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To better understand how to support UK breast surgeons in clinical trial participation and recruitment, the Association of Breast Surgery (ABS) Academic and Research (A&R) Committee surveyed the ABS membership on the challenges and barriers surrounding the recruitment of patients to breast cancer clinical trials. Improving patient outcomes depends on better engagement with clinical research. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: To examine the hospital management of unstable angina (UAP) in 1996 and 1998, according to patient demographic variables and disease severity. DESIGN: Medical record review. SETTING: 37 hospitals across New South Wales, Australia, representative of the secondary and tertiary care hospitals in the State. PARTICIPANTS: All patients (or a random sample of patients) with UAP admitted to these hospitals during five months in 1996 and six months in 1998 (1872 and 1368 patients respectively). MAIN RESULTS: In the two years between 1996 and 1998, there was an increase in the use of beta blockers and a corresponding decrease in the use of calcium channel blockers, as well as a decrease in the use of intravenous nitrates. Those aged 75 or more were roughly half as likely as those aged less than 65 to be prescribed heparin, aspirin and heparin, beta blockers, intravenous nitrates, and only one third as likely to be offered coronary angiography in hospital. They were one and a half times as likely to be prescribed calcium channel blockers compared with the youngest age group. A similar pattern was seen for gender, where men were more likely than women to be given aspirin, aspirin and heparin, and coronary angiography, and less likely to be given calcium channel blockers. Those with a past history were less likely, and those with more severe disease were more likely than others to be given most interventions. CONCLUSIONS: In view of the low use of evidence-based management of UAP among women and the elderly, it would seem appropriate for disease management guidelines to target these groups. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In diabetes haptoglobin (Hp) 2 vs Hp 1 allelic product is associated with cardiac and renal complications. Few studies report both Hp phenotype and Hp levels. In a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial substudy we evaluated the Hp phenotype, Hp levels, and fenofibrate effects., Materials and Methods: In 480 adults with type 2 diabetes (T2D) the Hp phenotype was assessed and the Hp level quantified (both using ELISAs assays) in plasma from baseline, after 6 weeks of fenofibrate, and (in n = 200) at 2 years post-randomization to fenofibrate or placebo., Results: The Hp phenotypes 1-1, 2-1, and 2-2 frequencies were 15%, 49%, and 36%, respectively. Baseline Hp levels differed by phenotype (P < 0.0001) and decreased (median 21%) after 6 weeks fenofibrate in all phenotypes (adjusted mean (95% CI): -0.27 (-0.32, -0.23) mg/mL in Hp 1-1, -0.29 (-0.31, -0.27) mg/mL in Hp 2-1 and -0.05 (-0.07, -0.02) mg/mL in Hp 2-2 (P = 0.005 and P = 0.055 vs Hp 1-1 and Hp 2-1, respectively)). At 2 years post-randomization the Hp levels in the placebo group had returned to baseline, whilst the fenofibrate-group levels remained similar to the 6 week levels., Conclusions: In type 2 diabetes, Hp levels differ by Hp phenotype and are decreased by fenofibrate in all phenotypes, but the effect is diminished in Hp 2-2., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Chest wall perforator flaps are emerging in oncoplastic breast conservation, mostly as an alternative to mastectomy. However, standardization and consensus on patient selection, techniques, and outcomes have not yet been reached. The aim of this international multicentre collaborative study was to explore practice patterns and outcomes in high-volume centres from different countries., Methods: Patients with both pre-invasive and invasive breast cancer treated at the Uppsala University Hospital in Uppsala, Sweden, the Royal Marsden Hospital in London, UK, and the Westmead Breast Cancer Institute in Sydney, Australia, were included in this study. The rationale for offering chest wall perforator flaps and surgical outcomes were prospectively documented., Results: In total, 603 patients were analysed median age of 54 (interquartile range (i.q.r.) 48-63) years, median BMI of 25.0 (i.q.r. 22.5-28.1) kg/m2, median tumour extent of 30 (IQR 19-45) mm, median breast volume of 280 (i.q.r. 216-430) ml, and median calculated resection ratio of 16% (i.q.r. 9%-28%). In 67.7%, the treating surgeon had offered chest wall perforator flaps to avoid mastectomy. The procedure was performed as day surgery in 69.5% of patients, with an overall complication rate of 8.6% and the majority of complications being classified as Clavien-Dindo grade I (5.3% of patients). The re-excision rate was 15.9%, with only 1.5% of patients converting to a mastectomy. There were no flap losses. At a median follow-up of 22 (range 12 to 98) months, rates of local recurrence, distant recurrence, and breast cancer-related mortality were 1.9%, 4.9%, and 1.7% respectively., Conclusion: Chest wall perforator flaps are a useful option to allow more women to avoid mastectomy. In experienced hands, the procedure is safe and should be offered to suitable patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: In Western countries, the current standard of care for resectable gastric cancer is perioperative chemotherapy. Preoperative chemoradiotherapy has been considered, but data are limited regarding this treatment as compared with perioperative chemotherapy alone., Methods: We conducted an international, phase 3 trial in which patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive preoperative chemoradiotherapy plus perioperative chemotherapy or perioperative chemotherapy alone (control). In both groups, patients received either epirubicin, cisplatin, and fluorouracil or fluorouracil, leucovorin, oxaliplatin, and docetaxel both before and after surgery; the preoperative-chemoradiotherapy group also received chemoradiotherapy (45 Gy in 25 fractions of radiation, plus fluorouracil infusion). The primary end point was overall survival, and secondary end points included progression-free survival, pathological complete response, toxic effects, and quality of life., Results: A total of 574 patients underwent randomization at 70 sites in Australasia, Canada, and Europe: 286 to the preoperative-chemoradiotherapy group and 288 to the perioperative-chemotherapy group. A higher percentage of patients in the preoperative-chemoradiotherapy group than in the perioperative-chemotherapy group had a pathological complete response (17% vs. 8%) and greater tumor downstaging after resection. At a median follow-up of 67 months, no significant between-group differences in overall survival or progression-free survival were noted. The median overall survival was 46 months with preoperative chemoradiotherapy and 49 months with perioperative chemotherapy (hazard ratio for death, 1.05; 95% confidence interval, 0.83 to 1.31), and the median progression-free survival was 31 months and 32 months, respectively. Treatment-related toxic effects were similar in the two groups., Conclusions: The addition of preoperative chemoradiotherapy to perioperative chemotherapy did not improve overall survival as compared with perioperative chemotherapy alone among patients with resectable gastric and gastroesophageal junction adenocarcinoma. (Funded by the National Health and Medical Research Council and others; TOPGEAR ClinicalTrials.gov number, NCT01924819.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: To describe the baseline symptom burden(SB) experienced by patients(pts) with recurrent ovarian cancer(ROC) prior and associations with progression free survival (PFS) and overall survival (OS)., Methods: We analysed baseline SB reported by pts. with platinum resistant/refractory ROC (PRR-ROC) or potentially‑platinum sensitive ROC receiving their third or greater line of chemotherapy (PPS-ROC≥3) enrolled in the Gynecologic Cancer InterGroup - Symptom Benefit Study (GCIG-SBS) using the Measure of Ovarian Symptoms and Treatment concerns (MOST). The severity of baseline symptoms was correlated with PFS and OS., Results: The 948 pts. reported substantial baseline SB. Almost 80% reported mild to severe pain, and 75% abdominal symptoms. Shortness of breath was reported by 60% and 90% reported fatigue. About 50% reported moderate to severe anxiety, and 35% moderate to severe depression. Most (89%) reported 1 or more symptoms as moderate or severe, 59% scored 6 or more symptoms moderate or severe, and 46% scored 9 or more symptoms as moderate or severe. Higher SB was associated with significantly shortened PFS and OS; five symptoms had OS hazard ratios larger than 2 for both moderate and severe symptom cut-offs (trouble eating, vomiting, indigestion, loss of appetite, and nausea; p < 0.001)., Conclusion: Pts with ROC reported high SB prior to starting palliative chemotherapy, similar among PRR-ROC and PPS-ROC≥3. High SB was strongly associated with early progression and death. SB should be actively managed and used to stratify patients in clinical trials. Clinical trials should measure and report symptom burden and the impact of treatment on symptom control., Competing Interests: Conflict of interest statement FR acknowledges travel grant from Pfizer. Y-CL acknowledges institutional research grant from Beigene, honoraria from Astra Zeneca for educational event and received honoraria from GSK for participation in advisory board. MF acknowledges institutional grants from Astra Zeneca, Beigene, Novartis; received honoraria from Astra Zeneca, GSK, MSD; consulting fees from Astra Zeneca, Novartis, GSK, Incyclix. JL acknowledges grants from Astra Zeneca, MSD/Merck; advisory board for Astra Zeneca, Clovis Oncology, GSK, Artios Pharma, MSD/Merck, VBL Therapeutics, BMS, Nuvation, Ellipses, Immagene, Incyte, Immunogen; educational events for Astra Zeneca, MSD/Merck, GSK, Eisai, Neopharm, and data safety monitoring board for Mersana. AO acknowledges data safety monitoring board for Morphosys, Astra Zeneca, BMS, and uncompensated leadership role for Ozmosis Research where he is CEO and Board member. FH acknowledges grants from GSK, Astra Zeneca, MSD, PharmaMar, Immunogen, consulting fees from Immunogen, MSD, Astra Zeneca; honoraria from GSK, Astra Zeneca, MSD, Pharma Mar; and has been on data safety monitoring boards for MSD, GSK and Astra Zeneca. JB acknowledges grants from Tesaro, Eisai, Immunogen, Karyopharm. MS acknowledges institutional grants from Astellas, Amgen, Astra Zeneca, Bionomics, BMS, Celgene, Medivation, Merck, Sharp and Dohme, Pfizer, Roche and Sanofi. MK, RO, EA-L, FJ, M-CK, YY, DB and AL declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome., Methods: The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors., Discussion: This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies., Competing Interests: SMcI reports honoraria from MSD, Roche, BD and Lilly, conference travel and support from Roche and Lilly, and institutional research funding from Novartis. RIC declares institutional research support from SECA and Astra Zeneca. EC reports honorarium from AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche, Conference fees/travel/accommodation: Roche, Novartis, and Educational grant: Daiichi-Sankyo and Research support: SECA, AstraZeneca. All other authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon type of non-Hodgkin lymphoma, associated with breast implant capsules. Despite improvements in our understanding of BIA-ALCL, communicating the prognosis to patients remains challenging due to limited long-term follow-up data. This has important implications for decision-making, including recommendations for subsequent reconstructive procedures. The aim of this study was to assess the longer-term oncological outcomes of patients receiving multidisciplinary treatment for BIA-ALCL., Methods: This was a retrospective cohort study of BIA-ALCL patients treated at a tertiary referral unit. The data are presented using simple descriptive statistics., Results: Between 2015 and 2022, 18 BIA-ALCL patients were treated at our institution. The median age at diagnosis was 48.5 (IQR 41-55) years. Ten patients developed BIA-ALCL after cosmetic breast augmentation, and 8 after breast reconstruction following mastectomy for cancer. All patients had a history of textured implant insertion. The median time from first implant surgery to diagnosis was 8.5 (IQR 7-12) years. All patients underwent en-bloc total capsulectomy with implant removal, and 2 received systemic therapy. Fifteen patients had Stage I (IA-IC) disease, 2 had Stage IIA and 1 Stage III BIA-ALCL, based on the TNM classification system. At a median follow-up of 45 (IQR 15-71) months, there were no episodes of local or systemic relapse or death., Conclusions: Surgical management for BIA-ALCL is sufficient in early-stage disease, and associated with excellent oncological outcomes. This information is reassuring for patients when discussing recurrence risk., (© 2023. Society of Surgical Oncology.)

Aims: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility., Materials and Methods: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures., Results: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04)., Conclusions: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Background: Observational studies have consistently found a link between low serum 25-hydroxyvitamin D concentration and higher risk of cognitive impairment. Results from randomized controlled trials have been mixed, and few have been conducted in the general population., Methods: We recruited 21,315 community-dwelling Australians aged between 60 and 84 years to participate in the D-Health Trial, a randomized, double-blind, placebo-controlled trial. The intervention was monthly oral doses of 60,000 international units of vitamin D or placebo for 5 years. We assessed cognitive function in a randomly sampled group of participants aged ≥70 years using the Telephone Interview for Cognitive Status (TICS) at 2 and 5 years after randomization. The primary outcome for this analysis was TICS score; the secondary outcome was the proportion of people who had cognitive impairment (defined as TICS score ≤25). We analyzed data using mixed models (linear and logistic)., Results: We interviewed 3887 participants at year 2 and 3614 participants at year 5. The mean TICS score at these time points was 32.3 and 32.2, respectively. Vitamin D supplementation did not affect cognitive function as measured by TICS score (mean difference between vitamin D and placebo groups 0.04; 95% CI -0.14 to 0.23), or alter risk of cognitive impairment (odds ratio 1.00; 95% CI 0.75 to 1.33)., Conclusions: Monthly bolus doses of vitamin D supplementation neither enhanced nor hindered cognitive function among older adults. Population-wide vitamin D supplementation of older adults that are largely vitamin D replete is unlikely to substantially benefit cognition., (© 2023 The American Geriatrics Society.)

Background: Low serum 25-hydroxy vitamin D concentration is associated with increased fracture risk. It is uncertain whether vitamin D supplementation reduces fractures, or whether intermittent doses are harmful. We aimed to investigate if supplementing adults living in Australia with monthly doses of 60 000 international units (IU) vitamin D 3 for 5 years or less altered the rate of fractures., Methods: We did a population-based, double-blind, randomised, placebo-controlled trial of oral vitamin D 3 supplementation (60 000 IU per month) for up to 5 years in adults aged 60-84 years living in Australia. We randomly assigned (1:1) 21 315 participants to either vitamin D or placebo. We ascertained fractures through linkage with administrative datasets. The main outcome was total fractures. Additional outcomes were non-vertebral, major osteoporotic (hip, wrist, proximal humerus, and spine), and hip fractures. We excluded participants (989 [4·6%]) without linked data, and estimated hazard ratios (HRs) and 95% CIs using flexible parametric survival models. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763, and the trial intervention ended in February, 2020., Findings: Between Feb 14, 2014, and June 17, 2015, we recruited 21 315 participants. For the current analysis, we included 20 326 participants (vitamin D 10 154 [50·0%]; placebo 10 172 [50·0%]). 9295 (45·7%) of 20 326 participants were women and the mean age was 69·3 years (SD 5·5). Over a median follow-up of 5·1 years (IQR 5·1-5·1), 568 (5·6%) participants in the vitamin D group and 603 (5·9%) in the placebo group had one or more fractures. There was no effect on fracture risk overall (HR 0·94 [95% CI 0·84-1·06]), and the interaction between randomisation group and time was not significant (p=0·14). However, the HR for total fractures appeared to decrease with increasing follow-up time. The overall HRs for non-vertebral, major osteoporotic, and hip fractures were 0·96 (95% CI 0·85-1·08), 1·00 (0·85-1·18), and 1·11 (0·86-1·45), respectively., Interpretation: These findings do not support concerns that bolus doses of vitamin D administered monthly increase fracture risk. Long-term supplementation might reduce the incidence of total fractures, but additional research is needed to clarify this effect., Funding: Australian National Health and Medical Research Council., Competing Interests: Declaration of interests PMW has funding from AstraZeneca for an unrelated study of ovarian cancer and funding from the National Health and Medical Research Council (NHMRC). PRE reports grants and speaker fees from Amgen, grants from Sanofi, grants from Alexion, and a grant from the NHMRC. PRE is past-president and a councilor (unpaid) of the American Society for Bone and Mineral Research, a board member (unpaid) of the International Osteoporosis Foundation, and chair of the board of directors (unpaid) of Health Bones Australia. REN has funding from Viatris for an unrelated study of pancreatic cancer, has received speaker fees and travels cost from Viatris to speak at the Australasian Gastrointestinal Trials Group annual meeting, and has grant payments from the NHMRC paid to QIMR Berghofer Medical Research Institute. REN is leader of one of the working groups of the Environmental Effects Assessment Panel (unpaid) of the UN Environment Program. DE reports funding from the NHMRC, paid to QIMR Berghofer Medical Research Institute. DCW reports funding from the NHMRC, paid to QIMR Berghofer Medical Research Institute, and speaker fees from Pierre Fabre Australia for the 2020 COSA Conference. DCW is also an unpaid director for a not-for-profit research institute (Sax Institute). MK is a board director of the Skin Cancer College Australasia, and a board director of Melanoma and Skin Cancer Trials Limited. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: De-escalation of axillary surgery for lymph node (LN) positive breast cancer is facilitated by marking involved nodes which, when removed with sentinel nodes constitute risk-adapted targeted axillary dissection (TAD). Whether after chemotherapy or for primary surgery, selected patients with biopsy-proven involvement of nodes may be eligible for axillary conservation. Likewise, impalpable recurrence or stage 4 patients with localised axillary disease may benefit. In these contexts, several devices are used to mark biopsied nodes to facilitate their accurate surgical removal. We report our experience using the paramagnetic MAGSEED (Endomag®, Cambridge, UK)., Methods: Local approval (BR2021&#95;149) was obtained to interrogate a prospective database of all axillary markers. The primary endpoint was successful removal of the marked LN., Results: Of 241 markers (in 221 patients) inserted between October 2018 and July 2022, all were retrieved. Of 74 patients who had Magseeds® inserted after completion of NACT (involved nodes initially marked using an UltraCor™Twirl™ marker), the Magseeds® were found outside the node in neighbouring axillary tissue in 18 (24.3%) patients. When Magseeds® were placed at commencement of NACT in 54 patients, in only 1 (1.8%) was the marker found outside the node - a statistically significantly lower rate (Chi 2 10.7581 p = 0.001038). For 'primary TAD' patients and those localised for recurrent or stage IV disease, all 93 had the Magseed® found within the biopsied node., Conclusion: This series supports our axillary nodal marking technique as safe and reliable. For TAD following NACT, placement at the start of treatment led to a significantly higher localisation rate., Competing Interests: Conflicts of interest statements Peter A Barry: Speaker on panel for Endomag satellite symposium at ASBrS scientific meeting, USA April 2022 (no honoraria received from Endomag in relation to this study). Kathryn Harborough no COI, Victoria Sinnett: no COI, Anna Heeney: no COI, Edward Robert St John: Is co-founder and chief medical officer at Concentric Health ltd, Cardiff. This is not related to the current study submitted., Basrull Bhaludin: no COI, Kate Downey no COI, Romney Pope no COI, Rachel Louise O'Connell: no COI, Marios Tasoulis no COI, Fiona MacNeill no COI, Jennifer E Rusby: no COI, Gerald Gui no COI. Aikaterina Micha no COI, Samantha Chen no COI, Katherine Dorothy Claudia Krupa: no COI., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Introduction: The optimal combination of radiotherapy and breast reconstruction has not yet been defined. Post-mastectomy radiotherapy (PMRT) has deleterious effects on breast reconstruction, leading to caution amongst surgeons. Pre-operative radiotherapy (PRT) is a growing area of interest, is demonstrated to be safe, and spares autologous flaps from radiotherapy. This study evaluates the aesthetic outcome of PRT and deep inferior epigastric artery perforator (DIEP) flap reconstruction within the Pre-operative Radiotherapy And Deep Inferior Epigastric artery Perforator (DIEP) flAp (PRADA) cohort., Methods: PRADA was an observational cohort study designed to evaluate the feasibility and safety of PRT for women undergoing neoadjuvant chemotherapy and DIEP reconstruction. Panel evaluation of 3D surface images (3D-SIs) and patient-reported outcome measures (BREAST-Q) for a subset of women in the study were compared with those of a DIEP-PMRT cohort who had undergone DIEP reconstruction and PMRT., Results: Seventeen out of 33 women from the PRADA study participated in this planned substudy. Twenty-eight women formed the DIEP-PMRT cohort (median follow-up 23 months). The median (inter-quartile range [IQR]) 'satisfaction with breasts' score at 12 months for the PRADA cohort was significantly better than the DIEP-PMRT cohort (77 [72-87] versus 64 [54-71], respectively), p=0.01). Median [IQR] panel evaluation (5-point scale) was also significantly better for the PRADA cohort than for the DIEP-PMRT cohort (4.3 [3.9-4.6] versus 3.6 [2.8-4] p=0.003)., Conclusions: Aesthetic outcome for the PRADA cohort was reported to be 'good' or 'excellent' in 93% of cases using a bespoke panel assessment with robust methodology. Patient satisfaction at one year is encouraging and superior to DIEP-PMRT at 23 months. Switching surgery-radiotherapy sequencing leads to similar breast aesthetic outcomes and warrants further large-scale, multi-centre evaluation in a randomised trial., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Purpose: Observational studies suggest that higher serum 25-hydroxy vitamin D (25(OH)D) concentration may be associated with lower risk of cataract. However, no randomized controlled trials have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery., Design: We conducted an ancillary study of the D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D conducted from 2014 through 2020 within the Australian general population., Participants: We invited 421 207 men and women 60 to 84 years of age to participate; including an additional 1896 volunteers, 40 824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis or those who were taking more than 500 international units (IU) supplemental vitamin D per day were excluded. A total of 21 315 were randomized, and 1390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months), leaving 19 925 included. The median follow-up was 5 years., Methods: Participants took 60 000 IU of vitamin D 3 (n = 10 662) or placebo (n = 10 653) orally once per month for a maximum of 5 years., Main Outcome Measures: The primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data., Results: Among 19 925 participants eligible for this analysis (mean age, 69.3 years; 46% women) 3668 participants (18.4%) underwent cataract surgery during follow-up (vitamin D: n = 1841 [18.5%]; placebo: n = 1827 [18.3%] ). The incidence of cataract surgery was similar between the two groups (incidence rate, 41.6 and 41.1 per 1000 person-years in the vitamin D and placebo groups, respectively; hazard ratio, 1.02; 95% confidence interval, 0.95-1.09). In prespecified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25(OH)D concentration, or ambient ultraviolet radiation., Conclusions: Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that vitamin D influences the immune system. Recent studies indicate that vitamin D supplementation may reduce the severity of infections, but this has not been confirmed., Objectives: The objective of this study was to assess the effect of vitamin D supplementation on hospitalization for infection., Methods: The D-Health Trial was a randomized, double-blind, placebo-controlled trial of monthly 60,000 international units of vitamin D 3 for 5 y among 21,315 Australians aged 60-84 y. Hospitalization for infection, ascertained through linkage with hospital admitted patient data, is a tertiary outcome of the trial. The primary outcome for this post-hoc analysis was hospitalization for any infection. Secondary outcomes were extended hospitalization for infection (length of stay >3 d and >6 d) and hospitalization for respiratory tract, skin, and gastrointestinal infections. We used negative binomial regression to estimate the effect of vitamin D supplementation on outcomes., Results: Participants (46% women, mean age: 69 y), were followed up for a median of 5 y. Vitamin D supplementation had little or no effect on the incidence of hospitalization for any infection [incidence rate ratio (IRR): 0.95; 95% CI: 0.86, 1.05], respiratory tract (IRR: 0.93; 95% CI: 0.81, 1.08), skin (IRR: 0.95; 95% CI: 0.76, 1.20), gastrointestinal infections (IRR: 1.03; 95% CI: 0.84, 1.26), or hospitalizations lasting >3 d (IRR: 0.94; 95% CI: 0.81, 1.09), with all CIs consistent with a null finding. People supplemented with vitamin D had fewer hospitalizations lasting >6 d (IRR: 0.80; 95% CI: 0.65, 0.99)., Conclusions: We did not find a protective effect of vitamin D on hospitalization for infection, but it reduced the number of extended hospitalizations. In populations where few people are vitamin D deficient, the effect of population-wide supplementation is likely to be small, but these findings support previous studies suggesting that vitamin D plays a role in infectious disease. The D-Health Trial is registered at the Australian New Zealand Clinical Trials Registry as ACTRN12613000743763., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Observational studies suggest a link between vitamin D and the composition of the gut microbiome, but there is little evidence from randomized controlled trials of vitamin D supplementation. We analyzed data from the D-Health Trial, a randomized, double-blind, placebo-controlled trial. We recruited 21,315 Australians aged 60-84 y and randomized them to 60,000 IU of vitamin D 3 or placebo monthly for 5 y. Stool samples were collected from a sample of 835 participants (417 in the placebo and 418 in the vitamin D group) approximately 5 y after randomization. We characterized the gut microbiome using 16S rRNA gene sequencing. We used linear regression to compare alpha diversity indices (i.e. Shannon index (primary outcome), richness, inverse Simpson index), and the ratio of Firmicutes to Bacteroidetes between the two groups. We analyzed between-sample (beta) diversity (i.e. Bray Curtis distance and UniFrac index) using principal coordinate analysis and used PERMANOVA to test for significant clustering according to randomization group. We also assessed the difference in the abundance of the 20 most abundant genera between the two groups using negative binomial regression model with adjustment for multiple testing. Approximately half the participants included in this analysis were women (mean age 69.4 y). Vitamin D supplementation did not alter the Shannon diversity index (mean 3.51 versus 3.52 in the placebo and vitamin D groups, respectively, p  = 0.50). Similarly, there was little difference between the groups for other alpha diversity indices, the abundance of different genera, and the Firmicutes-to-Bacteroidetes ratio. We did not observe clustering of bacterial communities according to randomization group. In conlusion, monthly doses of 60,000 IU of vitamin D supplementation for 5 y did not alter the composition of the gut microbiome in older Australians.

Background: Bony morphology is central to the pathomechanism of femoroacetabular impingement syndrome (FAIS), however isolated radiographic measures poorly predict symptom onset and severity. More comprehensive morphology measurement considered together with patient factors may better predict symptom presentation. This study aimed to determine the morphological parameter(s) and patient factor(s) associated with symptom age of onset and severity in FAIS., Methods: 99 participants (age 32.9 ± 10.5 years; body mass index (BMI 24.3 ± 3.1 kg/m 2 ; 42% females) diagnosed with FAIS received standardised plain radiographs and magnetic resonance scans. Alpha angle in four radial planes (superior to anterior), acetabular version (AV), femoral torsion, lateral centre-edge, anterior centre-edge (ACEA) and femoral neck-shaft angles were measured. Age of symptom onset (age at presentation minus duration of symptoms), international Hip Outcome Tool-33 (iHOT-33) and modified UCLA activity scores were recorded. Backward stepwise regression assessed morphological parameters and patient factors (age, sex, BMI, symptom duration, annual income, private/public healthcare system accessed) to determine variables independently associated with onset age and iHOT-33 score., Results: Earlier symptom onset was associated with larger superoanterior alpha angle ( p  = 0.007), smaller AV ( p  = 0.023), lower BMI ( p  = 0.010) and public healthcare system access ( p  = 0.041) (r 2  = 0.320). Worse iHOT-33 score was associated with smaller ACEA ( p  = 0.034), female sex ( p  = 0.040), worse modified UCLA activity score ( p  = 0.010) and public healthcare system access ( p  < 0.001) (r 2  = 0.340)., Conclusions: Age of symptom onset was chiefly predicted by femoral and acetabular bony morphology measures, whereas symptom severity predominantly by patient factors. Factors measured explained a small amount of variance in the data; additional unmeasured factors may be more influential.

Objectives: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio)., Design, Setting, Participants, and Intervention: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation., Results: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration., Conclusion: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length., Competing Interests: PM Webb has funding from Astra Zeneca for an unrelated study of ovarian cancer. PR Ebeling reports grants and other from Amgen, other from Sanofi, grants and other from Novartis, grants from Eli-Lilly, and grants from Alexion. RE Neale has funding from Viatris for an unrelated study of pancreatic cancer. All other authors declare no competing interests.

Objectives: To investigate whether vitamin D supplementation reduces depressive symptoms and incidence of antidepressant use., Methods: We used data from the D-Health Trial (N = 21,315), a randomized double-blind placebo-controlled trial of monthly vitamin D 3 for the prevention of all-cause mortality. Participants were Australians aged 60-84 years. Participants completed the Patient Health Questionnaire (PHQ-9) at 1, 2 and 5 years after randomization to measure depressive symptoms; national prescribing records were used to capture antidepressant use. We used mixed models and survival models., Results: Analyses of PHQ-9 scores included 20,487 participants (mean age 69·3 years, 46% women); the mean difference (MD) in PHQ-9 score (vitamin D vs. placebo) was 0·02 (95% CI -0·06, 0·11). There was negligible difference in the prevalence of clinically relevant depression (PHQ-9 score ≥10) (odds ratio 0·99; 95% CI 0·90, 1·08). We included 16,670 participants in the analyses of incident antidepressant use (mean age 69·4 years, 43% women). Incidence of antidepressant use was similar between the groups (hazard ratio [HR] 1·04; 95% CI 0·96, 1·12). In subgroup analyses, vitamin D improved PHQ-9 scores in those taking antidepressants at baseline (MD -0·25; 95% CI -0·49, -0·01; p-interaction = 0·02). It decreased risk of antidepressant use in participants with predicted 25(OH)D concentration <50 nmol/L (HR 0·88; 95% CI 0·75, 1·02; p-interaction = 0·01) and increased risk in those with predicted 25(OH)D ≥ 50 nmol/L (HR 1·10; 95% CI 1·01, 1·20)., Conclusion: Monthly supplementation with high-dose vitamin D 3 was not of benefit for measures of depression overall, but there was some evidence of benefit in subgroup analyses., Clinical Trial Registration: The trial is registered on the Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/., (© 2022 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background: Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection., Methods: The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21 315 Australians aged 60-84 years were randomized to 60 000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions, repeat prescription episodes, and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression., Results: Vitamin D supplementation slightly reduced the number of prescription episodes (IRR, 0.98; 95% confidence interval [CI], .95-1.01), total prescriptions (IRR, 0.97; 95% CI, .93-1.00), and repeat prescription episodes (IRR, 0.96; 95% CI, .93-1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR, 0.93; 95% CI, .87-.99)., Conclusions: Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system., Clinical Trials Registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/., Competing Interests: Potential conflicts of interest. R. E. N. has received funding from Viatris for an unrelated study of pancreatic cancer. P. M. W. has received funding from Astra Zeneca for an unrelated study of ovarian cancer. P. R. E. reports grants from Amgen, grants from Sanofi, and grants from Alexion. All other authors declare no potential conflicts of interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Incidence of bilateral risk-reducing mastectomies (RRMs) is increasing. The aim of this study was to compare satisfaction, aesthetic and oncological outcomes in women undergoing RRM with implant-based reconstruction comparing nipple-sparing mastectomy (NSM) with skin-sparing mastectomy (SSM) (sacrificing the nipple +/− nipple reconstruction). Women who had undergone bilateral RRM between 1997 and 2016 were invited. Aesthetic outcome and nipple symmetry were evaluated using standardized anthropometric measurements. The oncological outcome was assessed at last documented follow up. Ninety-three women (186 breasts) participated, 60 (64.5%) had NSM, 33 (35.5%) SSM. Median time between surgery and participation was 98.4 months (IQR: 61.7−133.9). Of the women, 23/33 (69.7%) who had SSM underwent nipple reconstruction. Nipple projection was shorter in the reconstructed SSM group than the maintained NSM group (p < 0.001). There was no significant difference in overall symmetry (p = 0.670), satisfaction regarding nipple preservation (p = 0.257) or overall nipple satisfaction (p = 0.074). There were no diagnoses of breast cancer at a median follow up of 129 months (IQR: 65−160.6). Women who undergo nipple-sparing RRM maintain long-term nipple symmetry. Nipple projection was less maintained after nipple reconstruction. Although satisfaction with the nipples was higher in the NSM group, this did not reach statistical significance. No breast cancers developed after RRM with long-term follow up.

Introduction: Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management., Methods: UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy., Results: 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February-August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%). For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure. For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy., Conclusion: This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3)., Methods: Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3-4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0-100)., Results: Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline., Conclusion: Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants., Competing Interests: Competing interests: YCL has received honoraria from GSK for participation on the Advisory Board. FJ acknowledges institutional research grants from GSK and has received honoraria for educational events from AstraZeneca, Astellas, Amgen, BMS, Bayer, Clovis, GSK, Ipsen, MSD, Janssen, Pfizer, and Sanofi. AO acknowledges institutional research grants from MSD K.K., Fuji Pharma, Kissei Pharmaceutical, Meiji Holdings, Taiho Pharmaceutical, Kaken Pharmaceutical, Chugai Pharmaceutical, Tsumura, Daiichi Sankyo, Shinnihonseiyaku, Mochida Pharmaceutical, CMIC Holdings, CMIC Holdings, ASKA Pharmaceutical, Takeda, Pfizer, AstraZeneca, and Terumo; and has received honoraria for educational events from Takeda and AstraZeneca. JL acknowledges institutional research grants from AstraZeneca and MSD/Merck and has received honoraria for educational events from AstraZeneca, Neopharm, GSK and Pfizer and participated on the data safety monitoring board of Regeneron. JS has received honoraria (educational events/travel) from AstraZeneca, Clovis, Clovis and Roche; and has participated on the data safety monitoring board or advisory board for AstraZeneca, Clovis, Eisei, GSK, Novocure, Pfizer, Roche, and Tesaro. MLF acknowledges institutional research grants from AstraZeneca, Novartis, and Beigene; has received honoraria (consultancy/educational events) from AstraZeneca, Novartis, GSK, MSD, Takeda, Lily, and ACT-Genomics; and participated on the data safety monitoring board for AGITG. MTK, RO, AL, FH, AD, FTR, JB, PD, AMO, EA-L, JSB, DB, AF, M-CK, KD and MRS declare no conflict of interest., (© IGCS and ESGO 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: Radiotherapy before mastectomy and autologous free-flap breast reconstruction can avoid adverse radiation effects on healthy donor tissues and delays to adjuvant radiotherapy. However, evidence for this treatment sequence is sparse. We aimed to explore the feasibility of preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction in patients with breast cancer requiring mastectomy., Methods: We conducted a prospective, non-randomised, feasibility study at two National Health Service trusts in the UK. Eligible patients were women aged older than 18 years with a laboratory diagnosis of primary breast cancer requiring mastectomy and post-mastectomy radiotherapy, who were suitable for DIEP flap reconstruction. Preoperative radiotherapy started 3-4 weeks after neoadjuvant chemotherapy and was delivered to the breast, plus regional nodes as required, at 40 Gy in 15 fractions (over 3 weeks) or 42·72 Gy in 16 fractions (over 3·2 weeks). Adverse skin radiation toxicity was assessed preoperatively using the Radiation Therapy Oncology Group toxicity grading system. Skin-sparing mastectomy and DIEP flap reconstruction were planned for 2-6 weeks after completion of preoperative radiotherapy. The primary endpoint was the proportion of open breast wounds greater than 1 cm width requiring a dressing at 4 weeks after surgery, assessed in all participants. This study is registered with ClinicalTrials.gov, NCT02771938, and is closed to recruitment., Findings: Between Jan 25, 2016, and Dec 11, 2017, 33 patients were enrolled. At 4 weeks after surgery, four (12·1%, 95% CI 3·4-28·2) of 33 patients had an open breast wound greater than 1 cm. One (3%) patient had confluent moist desquamation (grade 3). There were no serious treatment-related adverse events and no treatment-related deaths., Interpretation: Preoperative radiotherapy followed by skin-sparing mastectomy and immediate DIEP flap reconstruction is feasible and technically safe, with rates of breast open wounds similar to those reported with post-mastectomy radiotherapy. A randomised trial comparing preoperative radiotherapy with post-mastectomy radiotherapy is required to precisely determine and compare surgical, oncological, and breast reconstruction outcomes, including quality of life., Funding: Cancer Research UK, National Institute for Health Research., Competing Interests: Declaration of interests PTRT reports personal fees from Stryker Surgical and Cytoveris. DRL is an advisory board member for CMR Surgical. JEH reports personal fees from Stryker Surgical. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: To evaluate the risk algorithm by Aspelund et al. for predicting sight-threatening diabetic retinopathy (STDR) in Type 2 diabetes (T2D), and to develop a new STDR prediction model., Methods: The Aspelund et al. algorithm was used to calculate STDR risk from baseline variables in 1012 participants in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) ophthalmological substudy, compared to on-trial STDR status, and receiver operating characteristic analysis performed. Using multivariable logistic regression, traditional risk factors and fenofibrate allocation as STDR predictors were evaluated, with bootstrap-based optimism-adjusted estimates of predictive performance calculated., Results: STDR developed in 28 participants. The Aspelund et al. algorithm predicted STDR at 2- and 5-years with area under the curve (AUC) 0.86 (95% CI 0.77-0.94) and 0.86 (0.81-0.92), respectively. In the second model STDR risk factors were any DR at baseline (OR 24.0 [95% CI 5.53-104]), HbA1c (OR 1.95 [1.43-2.64]) and male sex (OR 4.34 [1.32-14.3]), while fenofibrate (OR 0.13 [0.05-0.38]) was protective. This model had excellent discriminatory ability (AUC = 0.89)., Conclusions: The algorithm by Aspelund et al. predicts STDR well in the FIELD ophthalmology substudy. Logistic regression analysis found DR at baseline, male sex, and HbA1c were predictive of STDR and, fenofibrate was protective., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Recent UK guidelines recommend that surveillance imaging should not be offered to patients who have undergone treatment for breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) unless clinically indicated. The aim of this study was to explore the evolving practice at a tertiary referral unit and quantify the direct economic costs (DEC) associated with post-treatment BIA-ALCL routine radiological surveillance prior to adoption of the guidelines. Eleven patients were treated for BIA-ALCL between 2015 and 2020. At a median follow-up of 38 months (IQR 12-47) there were no local or distant relapses. Two patients did not have any radiological surveillance and 1 had follow-up elsewhere. The remaining 8 patients had a combination of positron emission tomography/computed tomography (PET/CT) (n = 10), CT (n = 2), breast ultrasound (n = 6), mammogram (n = 4) and breast magnetic resonance imaging (MRI) (n = 1) as routine imaging follow-up not guided by clinical concerns. Total cost of imaging was £10,396 (€12,257) with a median cost of £1953 (€2304) per patient [IQR £526-2029 (€621-2394)]. This cost could have been saved based on current guidelines recommending no routine surveillance for asymptomatic patients., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls., Methods: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60-84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013., Results: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95-1.10). There was an interaction with body mass index (BMI) (P-interaction = 0.001); vitamin D increased risk in participants with BMI < 25 kg/m 2 (OR 1.25, 95% CI 1.09-1.43), but there was no effect in those with BMI ≥ 25 kg/m 2 (OR 0.95, 95% CI 0.87-1.04). Analyses of diary data were consistent with these findings. The incidence of hypercalcaemia and kidney stones did not differ between groups., Conclusions: Monthly high-dose vitamin D supplementation did not reduce risk of falling. A possible increased risk of falling with vitamin D supplementation in people with normal BMI warrants further investigation., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Background: Aromatase inhibitors have been used empirically to treat a subset of patients with hormone receptor positive uterine leiomyosarcomas(LMS) and carcinosarcomas (UCS) mainly supported by retrospective data. We evaluated the activity of anastrozole in two rare cohorts; patients with recurrent/metastatic LMS and UCS enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER+)/progesterone receptor positive (PR+) gynecological cancers., Method: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER &/or PR + ve LMS or UCS with measurable disease, treated until progression or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity., Results: 39 eligible patients were enrolled, 32 with LMS and 7 with UCS. For the LMS cohort CBR at 3 months was 35% (95% CI: 21-53%) with a median duration of clinical benefit of 5.8 months. Best response was a partial response in one patient. Two patients remained on treatment for more than one year. The median progression-free survival was 2.8 months (95% CI: 2.6-4.9). For the UCS cohort CBR at 3 months was 43% (95% CI: 16-75%) with a median duration of clinical benefit of 5.6 months. Stable disease was seen in 3 patients but no objective responses were seen. The median progression-free survival was 2.7 months (95% CI, 1.1-8.2). Safety was acceptable with 5/39 evaluable patients showing grade 3 toxicities., Conclusion: Whilst objective response rates with anastrozole are low, the clinical benefit rate and good tolerance suggests that aromatase inhibitor therapy may have a role in a subset of patients with metastatic LMS and UCS., Competing Interests: Declaration of competing interest Dr. Beale reports other from GSK, outside the submitted work. Dr. Sjoquist reports personal fees from Merck, personal fees from Amgen, personal fees from Servier, personal fees from BMS, personal fees from Ipsen, personal fees from Competitive Drug Development, outside the submitted work. Dr. Sykes reports grants from University of Sydney, during the conduct of the study. Dr. Edmondson reports non-financial support from Astra Zeneca, during the conduct of the study; grants from Tesaro (Glaxo Smith Kline), personal fees from Astra Zeneca, personal fees from Clovis Pharmaceuticals, outside the submitted work; Dr. Friedlander reports other from Astra Zeneca, during the conduct of the study, grants personal fees and other from Astra Zeneca, personal fees from MSD, personal fees from GSK, personal fees from Lilly, personal fees from Takeda, grants and personal fees from Novartis, other from Beigene, personal fees from ACT Genomics, outside the submitted work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We lack specific treatments for traumatic brain injury (TBI), which remains the leading cause of trauma-related morbidity and mortality. Treatment with valproic acid (VPA) improves outcomes in models of severe TBI with concurrent hemorrhage. However, it is unknown if VPA will have similar benefits after isolated nonlethal TBI, which is the more common clinical scenario. The goal of this study was to evaluate the effect of VPA treatment in a preclinical isolated TBI swine model on neurologic outcomes and brain lesion size and to perform detailed pharmacokinetic analyses for a future clinical trial., Methods: Yorkshire swine (n = 10; 5/cohort) were subjected to TBI (8-mm controlled cortical impact). An hour later, we randomized them to receive VPA (150 mg/kg) or saline placebo (control). Neuroseverity scores were assessed daily (0 [normal] to 36 [comatose]), brain lesion size was measured on postinjury 3, and serial blood samples were collected for pharmacokinetic studies., Results: Physiologic parameters and laboratory values were similar in both groups. Valproic acid-treated animals demonstrated significantly better neuroseverity scores on postinjury 1 (control, 9.2 ± 4.4; VPA, 0 ± 0; p = 0.001). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in microliter: control, 3,130 ± 2,166; VPA, 764 ± 208; p = 0.02). Pharmacokinetic data confirmed adequate plasma and tissue levels of VPA., Conclusion: In this clinically relevant model of isolated TBI, a single dose of VPA attenuates neurological impairment and decreases brain lesion size., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs., Methods: 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity., Results: The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5-13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5-13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%-24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade., Conclusions: This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs., Competing Interests: Declaration of Competing Interest SB: Institutional grants from Astrazeneca, Tesaro, GSK. Personal fees for advisory boards/lectures: Amgen, Astrazeneca, Clovis, Genmab, GSK, Immunogen, Mersana, MSD, Merck Sereno, Mersana, Oncxerna, Pfizer, Roche, Takeda, Tesaro, outside the submitted work. KS: Research funding to institution, Bayer and Amgen. Personal fees from Merck, Amgen, Servier, BMS, IPSEN, Competitive Drug Development, outside the submitted work. AC: Grants from Cancer Research UK and Astrazeneca, personal fees from AstraZeneca, GSK, Tesaro, Clovis Oncology, Eisai, outside the submitted work. RL: Personal fees from Tesaro and Roche outside the submitted work. MH: Research funding to institution Merck, BMS, Clovis Oncology. Honoraria for Advisory Boards/ Lectures: Amgen, AZ, Clovis Oncology, GSK, MSD, Roche outside the submitted work. CG: Research funding to institution: AstraZeneca, Novartis, Aprea, Nucana, Tesaro, BerGen Bio. Honorary for advisory boards/lectures: Roche, AstraZeneca, MSD, GSK, Tesaro, Nucana, Clovis, Foundation One, Sierra Oncology, Cor2Ed, Takeda. PS: Grant from University of Sydney. RE: Personal fees from Arquer Diagnostics, GSK, Clovis oncology outside submitted work. MF: personal fees from Astra Zeneca, MSD, GSK, Tesaro, Lilly, Takeda and Novartis; institutional grants from Astra Zeneca, Novartis and Beigene, other from Abbvie and ACT Genomics outside the submitted work. All other authors (MT, ROC, DM, SN, VMM, TB, JCG, PTG, OM, LA, CK, KC, LD, NB) report no disclosures of interest., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury., Methods: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy., Results: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment., Conclusions: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock., (Copyright © 2021 Elsevier Inc. All rights reserved.)

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors., (© 2021. The Author(s).)