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Background: Tumor Treating Fields (TTFields) therapy is a loco-regional, noninvasive treatment approved for newly diagnosed (nd)/recurrent (r) glioblastoma (GBM) and mesothelioma. Approval for ndGBM was based on the pivotal phase 3 EF-14 study where TTFields therapy/temozolomide (TMZ), administered in the adjuvant setting, significantly improved PFS and OS vs TMZ monotherapy. TTFields therapy-related adverse events (AEs) were mostly mild-to-moderate skin reactions, with no evidence of TTFields therapy-related systemic toxicity. Radiotherapy (RT) concomitant with TTFields therapy demonstrated an increased therapeutic effect in preclinical models. Supplementary evidence from two pilot phase 2 studies demonstrated that concomitant administration of TTFields therapy with standard of care RT/TMZ was feasible and well-tolerated. Here we present a phase 3 study examining the efficacy and safety of TTFields therapy concomitant with RT/TMZ in patients with ndGBM. Materials and Methods: TRIDENT (EF-32; NCT04471844) is a global, randomized, phase 3 study of patients ≥18 years of age (≥22 years in the US) with histologically confirmed ndGBM, ≥3 months life expectancy, ≥70 Karnofsky Performance Status, and adequate organ function. Patients will be stratified by the extent of resection and methylation status of the MGMT promoter. Approximately 950 patients will be assigned 1:1 to continuous TTFields therapy (200 kHz, ≥18 h/day) concomitant with RT/TMZ (experimental arm) or RT/TMZ alone (control arm). Patients will first receive 6 weeks of experimental or control therapy, TTFields therapy will then be added to the control group and all patients will receive 6 cycles of maintenance TMZ and continuous TTFields therapy. Once initiated, TTFields therapy use will continue until second disease progression (PFS2) or until 24 months (if clinically able) from the time of randomization. The primary endpoint is median OS; secondary endpoints include 1- and 2- year OS rates, PFS, 6- and 12-month PFS rates, and PFS2 (all per Response Assessment in Neuro-Oncology [RANO]), overall radiological response (per RANO), severity and frequency of AEs, quality of life (QoL; per European Organisation for Research and Treatment of Cancer QoL Questionnaires), neurological function (per Neurological Assessment in Neuro-Oncology scale), and tumor pathology post study treatments (when available). The ability of TTFields therapy to prolong OS in a dose-dependent manner is an exploratory endpoint. The primary endpoint is based on the hypothesis that TTFields therapy/RT/TMZ can significantly improve OS (vs RT/TMZ) and will be tested using a stratified log-rank test. The sample size is calculated for a hazard ratio of Citation Format: Wenyin Shi, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel A. Goldlust, Seema Nagpal, Leonardo Lustgarten, Stephanie E. Combs, David Roberge, Ryo Nishikawa, David Reardon, Rachel Grossman, Martin Glas. TRIDENT phase 3 study (EF-32): First-line Tumor Treating Fields (TTFields; 200 kHz) therapy concomitant with chemo-radiation, followed by maintenance TTFields/temozolomide in newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT061.

Aims Within the UK, around 70,000 patients suffer neck of femur (NOF) fractures annually. Patients presenting with this injury are often frail, leading to increased morbidity and a 30-day mortality rate of 6.1%. COVID-19 infection has a broad spectrum of clinical presentations with the elderly, and those with pre-existing comorbidities are at a higher risk of severe respiratory compromise and death. Further increased risk has been observed in the postoperative period. The aim of this study was to assess the impact of COVID-19 infection on the complication and mortality rates of NOF fracture patients. Methods All NOF fracture patients presenting between March 2020 and May 2020 were included. Patients were divided into two subgroup: those with or without clinical and/or laboratory diagnosis of COVID-19. Data were collected on patient demographics, pattern of injury, complications, length of stay, and mortality. Results Overall, 132 patients were included. Of these, 34.8% (n = 46) were diagnosed with COVID-19. Bacterial pneumonia was observed at a significantly higher rate in those patients with COVID-19 (56.5% vs 15.1%; p =< 0.000). Non respiratory complications such as acute kidney injury (30.4% vs 9.3%; p =0.002) and urinary tract infection (10.9% vs 3.5%; p =0.126) were also more common in those patients with COVID-19. Length of stay was increased by a median of 21.5 days in patients diagnosed with COVID-19 (p < 0.000). 30-day mortality was significantly higher in patients with COVID-19 (37.0%) when compared to those without (10.5%; p

Aims Within the UK, around 70,000 patients suffer neck of femur (NOF) fractures annually. Patients presenting with this injury are often frail, leading to increased morbidity and a 30-day mortality rate of 6.1%. COVID-19 infection has a broad spectrum of clinical presentations with the elderly, and those with pre-existing comorbidities are at a higher risk of severe respiratory compromise and death. Further increased risk has been observed in the postoperative period. The aim of this study was to assess the impact of COVID-19 infection on the complication and mortality rates of NOF fracture patients. Methods All NOF fracture patients presenting between March 2020 and May 2020 were included. Patients were divided into two subgroup: those with or without clinical and/or laboratory diagnosis of COVID-19. Data were collected on patient demographics, pattern of injury, complications, length of stay, and mortality. Results Overall, 132 patients were included. Of these, 34.8% (n = 46) were diagnosed with COVID-19. Bacterial pneumonia was observed at a significantly higher rate in those patients with COVID-19 (56.5% vs 15.1%; p =< 0.000). Non respiratory complications such as acute kidney injury (30.4% vs 9.3%; p =0.002) and urinary tract infection (10.9% vs 3.5%; p =0.126) were also more common in those patients with COVID-19. Length of stay was increased by a median of 21.5 days in patients diagnosed with COVID-19 (p < 0.000). 30-day mortality was significantly higher in patients with COVID-19 (37.0%) when compared to those without (10.5%; p Conclusion This study has shown that patients with a neck of femur fracture have a high rate of mortality and complications such as bacterial pneumonia and acute kidney injury when diagnosed with COVID-19 within the perioperative period. We have demonstrated the high risk of in hospital transmission of COVID-19 and the association between the infection and an increased length of stay for the patients affected. Cite this article: Bone Joint Open 2020;1-11:669–675.

BackgroundScaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. Immediate surgical fixation of this fracture has increased.ObjectiveTo compare the clinical effectiveness and cost-effectiveness of surgical fixation with cast treatment and early fixation in adults with scaphoid waist fractures that fail to unite.DesignMulticentre, pragmatic, open-label, parallel two-arm randomised controlled trial with an economic evaluation and a nested qualitative study.SettingOrthopaedic departments of 31 hospitals in England and Wales recruited from July 2013, with final follow-up in September 2017.ParticipantsAdults (aged ≥ 16 years) presenting within 2 weeks of injury with a clear, bicortical fracture of the scaphoid waist on plain radiographs.InterventionsEarly surgical fixation using Conformité Européenne-marked headless compression screws. Below-elbow cast immobilisation for 6–10 weeks and urgent fixation of confirmed non-union.Main outcome measuresThe primary outcome and end point was the Patient-Rated Wrist Evaluation total score at 52 weeks, with a clinically relevant difference of 6 points. Secondary outcomes included Patient-Rated Wrist Evaluation pain and function subscales, Short Form questionnaire 12-items, bone union, range of movement, grip strength, complications and return to work.ResultsThe mean age of 439 participants was 33 years; 363 participants were male (83%) and 269 participants had an undisplaced fracture (61%). The primary analysis was on 408 participants with valid Patient-Rated Wrist Evaluation outcome data for at least one post-randomisation time point (surgery,n = 203 of 219; cast,n = 205 of 220). There was no clinically relevant difference in the Patient-Rated Wrist Evaluation total score at 52 weeks: the mean score in the cast group was 14.0 (95% confidence interval 11.3 to 16.6) and in the surgery group was 11.9 (95% confidence interval 9.2 to 14.5), with an adjusted mean difference of –2.1 in favour of surgery (95% confidence interval –5.8 to 1.6;p = 0.27). The non-union rate was low (surgery group,n = 1; cast group,n = 4). Eight participants in the surgery group had a total of 11 reoperations and one participant in the cast group required a reoperation for non-union. The base-case economic analysis at 52 weeks found that surgery cost £1295 per patient more (95% confidence interval £1084 to £1504) than cast treatment. The base-case analysis of a lifetime-extrapolated model confirmed that the cast treatment pathway was more cost-effective. The nested qualitative study identified patients’ desire to have a ‘sense of recovering’, which surgeons should address at the outset.LimitationThere were 17 participants who had initial cast treatment and surgery for confirmed non-union, which in 14 cases was within 6 months from randomisation and in three cases was after 6 months. Three of the four participants in the cast group who had a non-union at 52 weeks were not offered surgery.ConclusionsAdult patients with an undisplaced or minimally displaced scaphoid waist fracture should have cast immobilisation and suspected non-unions immediately confirmed and urgently fixed. Patients should be followed up at 5 years to investigate the effect of partial union, degenerative arthritis, malunion and screw problems on their quality of life.Trial registrationCurrent Controlled Trials ISRCTN67901257.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 52. See the NIHR Journals Library website for further project information.

Background\ud Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less.\ud Methods\ud This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs. An independent remote randomisation service used a computer-generated allocation sequence with randomly varying block sizes to randomly assign participants (1:1) to receive either early surgical fixation (surgery group) or below-elbow cast immobilisation followed by immediate fixation if non-union of the fracture was confirmed (cast immobilisation group). Randomisation was stratified by whether or not there was displacement of either a step or a gap of 1–2 mm inclusive on any radiographic view. The primary outcome was the total patient-rated wrist evaluation (PRWE) score at 52 weeks after randomisation, and it was analysed on an available case intention-to-treat basis. This trial is registered with the ISRCTN registry, ISRCTN67901257, and is no longer recruiting, but long-term follow-up is ongoing.\ud Findings\ud Between July 23, 2013, and July 26, 2016, 439 (42%) of 1047 assessed patients (mean age 33 years; 363 [83%] men) were randomly assigned to the surgery group (n=219) or to the cast immobilisation group (n=220). Of these, 408 (93%) participants were included in the primary analysis (203 participants in the surgery group and 205 participants in the cast immobilisation group). 16 participants in the surgery group and 15 participants in the cast immobilisation group were excluded because of either withdrawal, no response, or no follow-up data at 6, 12, 26, or 52 weeks. There was no significant difference in mean PRWE scores at 52 weeks between the surgery group (adjusted mean 11·9 [95% CI 9·2–14·5]) and the cast immobilisation group (14·0 [11·3 to 16·6]; adjusted mean difference −2·1 [95% CI −5·8 to 1·6], p=0·27). More participants in the surgery group (31 [14%] of 219 participants) had a potentially serious complication from surgery than in the cast immobilisation group (three [1%] of 220 participants), but fewer participants in the surgery group (five [2%]) had cast-related complications than in the cast immobilisation group (40 [18%]). The number of participants who had a medical complication was similar between the two groups (four [2%] in the surgery group and five [2%] in the cast immobilisation group).\ud Interpretation\ud Adult patients with scaphoid waist fractures displaced by 2 mm or less should have initial cast immobilisation, and any suspected non-unions should be confirmed and immediately fixed with surgery. This treatment strategy will help to avoid the risks of surgery and mostly limit the use of surgery to fixing fractures that fail to unite.\ud Funding\ud National Institute for Health Research Health Technology Assessment Programme.

Purpose The CellSearch® system has been used to identify circulating tumor cells (CTCs) in cerebrospinal fluid (CSF) to diagnose leptomeningeal metastasis (LM) in patients with epithelial cancers. Using this system, we prospectively explored sequential CSF CTC enumeration in patients with LM from HER2+ cancers receiving intrathecal (IT) trastuzumab to capture dynamic changes in CSF CTC enumeration. Methods CSF from patients enrolled in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was obtained on day 1 of each cycle and was evaluated by the CellSearch® platform for CTC enumeration. The results were correlated with CSF cytology from the same sample, along with clinical and radiographic response. Results Fifteen out of 34 patients with HER2+ LM were enrolled in CSF CTC analysis; 14 were women. Radiographic LM was documented in 14 (93%) patients; CSF cytology was positive in 6 (40%) and CSF CTCs were identified in 13 (87%). Median CSF CTC was 22 CTCs (range 0–200 +) per 3 ml. HER2/neu expression analysis of CTCs was performed in 8 patients; 75% had confirmed expression of HER2/neu positivity in CSF and HER2/neu expression was absent in 25%. Four of 10 patients received 7 or more cycles of IT trastuzumab; in 3 of these patients, increase in CSF CTCs enumeration from baseline was detected 2–3 months prior to changes seen on MRI, and while CSF cytology remained negative. Conclusion Our study demonstrates that enumeration of CSF CTCs may provide dynamic, quantitative assessment of tumor burden in the central nervous system compartment during treatment for LM and prior to changes on MRI or CSF cytology. Trial Registration: Clinicaltrials.gov: NCT01325207; registered March 29th, 2011.

OBJECTIVE: To determine the association between pre-intubation respiratory support and outcomes in patients with acute respiratory failure, and to determine the impact of immunocompromised diagnoses on outcomes after adjustment for illness severity. DESIGN: Retrospective multicenter cohort study. SETTING: Eighty-two centers in the Virtual Pediatric Systems database. PATIENTS: Children 1 month through 17 years old intubated in the PICU who received invasive mechanical ventilation for ≥24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: High-flow nasal cannula (HFNC) and/or non-invasive positive pressure ventilation (NIPPV) was used prior to intubation in 1,825 (34%) of 5,348 PICU intubations across 82 centers. When stratified by immunocompromised (IC) status, 50% of patients had no IC diagnosis, while 41% were IC without prior hematopoietic cell transplant (HCT) and 9% had prior HCT. Compared to patients intubated without prior support, pre-intubation exposure to HFNC (aOR 1.33, 95%CI 1.10–1.62) or NIPPV (aOR 1.44, 95%CI 1.20–1.74) was associated with increased odds of PICU mortality. Within subgroups of IC status, pre-intubation respiratory support was associated with increased odds of PICU mortality in IC patients (HFNC: aOR 1.50, 95%CI 1.11–2.03; NIPPV: aOR 1.76, 95%CI 1.31–2.35) and HCT patients (HFNC: aOR 1.75, 95%CI 1.07–2.86; NIPPV: aOR 1.85, 95%CI 1.12–3.02) compared to IC/HCT patients intubated without prior respiratory support. Pre-intubation exposure to HFNC/NIPPV was not associated with mortality in patients without an IC diagnosis. Duration of HFNC/NIPPV >6hr was associated with increased mortality in IC HCT patients (HFNC: aOR 2.41, 95%CI 1.05–5.55; NIPPV: aOR 2.53, 95%CI 1.04–6.15) patients compared HCT patients with

BACKGROUND Tumor Treating Fields therapy (TTFields; 200 kHz) comprise alternating electric fields that disrupt cancer cell division, and is approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. Additionally, TTFields added to RT/TMZ was reported as feasible and well-tolerated in 2 clinical pilot phase 2 studies. MATERIALS AND METHODS TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomized trial comparing TTFields (200 KHz, ≥18 h/day)/RT/TMZ vs RT/TMZ alone. Adult patients (N=950; ≥18 years of age [≥22 years of age; US]) with histologically confirmed ndGBM, Karnofsky Performance Status ≥70, life expectancy ≥3 months, adequate organ function and eligible for RT/TMZ will be enrolled. Patients will be stratified by extent-of-resection and MGMT promoter methylation status and randomized 1:1 to receive continuous TTFields/RT/TMZ or RT/TMZ during the investigational period. Subsequently, all patients will receive TTFields/6 cycles of maintenance TTFields/TMZ; TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO). The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs and quality-of-life, OS per TTFields duration-of-usage. The study is powered at 80% to detect a hazard ratio of

Patients with human epidermal growth factor receptor 2-positive (HER2-positive) cancers have a high incidence of central nervous system (CNS) spread, but unfortunately systemic trastuzumab which targets the HER2 receptor has little CNS penetration. The purpose of this study was to determine the maximum tolerated dose of intrathecal trastuzumab and its efficacy in patients with HER2-positive LMD.This multicenter study enrolled 34 LMD patients in a combined Phase I/II study in treating patients with intrathecal trastuzumab. Any HER2-positive histology was allowed in the Phase I; the Phase II was limited to HER2-positive breast cancer.Intrathecal trastuzumab was well tolerated, with one dose limiting toxicity of grade 4 (arachnoiditis) occurring at the 80 mg twice weekly dose. The recommended Phase II dose was 80 mg intrathecally twice weekly. Twenty-six patients at dose level 80mg were included in evaluation for efficacy: partial response was seen in 5 (19.2%) patients, stable disease was observed in 13 (50.0%), and 8 (30.8%) of the patients had progressive disease. Median overall survival (OS) for Phase 2 dose treated patients was 8.3 months (95% CI 5.2 to 19.6). The Phase II HER2-positive breast cancer patients median OS was 10.5 months (95% CI 5.2 to 20.9). Pharmacokinetic (PK) studies were limited in the setting of concurrent systemic trastuzumab administration, however, did show stable CSF concentrations with repeated dosing suggest that trastuzumab does not accumulate in the CSF in toxic concentrations.This study suggests promise for potentially improved outcomes of HER-positive LMD patients when treated with intrathecal trastuzumab while remaining safe and well-tolerated for patients.

The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.

This paper aimed to summarise existing literature on strategies to improve the healthiness of retail food environments in the East Asia and Pacific (EAP) region, and propose a prioritised research agenda on this topic.Little research on retail food environments has been conducted in the EAP region. Several approaches for measuring retail food environments were identified, although none have been tailored to the EAP context. A small number of policies and initiatives to promote healthy retail food environments have been implemented in EAP. Lessons learnt from successful implementation of initiatives in other regions could be applied in EAP. Retail food environments have a strong influence on food choices and health outcomes. Research can contribute to efforts to improve the healthiness of retail food environments in EAP by (1) describing the current state of retail food environments to highlight areas of good practice and concern and (2) identifying policies and initiatives that are likely to be effective, and mechanisms for their successful implementation.