Disruption of diabetes and hypertension care during the COVID-19 pandemic and recovery approaches in the Latin America and Caribbean region: a scoping review protocol.

INTRODUCTION: The COVID-19 pandemic significantly disrupted primary healthcare globally, with particular impacts on diabetes and hypertension care. This review will examine the impact of pandemic disruptions of diabetes and hypertension care services and the evidence for interventions to mitigate or reverse pandemic disruptions in the Latin America and Caribbean (LAC) region. METHODS AND ANALYSES: This scoping review will examine care delivery disruption and approaches for recovery of primary healthcare in the LAC region during the COVID-19 pandemic, focusing on diabetes and hypertension awareness, detection, treatment and control. Guided by Arksey and O'Malley's scoping review methodology framework, this protocol adheres to the Joanna Briggs Institute guidelines for scoping review protocols and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance for protocol development and scoping reviews. We searched MEDLINE, CINAHL, Global Health, Embase, Cochrane, Scopus, Web of Science and LILACS for peer-reviewed literature published from 2020 to 12 December 2022 in English, Spanish or Portuguese. Studies will be considered eligible if reporting data on pandemic disruptions to primary care services within LAC, or interventions implemented to mitigate or reverse pandemic disruptions globally. Studies on COVID-19 or acute care will be excluded. Two reviewers will independently screen each title/abstract for eligibility, screen full texts of titles/abstracts deemed relevant and extract data from eligible full-text publications. Conflicts will be resolved through discussion and with the help of a third reviewer. Appropriate analytical techniques will be employed to synthesise the data, for example, frequency counts and descriptive statistics. Quality will be assessed using the Newcastle Ottawa Quality Assessment Scale. ETHICS AND DISSEMINATION: No ethics approval was needed as this is a scoping review of published literature. Results will be disseminated in a report to the World Bank and the Pan American Health Organization, in peer-reviewed scientific journals, and at national and international conferences.

DPD deficiency in an Irish oncology centre: Prevalence and clinical implications.

INTRODUCTION: Fluorouracil (5FU) and capecitabine are metabolised by dihydropyrimidine dehydrogenase (DPD). Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine. In April 2020, the EMEA recommended patients undergo prospective screening for DPD deficiency before starting treatment, and this was introduced in our hospital. METHODS: We retrospectively reviewed records of all patients receiving 5FU/capecitabine in a tertiary Irish cancer centre from May 2020 to April 2021 (n = 197), and those starting first-line treatment in May 2019-April 2020 (n = 97). Our primary outcome was to estimate the prevalence of DPYD variant genes by prospective genotypic screening, with secondary outcomes including variant prevalence by prospective and reactive screening in patients receiving first-line treatment, and 5FU toxicity/tolerability in those with detected variants. RESULTS: In those treated 2020-2021, cancer subtypes included colorectal (n = 120, 61%), breast (n = 34, 17%), and biliary/pancreatic cancers (n = 21, 11%). Median patient age was 62 (range 25-86 years); 40% (n = 79) of patients were screened overall, with a prospective-screening deficiency prevalence of 6.8% (n = 3 of 44). Three patients had pathogenic DPYD-variants detected by prospective screening and tolerated treatment with 50% up-front dose reduction of 5FU, two had variants of uncertain significance detected by reactive screening. DISCUSSION: Other Irish studies estimated prevalence at 11-12%. As the number of variants detected was small, and screening rates were incomplete, our study may have underestimated prevalence. CONCLUSIONS: Approximately 6.8% of Irish patients may carry DPD deficiencies, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients.

Protocol Development for a Qualitative Methodological Study Within a Trial (Qual-SWAT): The KARMA-Dep-2 Trial.

Background: Despite methodological improvements in clinical trial design and conduct more generally, methodological limitations persist in trials concerning mental health care. A qualitative Study Within A Trial (Qual-SWAT), embedded in the KARMA-Dep-2 host trial, will be undertaken to explore and gain an understanding of two methodological questions in randomised trials specific to mental health care: (1) what are the key barriers and enablers of participation in randomised trials in mental health; and (2) how can randomised trials become part of routine mental health care. These issues will be examined from patient-participant and clinician- / researcher-participant perspectives, in alignment with PRioRiTy research themes. Methods: A descriptive qualitative study design will be used. Data will be collected via one-to-one semi-structured interviews, conducted via Microsoft Teams. The interview data will be analysed using Braun and Clarke's Thematic Analysis approach. One-to-one interviews will be conducted with three participant groups ( N = 30): 1) host trial patient-participants ( n = 10); 2) potentially eligible host trial patient-participants who refused enrolment in the host trial ( n = 10); and 3) clinician- / researcher-participants who are associated with work on the host trial ( n = 10). Ethics and dissemination: Ethical approval has been granted by St. Patrick's Mental Health Services Research Ethics Committee, Ireland (Ref: Protocol 09/20). When the study is completed, a report will be prepared and submitted to the Health Research Board (HRB). Findings will be shared with the host trial team and study participants, and submitted for publication. Host trial registration: ClinicalTrials.gov ( NCT04939649); EudraCT ( 2019-003109-92). Official title: Ketamine as an Adjunctive Therapy for Major Depression - A Randomised Controlled Trial: [KARMA-Dep (2)].

ExPeCT: a randomised trial examining the impact of exercise on quality of life in men with metastatic prostate cancer.

PURPOSE: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer. METHODS: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months. RESULTS: A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen's d = - 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1-3) and 67% (months 3-6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24). CONCLUSION: In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015.

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Dynamics of Electronically Excited Metal Atoms (Zn and Cd) in Rare Gas Matrices: Simulation of Multiple-band Emission using Molecular Dynamics with Quantum Transitions.

Molecular dynamics with quantum transitions approach is employed to simulate the spectroscopic characteristics of the 1 P1 ↔1 S0 transitions in atomic zinc and cadmium in order to gain insight into the excited state behavior of these atoms isolated in solid rare gases neon, argon, and krypton. The absorption and emission spectra are simulated. Non-radiative processes play a fundamental role in the transfer of population among the three electronic states initially accessed in absorption. Three distinct relaxation pathways were identified. Two of these are related to the dynamical modes described in previous works [McCaffrey and Kerins, J. Chem. Phys. 106, 7885 (1997); Kerins and McCaffrey, J. Chem. Phys. 109, 3131 (1998)] in which the system evolves to form a square planar configuration around the metal atom. The third distinct pathway involves motion on a hexagonal close packed plane. The temperature dependence of complex formation was also determined for the three relaxation pathways.

Analysis by region of outcomes for patients with advanced renal cell carcinoma treated with cabozantinib or everolimus: a sub-analysis of the METEOR study.

INTRODUCTION: METEOR was a phase 3 trial (NCT01865747) of cabozantinib versus everolimus in adults with advanced or metastatic clear cell RCC previously treated with VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs). This post hoc analysis of METEOR compared outcomes for patients recruited from European and non-European countries. MATERIAL AND METHODS: Adults with advanced/metastatic clear cell RCC who had received ≥ 1 prior VEGFR-TKI treatment were randomized 1:1 to receive cabozantinib or everolimus. Patients were categorized by recruitment region: Europe or outside of Europe (rest of world [RoW]). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs) were compared between regional subgroups. RESULTS: In total, there were 320 eligible patients from Europe (cabozantinib, 167; everolimus, 153) and 338 from RoW (North America, 240 patients; Asia-Pacific, 86; Latin America, 12; randomized as cabozantinib, 163; everolimus, 175). PFS and OS were longer with cabozantinib than with everolimus and similar for the Europe and RoW subgroups. For PFS, the hazard ratio (HR) for cabozantinib versus everolimus was 0.54 for the Europe subgroup (p < .001) and 0.50 for the RoW subgroup (p < .001). For OS, the HR was 0.75 for the Europe subgroup (p = .034) and 0.69 for the RoW subgroup (p = .006). ORR in the Europe subgroup was 15% for cabozantinib and 3.9% for everolimus (p < .001). For the RoW subgroup, ORR was 20% for cabozantinib and 2.9% for everolimus (p < .001). Incidence of grade 3/4 AEs were similar for the Europe (cabozantinib, 74%; everolimus, 58%) and RoW subgroups (cabozantinib, 69%; everolimus, 64%). CONCLUSION: In the METEOR trial, efficacy outcomes for patients recruited from European and non-European countries favored cabozantinib over everolimus. The efficacy and safety results for the regional subgroups were consistent with those of the overall METEOR population.

Health-Related Quality of Life in Metastatic, Hormone-Sensitive Prostate Cancer: ENZAMET (ANZUP 1304), an International, Randomized Phase III Trial Led by ANZUP.

PURPOSE: We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). METHODS: HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). RESULTS: HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9; P < .001), cognitive function (4.0, 95% CI, 2.5 to 5.5; P < .001), and physical function (2.6, 95% CI, 1.3 to 3.9; P < .001), but not OHQL (1.2, 95% CI, -0.2 to 2.7; P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17%; P < .0001), cognitive function (31% v 20%; P = .001), and physical function (31% v 22%; P < .001), but not fatigue (24% v 18%; P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. CONCLUSION: Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.

Characterization of Treatments and Disease Course for Women with Breast Cancer Brain Metastases: 5-Year Retrospective Single Institution Experience.

PURPOSE: Around 30% of patients with breast cancer will develop brain metastases (BM). We sought to characterize the disease course, treatments and outcome for our patient cohort. MATERIALS AND METHODS: We extracted clinicopathological data from electronic records from January 2015 to December 2020. Results were generated using SPSS statistics v27. RESULTS: We identified 98 patients. Median overall survival (OS) from BM diagnosis was 3 months [hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-], 8 months [HR+/HER2+], 7 months [HR-/HER2+] and 2 months [triple negative breast cancer (TNBC)]. Whole brain radiotherapy (WBRT) (n=48, 70%) was most frequently used followed by surgery (n=15, 22%) and stereotactic radiosurgery (n=6, 8%). In patients who received WBRT alone (n=40) the median OS post WBRT was 2.6 months. CONCLUSION: After BM development, half of the patients had systemic therapy and 70% had local therapy, but only the HER2 subgroup had a prolonged OS likely reflecting central nervous system (CNS) activity of anti-HER2 drugs. TNBC patients had the worst prognosis. Although our cohort is small, OS was >1 year for 60% of HER2+ patients who received trastuzumab emtansine after BM development, which is encouraging for antibody drug conjugates and CNS activity. Patients who received WBRT had a higher burden of CNS disease and had an OS of less than 3 months.

Radium-223 in combination with enzalutamide in metastatic castration-resistant prostate cancer: a multi-centre, phase II open-label study.

BACKGROUND: Radium-223 and enzalutamide are approved agents for patients with metastatic castration-resistant prostate cancer (mCRPC). Combining radium-223 and enzalutamide to improve outcomes is of clinical interest due to their differing modes of action and non-overlapping toxicity profiles. METHODS: This phase II study enrolled patients with mCRPC and bone metastases. Patients received six cycles of radium-223 in combination with enzalutamide, followed by enzalutamide alone. The primary endpoint was safety for the combination; secondary endpoints included radiographic/clinical progression-free survival (PFS), PSA PFS, overall survival (OS), change in alkaline phosphatase, patient-reported pain outcomes and skeletal related events. RESULTS: Forty-five patients received the combination treatment: 42 patients (93.3%) received all six cycles. Fourteen patients (31.1%) developed grade 3 or 4 toxicities, most commonly fatigue and neutropaenia. Fractures during the combination period occurred in four patients (8.9%). A further 13 patients (28.9%) developed fractures after completing combination treatment, giving a total of 17 patients (37.8%) who developed a fracture at any time on study. The median time to fracture was greater than 17.2 months [95% confidence interval (CI), 17.2-not estimable]. The median time to PSA progression was 18.1 months (95% CI, 12.68-22.60) and the median time to radiological/clinical progression was 28.0 months (95% CI, 22.54-not reached). At the primary analysis, 19 (42.2%) out of 45 patients had died with a median OS not reached (mean 34.8 months, standard error 1.4). CONCLUSION: In men with progressive mCRPC and bone metastases, the combination of radium-223 and enzalutamide was tolerable with the majority of patients completing the combination treatment. Bone fractures during the combination period were uncommon; however, we did identify a higher incidence of fractures occurring in patients after completing combination treatment. Bone health agents should be administered and bone health should be closely monitored following treatment with radium-223 and enzalutamide.

Circulating Tumour Cell Numbers Correlate with Platelet Count and Circulating Lymphocyte Subsets in Men with Advanced Prostate Cancer: Data from the ExPeCT Clinical Trial (CTRIAL-IE 15-21).

Interactions between circulating tumour cells (CTCs) and platelets are thought to inhibit natural killer(NK)-cell-induced lysis. We attempted to correlate CTC numbers in men with advanced prostate cancer with platelet counts and circulating lymphocyte numbers. Sixty-one ExPeCT trial participants, divided into overweight/obese and normal weight groups on the basis of a BMI ≥ 25 or <25, were randomized to participate or not in a six-month exercise programme. Blood samples at randomization, and at three and six months, were subjected to ScreenCell filtration, circulating platelet counts were obtained, and flow cytometry was performed on a subset of samples (n = 29). CTC count positively correlated with absolute total lymphocyte count (r2 = 0.1709, p = 0.0258) and NK-cell count (r2 = 0.49, p < 0.0001). There was also a positive correlation between platelet count and CTC count (r2 = 0.094, p = 0.0001). Correlation was also demonstrated within the overweight/obese group (n = 123, p < 0.0001), the non-exercise group (n = 79, p = 0.001) and blood draw samples lacking platelet cloaking (n = 128, p < 0.0001). By flow cytometry, blood samples from the exercise group (n = 15) had a higher proportion of CD3+ T-lymphocytes (p = 0.0003) and lower proportions of B-lymphocytes (p = 0.0264) and NK-cells (p = 0.015) than the non-exercise group (n = 14). These findings suggest that CTCs engage in complex interactions with the coagulation cascade and innate immune system during intravascular transit, and they present an attractive target for directed therapy at a vulnerable stage in metastasis.

Should isolated morbid obesity influence the decision to operate in hip and knee arthroplasty?

AIMS: We studied the outcomes of hip and knee arthroplasties in a high-volume arthroplasty centre to determine if patients with morbid obesity (BMI ≥ 40 kg/m2) had unacceptably worse outcomes as compared to those with BMI < 40 kg/m2. METHODS: In a two-year period, 4,711 patients had either total hip arthroplasty (THA; n = 2,370), total knee arthroplasty (TKA; n = 2,109), or unicompartmental knee arthroplasty (UKA; n = 232). Of these patients, 392 (8.3%) had morbid obesity. We compared duration of operation, anaesthetic time, length of stay (LOS), LOS > three days, out of hours attendance, emergency department attendance, readmission to hospital, return to theatre, and venous thromboembolism up to 90 days. Readmission for wound infection was recorded to one year. Oxford scores were recorded preoperatively and at one year postoperatively. RESULTS: On average, the morbidly obese had longer operating times (63 vs 58 minutes), longer anaesthetic times (31 vs 28 minutes), increased LOS (3.7 vs 3.5 days), and significantly more readmissions for wound infection (1.0% vs 0.3%). There were no statistically significant differences in either suspected or confirmed venous thromboembolism. Improvement in Oxford scores were equivalent. CONCLUSION: Although morbidly obese patients had less favourable outcomes, we do not feel that the magnitude of difference is clinically significant when applied to an individual, particularly when improvement in Oxford scores were unrelated to BMI. Cite this article: Bone Jt Open 2021;2(7):515-521.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Overall Survival of Men with Metachronous Metastatic Hormone-sensitive Prostate Cancer Treated with Enzalutamide and Androgen Deprivation Therapy.

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

BACKGROUND: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. METHODS: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. RESULTS: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. CONCLUSION: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Competing mortality risks: predicted cardiovascular disease risk versus predicted risk of breast cancer mortality in patients receiving adjuvant chemotherapy in a single Irish center.

BACKGROUND: Due to advances in care, most women diagnosed with breast cancer do not die from the disease itself. Instead, cardiovascular disease (CVD) remains the most frequent cause of death. Many breast cancer patients are older and have established CVD risk factors. They are at further risk due to exposure to anthracyclines, HER2 targeted agents, endocrine therapy and radiotherapy. In this study, we compared the 10-year predicted risk of breast cancer mortality versus that of cardiovascular (CV) morbidity/mortality in breast cancer patients receiving adjuvant chemotherapy using online predictive risk calculators. Furthermore, we evaluated the predicted outcome of CV risk factor optimisation on their overall CV risk. METHODS: This was a cross sectional study. All patients with resected Stage I-III breast cancer who received adjuvant chemotherapy at our centre from September 2015 to November 2016 were identified. Data recorded included demographics, tumor characteristics, treatments and CV risk factors. To calculate predicted 10-year risk of CVD and impact of lifestyle changes, we used the JBS3 (Joint British Society) online risk calculator. To calculate the predicted 10-year risk of breast cancer mortality, we used the PREDICT calculator. Biostatistical methods included Wilcoxon signed rank test for predicted CVD risk pre and post cardiovascular risk optimization. RESULTS: We identified 102 patients. Of this cohort, 76 patients were ≥ 50 years & 26 were < 50 years of age. The group had significant baseline cardiovascular risk factors: increased BMI (68 %, n = 70), ex-smoking (34 %, n = 35), current smoking (13 %, n = 13), hypertension (47 %, n = 47) and dyslipidemia (57 %). Of the total group, 48 % had a high (> 20 %) and 37 % had a moderate (10-20 %) 10-year predicted breast cancer mortality risk. Regarding 10-year predicted risk of CVD, 11 % and 22 % fell into the high (> 20 %) and moderate (10-20 %) risk categories, respectively. Assuming CV risk factor optimisation, there was a predicted improvement in median 10-year CV risk from 26.5 to 9.9 % (p = .005) in the high CVD risk group and from 14.0 to 6.6 % (p < .001) in the moderate CVD risk group. CONCLUSIONS: Benefits predicted with a CVD risk intervention model indicates that this should be incorporated into routine breast oncology care.

Virtual oncology clinics during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in radical changes in the delivery of healthcare worldwide. Our oncology service (at an Irish national cancer centre) rapidly transitioned to the use of telemedicine or virtual clinics (VC) to minimise potential risk of exposure to COVID-19 amongst an immunosuppressed, high-risk population. Our study aimed to evaluate the use of VC in this setting. METHODS: An 18-point questionnaire was designed to investigate the patient experience of VC during the COVID-19 pandemic in Ireland and compliance with guidelines developed in Ireland to conduct VC and the role of VC in the future. Questionnaires were distributed following the receipt of verbal consent from patients during the VC. Descriptive statistics were utilised for data analysis using SPSS®. RESULTS: One hundred and four patients returned completed surveys (n = 104/164, 63% response rate). Overall satisfaction levels were high with most patients (n = 58/100, 58%; no answer provided (NAP), n = 4) equally satisfied or nearly equally satisfied with VC in comparison to a usual clinic encounter. The majority of patients felt that there should be a role for VC in the future (n = 84/102, 82%; NAP, n = 2). The majority of patients (n = 61/99, 61%; NAP, n = 5) were very relieved to avoid a hospital visit due to perceived risk of potential exposure to COVID-19. CONCLUSION: The majority of oncology patients were satisfied with a VC encounter. VC may have a role in the future of medical care in Ireland post the COVID-19 pandemic.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: outcomes from a national centre in the current era.

BACKGROUND: Multimodal therapy incorporating cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival for selected patients with colorectal peritoneal metastases (CPMs). Many countries have centralised management of these patients, aiming to improve outcomes. There is ongoing debate on the need for and complications associated with HIPEC administration. We report indications and outcomes after CRS/HIPEC treated in a national centre in the modern era. METHODS: A retrospective review of all CPM patients who underwent CRS and HIPEC since the initiation of an Irish national program in 2013. The primary endpoint was the overall survival associated with CRS/HIPEC. RESULTS: During the study period (April 2013-June 2020), 123 patients proceeded to planned CRS/HIPEC for CPM. Median age was 58 (IQR 47-67) and 55 patients (44.7%) were male. In 65 patients (52.8%), CPM was synchronous. In 7/123 (5.8%), disease was unresectable. The median peritoneal cancer index (PCI) was 10 (IQR 5-17). Overall, 104/123 (84.5%) underwent a complete cytoreduction (CC0/CC1). Thirteen out of 123 (10.5%) patients also had a synchronous liver resection. Forty out of 123 (32.5%) patients had adverse pathological features (poorly differentiated or signet ring cells). The median survival in patients after CC0, CC1 and CC2/3 resection was 50, 18 and 11 months respectively (*p = < 0.0001, Log-rank Mantel-Cox). In total, 14/123(11.4%) had a major post-operative complication and 4/123 (3.3%) required re-operation. There was one (0.8%) post-operative death. The median length of stay was 14 days (IQR 9-19). CONCLUSION: This study reports encouraging outcomes in patients with CPM undergoing CRS and HIPEC, especially when complete cytoreduction is achieved.

A Multicenter Retrospective Review of Systemic Anti-Cancer Treatment and Palliative Care Provided to Solid Tumor Oncology Patients in the 12 Weeks Preceding Death in Ireland.

BACKGROUND: Systemic anti-cancer treatment (SACT) can improve symptoms and survival in patients with incurable cancer but there may be harmful consequences. Information regarding the use of SACT at the end-of-life and its impact on patients has not been described in Ireland. AIMS: The study aimed to quantify and describe the use of SACT at end-of-life. The primary outcome of interest was the number of patients who received treatment in the last 12, 4 and 2 weeks of life. Secondary outcomes included the frequency of admissions and procedures, location of death, and timing of specialist palliative care (SPC) referral. METHODS: Retrospective review. Fisher exact testing was used for analyses. Patients were included if they died between January 2015 and July 2017 and received at least 1 dose of treatment for a solid tumor malignancy. RESULTS: Five hundred and eighty two patients were included. Three hundred and thirty eight (58%), 128 (22%) and 36 (6%) received treatment in the last 12, 4 and 2 weeks of life respectively. Patients who received chemotherapy in the last 12 weeks of life were more likely to be admitted to hospital, undergo a procedure, and die in hospital than those who did not (P < 0.001 for all). Median time of SPC referral before death was shorter in those patients who received chemotherapy than those who did not (61 v129 days, p = 0.0001). CONCLUSION: Patients who received chemotherapy had a higher likelihood of hospital admission, invasive procedure, and in-hospital death. They were less likely to have been referred early to SPC services.

Platelet cloaking of circulating tumour cells in patients with metastatic prostate cancer: Results from ExPeCT, a randomised controlled trial.

BACKGROUND: Circulating tumour cells (CTCs) represent a morphologically distinct subset of cancer cells, which aid the metastatic spread. The ExPeCT trial aimed to examine the effectiveness of a structured exercise programme in modulating levels of CTCs and platelet cloaking in patients with metastatic prostate cancer. METHODS: Participants (n = 61) were randomised into either standard care (control) or exercise arms. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analysed for the presence of CTCs, CTC clusters and platelet cloaking. CTC data was correlated with clinico-pathological information. RESULTS: Changes in CTC number were observed within group over time, however no significant difference in CTC number was observed between groups over time. Platelet cloaking was identified in 29.5% of participants. A positive correlation between CTC number and white cell count (WCC) was observed (p = 0.0001), in addition to a positive relationship between CTC clusters and PSA levels (p = 0.0393). CONCLUSION: The presence of platelet cloaking has been observed in this patient population for the first time, in addition to a significant correlation between CTC number and WCC. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT02453139.