication; understanding service users; knowledge of services; and fostering hope and believing that recovery is possible. These qualities specifically reflecting the service user perspective must be central to mental health nursing curricula to facilitate the development of holistic care and recovery-oriented practice. These findings were utilized to directly inform development of a co-produced mental health nursing learning module, to maximize genuine service user involvement, and to fully realize the benefits of service user led education for undergraduate nursing students.

Improving Service User Involvement in Mental Health Nursing Education: Suggestions from Those with Lived Experience.

Service user involvement in mental health nursing education is increasing and a developing evidence base is demonstrating more positive attitudes towards people labelled with a mental illness. To date, most research on this approach has focussed on the perspectives of nursing students, with very limited research drawing on the expertise and opinions of service users. The aim of this study was to explore potential improvements in mental health nursing education, and ways service user involvement can be enhanced as defined by service users themselves. An international qualitative research project was undertaken involving focus groups with service users (n = 50) from Australia and five European countries. The research was coproduced between Experts by Experience (service users) and mental health nurse academics. Data were analysed thematically. Findings reflected two broad themes: (1) improvements to content, including: further emphasis on developing emotional intelligence, understanding mental distress and broader context of care; (2) Improvements to service user involvement, including: support, format, and teaching and learning techniques. These findings provide direction for maximising the benefits of service user involvement and show the value of the expertise of service users.

Integrated multimodality and multi-disciplinary team approach to pre-sacral lesions.

The purpose of this article is to describe the clinical and radiological features of presacral lesions. CT and MRI are the diagnostic modalities of choice and are complimentary in the assessment of presacral lesions. Imaging findings of presacral lesions on CT and MRI are described with the use of examples. Preoperative biopsy, surgical and non-surgical managements are outlined. While the general radiologist cannot be familiar with every rare presacral condition, characterisation of a presacral lesion based on anatomy, demographics and imaging features can guide us in making a sound differential.

Expert by experience involvement in mental health nursing education: The co-production of standards between Experts by Experience and academics in mental health nursing.

WHAT IS KNOWN ON THE SUBJECT: Expert by Experience (EBE) involvement in mental health nursing education has demonstrated benefits, including enhancing understanding of holistic and recovery-focused practice and enhanced application of interpersonal skills. Structure and support for EBE involvement is lacking; often resulting in inadequate preparation and debriefing and tokenistic involvement. Service user involvement in mental health nursing education should be underpinned by lived experience perspectives. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: An exploration of EBE involvement in nursing education from the perspective of those with lived experience. The development of standards designed to provide structure to better support future EBEs involved in higher education. An exemplar for co-production of standards between EBE and nurse academics which has applicability for other contexts. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The standards could potentially strengthen EBE involvement in mental health nursing education, enhance their confidence and increase the retention of EBEs by creating an inclusive working culture. By increasing support for EBEs, the benefits to mental health nursing practice are likely to be maximized. ABSTRACT: Introduction Involving people with lived experience of mental distress in mental health nursing education has gained considerable traction yet broader implementation remains ad hoc and tokenistic. Effective involvement requires curricula be informed by lived experience of service use. Aim To develop standards to underpin expert by experience involvement in mental health nursing education based on lived experience of service use. Methods Phase one used qualitative descriptive methods, involving focus groups with service users (n = 50) from six countries to explore perceptions of service user involvement in mental health nursing education. Phase two utilized these findings through consensus building to co-produce standards to support Experts by Experience involvement in mental health nursing education. Results Three themes emerged in Phase one: enablers and barriers, practical and informational support, and emotional and appraisal support. These themes underpinned development of the standards, which reflect nine processes: induction and orientation, external supervision, supportive teamwork, preparation for teaching and assessing, "intervision," mutual mentorship, pre- and post-debriefing, role clarity and equitable payment. Conclusions These standards form the framework entitled; Standards for Co-production of Education (Mental Health Nursing) (SCo-PE [MHN]). Implications for Practice The standards aim to support implementation of Expert by Experience roles in mental health nursing education.

'To be treated as a human': Using co-production to explore experts by experience involvement in mental health nursing education - The COMMUNE project.

Increasingly, experts as deemed by personal experience or mental health service use, are involved in the education of nurses; however, accompanying research is limited and focuses primarily on opinions of nurse educators and students. The aim of this study was to develop an understanding of the potential contribution to mental health nursing education by those with experience of mental health service use. The research was part of the international COMMUNE (Co-production of Mental Health Nursing Education) project, established to develop and evaluate co-produced mental health content for undergraduate nursing students. A qualitative descriptive design was adopted with data collected through focus group interviews in seven sites across Europe and Australia. Experts by experience (people with experience of distress, service use, and recovery) co-produced the project in partnership with nursing academics. Co-production enriched the process of data collection and facilitated the analysis of data from multiple perspectives. Two themes are presented in this paper. The first focuses on how experts by experience can enhance students' understanding of recovery by seeing the strengths inherent in the 'human' behind the diagnostic label. The second highlights the importance of communication and self-reflection on personal values, where students can explore their own thoughts and feelings about mental distress alongside those with lived experience. Interacting with experts by experience in the classroom can assist in challenging stigmatizing attitudes prior to nursing placements. These findings can be used to inform international nursing curricula by increasing the focus on nursing skills valued by those who use the services.

Effect on Overall Survival of Locoregional Treatment in a Cohort of De Novo Metastatic Prostate Cancer Patients: A Single Institution Retrospective Analysis From the Royal Marsden Hospital.

BACKGROUND: The optimal management of the primary tumor in metastatic at diagnosis (M1) prostate cancer (PCa) patients is not yet established. We retrospectively evaluated the effect of locoregional treatment (LRT) on overall survival (OS) hypothesizing that this could improve outcome through better local disease control and the induction of an antitumor immune response (abscopal effect). PATIENTS AND METHODS: M1 at diagnosis PCa patients referred to the Prostate Targeted Therapy Group at the Royal Marsden between June 2003 and December 2013 were identified. LRT was defined as either surgery, radiotherapy (RT) or transurethral prostatectomy (TURP) administered to the primary tumor at any time point from diagnosis to death. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. RESULTS: Overall 300 patients were identified; 192 patients (64%) experienced local symptoms at some point during their disease course; 72 patients received LRT (56.9% TURP, 52.7% RT). None of the patients were treated with prostatectomy. LRT was more frequently performed in patients with low volume disease (35.4% vs. 16.2%; P < .001), lower prostate-specific antigen (PSA) level at diagnosis (median PSA: 75 vs. 184 ng/mL; P = .005) and local symptoms (34.2% vs. 4.8%; P < .001). LRT was associated in UV and MV analysis with longer OS (62.1 vs. 55.8 months; hazard ratio [HR], 0.74; P = .044), which remained significant for RT (69.4 vs. 55.1 months; HR, 0.54; P = .002) but not for TURP. RT was associated with better OS independent of disease volume at diagnosis. CONCLUSION: These data support the conduct of randomized phase III trials to evaluate the benefit of local control in patients with M1 disease at diagnosis.

BRAF inhibitor treatment of melanoma causing colonic polyps: An alternative hypothesis.

Colonic polyps may arise from BRAF inhibitor treatment of melanoma, possibly due to paradoxical activation of the mitogen-activated protein (MAP)-kinase pathway. In an alternative evidence based scenario, tubular colonic adenomas with APC gene mutations have also been identified in the context of BRAF inhibitor treatment, in the absence of mutations of MAPK genes. A minority of colorectal cancers develop by an alternative "serrated polyp pathway". This article postulates a novel hypothesis, that the established phenotypic and molecular characteristics of serrated colonic polyps/CRC offer an intriguing insight into the pathobiology of BRAF inhibitor induced colonic polyps. Serrated polyps are characterized by a CpG island methylation phenotype, MLH1 silencing and cellular senescence. They also have BRAF mutations. The contention is that BRAF inhibitor induced polyps mimic the afore-described histology and molecular features of serrated polyps with the exception that instead of the presence of BRAF mutations they induce C-RAF homodimers and B-RAF: C-RAF heterodimers.

Monocytes, Macrophages, and Osteoclasts in Osteosarcoma.

Macrophages appear to have a fundamental role in the pathogenesis of osteosarcoma. These highly diverse plastic cells are subdivided into classical or inflammatory macrophages known as M1 and alternative macrophages, which decrease inflammation and are reparative, called M2. Although primary and metastatic osteosarcomas are infiltrated with M2 macrophages, targeting the M1 macrophages with the immune adjuvant muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) has been the greatest recent therapeutic advance in osteosarcoma. This discrepancy between the presence of M2 and activation of M1 macrophages is intriguing and is likely explained either by the plasticity of M1 and M2 macrophages or nonclassical patrolling monocytes (PMos). To date, MTP-PE has been approved in combination with chemotherapy for nonmetastatic osteosarcoma, but its use in metastatic tumors has not been investigated. In this review, we focus on macrophages, monocytes, and osteoclasts, their role in osteosarcoma, and the potential for targeting these cells in this disease.

FOXM1 in sarcoma: role in cell cycle, pluripotency genes and stem cell pathways.

FOXM1 is a pro-proliferative transcription factor that promotes cell cycle progression at the G1-S, and G2-M transitions. It is activated by phosphorylation usually mediated by successive cyclin - cyclin dependent kinase complexes, and is highly expressed in sarcoma. p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21. Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.FOXM1 stimulates transcription of pluripotency related genes including SOX2, KLF4, OCT4, and NANOG many of which are important in sarcoma, a disorder of mesenchymal stem cell/ partially committed progenitor cells. In a selected specific, SOX2 is uniformly expressed in synovial sarcoma. Embryonic pathways preferentially used in stem cell such as Hippo, Hedgehog, and Wnt dominate in FOXM1 stoichiometry to alter rates of FOXM1 production or degradation. In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP). A complex involving YAP and the transcription factor TEAD elevates FOXM1 in these sarcoma subtypes. In another scenario 80% of desmoid tumors have nuclear localization of ß-catenin, the Wnt pathway effector molecule. Thiazole antibiotics inhibit FOXM1 and because they have an auto-regulator loop FOXM1 expression is also inhibited. Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.