Cybersecurity and critical care staff: A mixed methods study.

INTRODUCTION: Cyberattacks on healthcare organisations are becoming increasingly common and represent a growing threat to patient safety. The majority of breaches in cybersecurity have been attributed to human error. Intensive care departments are particularly vulnerable to cyberattacks. The aim of this study was to investigate cybersecurity awareness, knowledge and behaviours among critical care staff. METHODS: This was a multi-site cross-sectional survey study administered to critical care staff. Cybersecurity awareness was evaluated using the validated HAIS-Q instrument. Knowledge and behaviours were evaluated by direct questioning and scenario-based multiple-choice questions. Free text options were also offered to respondents. Thematic analysis was performed on free text sections. RESULTS: Median scores of 12-15 in each of the HAIS-Q focus areas were achieved, indicating high levels of cybersecurity awareness among critical care staff. However, self-reported confidence in cybersecurity practices, especially identifying signs of cybersecurity breaches and reporting cybersecurity incidents, were relatively low. Participants responses to the scenarios demonstrated a lack of knowledge and awareness of some of the mechanisms of cyberattacks. Barriers to safe cybersecurity practices among staff that emerged from the qualitative analysis included: a lack of training and education; heavy workloads and staff fatigue; perceived lack of IT support and poor IT infrastructure. CONCLUSION: Critical care staff appear to have a high-level cybersecurity awareness. However, in practice safe cybersecurity practices are not always followed. ICU departments and hospitals must invest in the human aspect of cybersecurity to strength their cyber-defences and to protect patients.

Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies.

PURPOSE: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. METHODS: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. RESULTS: IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], PINTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], PINTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status. CONCLUSION: IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.

Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II-III colorectal cancer from the SCOT and QUASAR 2 trials: a retrospective analysis.

BACKGROUND: Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS: We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS: After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION: Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

JAK/STAT3 represents a therapeutic target for colorectal cancer patients with stromal-rich tumors.

Colorectal cancer (CRC) is a heterogenous malignancy underpinned by dysregulation of cellular signaling pathways. Previous literature has implicated aberrant JAK/STAT3 signal transduction in the development and progression of solid tumors. In this study we investigate the effectiveness of inhibiting JAK/STAT3 in diverse CRC models, establish in which contexts high pathway expression is prognostic and perform in depth analysis underlying phenotypes. In this study we investigated the use of JAK inhibitors for anti-cancer activity in CRC cell lines, mouse model organoids and patient-derived organoids. Immunohistochemical staining of the TransSCOT clinical trial cohort, and 2 independent large retrospective CRC patient cohorts was performed to assess the prognostic value of JAK/STAT3 expression. We performed mutational profiling, bulk RNASeq and NanoString GeoMx® spatial transcriptomics to unravel the underlying biology of aberrant signaling. Inhibition of signal transduction with JAK1/2 but not JAK2/3 inhibitors reduced cell viability in CRC cell lines, mouse, and patient derived organoids (PDOs). In PDOs, reduced Ki67 expression was observed post-treatment. A highly significant association between high JAK/STAT3 expression within tumor cells and reduced cancer-specific survival in patients with high stromal invasion (TSPhigh) was identified across 3 independent CRC patient cohorts, including the TrasnSCOT clinical trial cohort. Patients with high phosphorylated STAT3 (pSTAT3) within the TSPhigh group had higher influx of CD66b + cells and higher tumoral expression of PDL1. Bulk RNAseq of full section tumors showed enrichment of NFκB signaling and hypoxia in these cases. Spatial deconvolution through GeoMx® demonstrated higher expression of checkpoint and hypoxia-associated genes in the tumor (pan-cytokeratin positive) regions, and reduced lymphocyte receptor signaling in the TME (pan-cytokeratin- and αSMA-) and αSMA (pan-cytokeratin- and αSMA +) areas. Non-classical fibroblast signatures were detected across αSMA + regions in cases with high pSTAT3. Therefore, in this study we have shown that inhibition of JAK/STAT3 represents a promising therapeutic strategy for patients with stromal-rich CRC tumors. High expression of JAK/STAT3 proteins within both tumor and stromal cells predicts poor outcomes in CRC, and aberrant signaling is associated with distinct spatially-dependant differential gene expression.

Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial.

PURPOSE: Patients with glioblastoma who are older or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiation therapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. METHODS AND MATERIALS: Phase 1 of the PARADIGM trial was a 3+3 dose-escalation study testing olaparib in combination with radiation therapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 years or older (World Health Organization PS 0-1) or aged 18 to 69 years with PS 2. The primary outcome was the recommended phase 2 dose of olaparib. Secondary endpoints included safety and tolerability, overall survival, and progression-free survival. Effects on cognitive function were assessed via the Mini Mental State Examination. RESULTS: Of 16 eligible patients (56.25% male; median age, 71.5 years [range, 44-78]; 75% PS 0-1), 1 dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the recommended phase 2 dose was determined as 200 mg twice daily. Median overall survival and progression-free survival were 10.8 months (80% CI, 7.3-11.4) and 5.5 months (80% CI, 3.9-5.9), respectively. Mini Mental State Examination plots indicated that cognitive function was not adversely affected by the olaparib-radiation therapy combination. CONCLUSIONS: Olaparib can be safely combined with hypofractionated brain radiation therapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomized phase 2 study and support future trials of PARP inhibitors in combination with radiation therapy for patients with brain tumors.

Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): protocol of a prospective, multicentre, observational study.

INTRODUCTION: Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (<1/3 hemithorax on chest radiograph), which is either too small to safely aspirate fluid for cytology using a needle, or from which fluid cytology is negative. Thoracoscopy (local anaesthetic thoracoscopy (LAT) or video-assisted thoracoscopic surgery (VATS)) is the gold-standard diagnostic test for pleural malignancy in patients with larger symptomatic effusions. Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY) will prospectively evaluate thoracoscopic staging in lung cancer associated-mini-PE for the first time. METHODS AND ANALYSIS: STRATIFY is a prospective multicentre observational study. Recruitment opened in January 2020. The primary objective is to determine the prevalence of detectable occult pleural metastases (OPM). Secondary objectives include assessment of technical feasibility and safety, and the impact of thoracoscopy results on treatment plans, overall survival and recurrence free survival. Inclusion criteria are (1) suspected/confirmed stages I-III lung cancer, (2) mini-PE, (3) Performance Status 0-2 (4), radical treatment feasible if OPM excluded, (5) ≥16 years old and (6) informed consent. Exclusion criteria are any metastatic disease or contraindication to the chosen thoracoscopy method (LAT/VATS). All patients have LAT or VATS within 7 (±5) days of registration, with results returned to lung cancer teams for treatment planning. Following an interim analysis, the sample size was reduced from 96 to 50, based on a lower-than-expected OPM rate. An MRI substudy was removed in November 2022 due to pandemic-related site setup/recruitment delays. These also necessitated a no-cost recruitment extension until October 2023. ETHICS AND DISSEMINATION: Protocol approved by the West of Scotland Research Ethics Committee (Ref: 19/WS/0093). Results will be published in peer-reviewed journals and presented at international meetings. TRIAL REGISTRATION NUMBER: ISRCTN13584097.

Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets.

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multi-parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin, and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.

Nephrectomy for xanthogranulomatous pyelonephritis-a not-so-simple solution.

BACKGROUND: Xanthogranulomatous pyelonephritis (XGP) is a rare chronic inflammatory condition of the kidney, associated with high patient morbidity, often requiring targeted antibiotic therapy and surgical removal of the affected kidney. AIM: We report the outcomes of patients undergoing nephrectomy for XGP in our institution over a 12-year period. METHODS: Following ethical approval, a retrospective review of histological samples of renal tissue demonstrating features of XGP from June 2010 to 2022 was conducted. Laboratory, imaging, and clinical data of included participants were collected. RESULTS: Eleven patients were included (8 women, 3 men), mean age of 58.1 (35-81). Recurrent urinary tract infection was the most common clinical presentation (55%, n = 6). Other presentations included flank pain (36%, n = 4), collection/ abscess (45%, n = 5), and nephro-cutaneous fistulae (9%, n = 1). The majority of patients had bacteriuria (91%, n = 10), and Escherichia coli was the most common bacteria isolated (55%, n = 6). Antibiotic resistance was seen in 60% of positive urine samples (n = 6). An open nephrectomy was performed in all but one case (91%, n = 10). A postoperative complication occurred in 73% (n = 8), with 50% (n = 4) of complications Clavien Dindo grade 3 or higher, including one patient mortality. CONCLUSIONS: XGP is a difficult and complex condition to treat. All patients in this series presented with infection or associated sequelae thereof. Complex XGP cases therefore often require open nephrectomy and have high rates of postoperative complications. Careful consideration of antibiotic and operative intervention is therefore essential to ensure the best outcome for these patients.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis.

BACKGROUND: In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. METHODS: The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. RESULTS: KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. CONCLUSION: KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.

Understanding the mental health needs of Scotland's prison population: a health needs assessment.

Introduction: This study reports on an assessment of mental health needs among Scotland's prison population which aimed to describe the scale and nature of need as well as identify opportunities to improve upon the services available. The project was commissioned by the Scottish Government to ensure that future changes to the services available to support the mental health and wellbeing of people in prison would be evidence-based and person-centered. Methods: A standardized approach to health needs assessments was employed. The study was comprised of four phases. In phase I a rapid literature review was undertaken to gather evidence on the prevalence of mental health needs experienced by people in prison in the UK. In Phase II a multi-method and multi-informant national mapping exercise involving providers to all Scottish prisons was undertaken to describe the mental health services available, and any gaps in these services, for people in and leaving prison. In Phase III prevalence estimates of several mental health needs were derived for Scotland's current prison population, modeled from a national survey dataset of Scotland's community population using logistic regression. Finally in Phase IV, professional stakeholders and individuals with lived experience were interviewed to understand their experiences and insights on challenges to supporting the mental health and wellbeing of people in prison, and ideas on how these challenges could be overcome. Results: Evidence across the four phases of this needs assessment converged indicating that existing provision to support the mental health of people in prison in Scotland was considered inadequate to meet these needs. Barriers to effective partnership working for justice, health, social work and third sector providers appear to have led to inadequate and fragmented care, leaving prisoners without the support they need during and immediately following imprisonment. Conclusions: Joint and coordinated action from justice, health and social care, and third sector providers is needed to overcome enduring and structural challenges to supporting the mental health of people in prison. Eighteen evidence-based recommendations were proposed to the Scottish Government relating to the high-level and operational-level changes required to adequately meet the prison population's mental health needs.

Addressing the sustainability challenges for polymers in liquid formulations.

Polymers in liquid formulations, or PLFs, are present in many of the products we use, from the shampoo we use to wash our hair, to the paint on the walls, and the lubricants in our car. They provide high functionality in these and a multitude of other applications, delivering many positive benefits to society. They are essential to global markets worth more than $1 trillion and so large quantities of these materials are made and sold each year - 36.3 million metric tonnes, the volume of 14 500 Olympic sized swimming pools! The chemical industry and the wider supply chain therefore have a responsibility to ensure that the way PLFs are made, used and disposed of at their end of life has a minimal effect on the environment. To date this seems to be a 'hidden problem', not receiving the same attention as other polymer related products, such as plastic packaging waste, yet there are clear challenges to address the sustainability concerns for these materials. To ensure that the PLF industry is economically and environmentally sustainable in the future, some key challenges need to be addressed, ensuring that new approaches to PLF production, use and end-of-life treatment are developed and utilised. Collaboration is key here, and with the UK already possessing a wealth of world-leading expertise and capability, there is an opportunity to leverage this in a coherent, focussed way to improve the overall environmental profile of these products.

Surgical treatment of urachal remnants in an adult population-a single-centre experience.

BACKGROUND: Urachal remnants are a rare congenital defect resulting from failure of obliteration of a fibrous tube that connects the umbilicus to the bladder dome during embryological development. Oftentimes a urachal remnant will go undiagnosed, but occasionally a patient may present with a variety of symptoms, ultimately leading to the identification of the remnant. Given its rarity, there is very limited literature available on the management of symptomatic urachal remnants, especially in adults. Surgical resection has been the first-line management of urachal remnants for years, especially given the risk of the development of urachal adenocarcinoma secondary to recurrent infection, persistent irritation, and urinary stasis associated with some urachal remnants. AIM: We present our experience in the management of symptomatic urachal remnants in adults at our institute and perform a brief literature review of the same. METHODS: A retrospective review of all cases who underwent surgical management of symptomatic urachal remnants between December 2015 and January 2022 was performed. Seven cases of urachal remnant excision in total were identified over the time period. Patient characteristics and perioperative parameters were analysed. Post-operative complications were measured in accordance with the Clavien-Dindo grading system. RESULT: In total, 7 cases of urachal remnants were treated at our institute over the study period. Four patients were treated with a TURBT and 3 patients were treated with a laparoscopic partial cystectomy. There were no intraoperative complications and one post-operative complication requiring readmission for intravenous antibiotics. There was one mortality but this was not as a direct result of the operative procedure. Mean length of stay was 1.71 days. Two of patients had histologically confirmed urachal adenocarcinoma and the remaining five patients had benign histology. Each patient was seen in the outpatients department 6 weeks post-operatively for clinical review and review of histology. No further follow-up was required for the patients with benign histology given resolution of symptoms and follow-up for the malignant histology was arranged appropriately following MDM. CONCLUSION: There is a paucity of data available on the management of urachal remnants in the adult population; however, an endoscopic or laparoscopic approach is a safe and effective method of excising symptomatic urachal remnants.

SCOT: Tumor Sidedness and the Influence of Adjuvant Chemotherapy Duration on Disease Free Survival (DFS).

AIM: Patients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. METHODS: The SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. RESULTS: 6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. CONCLUSIONS: This is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.

CA-125 Early Dynamics to Predict Overall Survival in Women with Newly Diagnosed Advanced Ovarian Cancer Based on Meta-Analysis Data.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

Randomised controlled trial of the short-term effects of osmotic-release oral system methylphenidate on symptoms and behavioural outcomes in young male prisoners with attention deficit hyperactivity disorder: CIAO-II study.

BACKGROUND: Research has shown that 20-30% of prisoners meet the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Methylphenidate reduces ADHD symptoms, but effects in prisoners are uncertain because of comorbid mental health and substance use disorders. AIMS: To estimate the efficacy of an osmotic-release oral system methylphenidate (OROS-methylphenidate) in reducing ADHD symptoms in young adult prisoners with ADHD. METHOD: We conducted an 8-week parallel-arm, double-blind, randomised placebo-controlled trial of OROS-methylphenidate versus placebo in male prisoners (aged 16-25 years) meeting the DSM-5 criteria for ADHD. Primary outcome was ADHD symptoms at 8 weeks, using the investigator-rated Connors Adult ADHD Rating Scale (CAARS-O). Thirteen secondary outcomes were measured, including emotional dysregulation, mind wandering, violent attitudes, mental health symptoms, and prison officer and educational staff ratings of behaviour and aggression. RESULTS: In the OROS-methylphenidate arm, mean CAARS-O score at 8 weeks was estimated to be reduced by 0.57 points relative to the placebo arm (95% CI -2.41 to 3.56), and non-significant. The responder rate, defined as a 20% reduction in CAARS-O score, was 48.3% for the OROS-methylphenidate arm and 47.9% for the placebo arm. No statistically significant trial arm differences were detected for any of the secondary outcomes. Mean final titrated dose was 53.8 mg in the OROS-methylphenidate arm. CONCLUSIONS: ADHD symptoms did not respond to OROS-methylphenidate in young adult prisoners. The findings do not support routine treatment with OROS-methylphenidate in this population. Further research is needed to evaluate effects of higher average dosing and adherence to treatment, multi-modal treatments and preventative interventions in the community.

Behavioral Crisis and First Response: Qualitative Interviews with Chicago Stakeholders.

Improving interactions between first responders and individuals experiencing behavioral crisis is a critical public health challenge. To gain insight into these interactions, key informant qualitative interviews were conducted with 25 Chicago stakeholders. Stakeholders included directors and staff of community organizations and shelters that frequently engage first responders. Interviews included granular depictions related to the expectations and outcomes of 911 behavioral crisis calls, and noted areas requiring improved response. Stakeholders called 911 an average of 2 to 3 times per month, most often for assistance related to involuntary hospitalization. Engagements with first responders included unnecessary escalation or coercive tactics, or conversely, refusal of service. While stakeholders lauded the value of police trained through the city's Crisis Intervention Team program, they emphasized the need for additional response strategies that reduce the role of armed police, and underscored the need for broader social and behavioral health services for individuals at-risk of such crises.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Reconstruction of the male external genitalia in diverse disease processes: Our reconstructive algorithm, techniques, and experience.

Background: Male genital form and function may be rendered abnormal by a number of disease processes, with profound associated psychological and functional consequences. The aim of the study is to review our reconstructive experience with cases of genital loss or distortion due to nonmalignant diseases processes and atypical neoplasia. Materials and methods: A retrospective review of a prospectively maintained database was performed to identify reconstructive cases performed from 2018 to 2020 under the care of a single surgeon. Male patients 18 years or older with a disease diagnosis other than squamous cell carcinoma affecting genital form were included. Disease processes, patient factors, surgical techniques, and both functional and cosmetic outcomes were reviewed. Results: Fourteen cases were identified. The patients had a mean age of 52.2 years (range, 21-72 years). Acquired buried penis was present in 8 patients. Etiology of genital abnormality included balanitis xerotica obliterans (n = 6), excess skin loss at circumcision (n = 2), self-injection of petroleum jelly to penile shaft (n = 1), Fournier gangrene (n = 1), hidradenitis suppurativa (n = 1), extramammary Paget disease (n = 1), idiopathic lymphoedema (n = 1), and penoscrotal webbing (n = 1). Reconstructive techniques performed included penile debridement/shaft skin release, scrotectomy, suprapubic apronectomy, and division of penoscrotal webbing, in combination with split-thickness skin grafting where required. A penile implant was inserted in one patient. Reconstructive planning, techniques, and outcomes are described. Conclusions: A variety of reconstructive techniques in andrology can be used to improve the aesthetic and functional outcomes of multiple disease processes affecting the male external genitalia.

Retrospective national cohort study of pregnancy outcomes for women with type 1 and type 2 diabetes mellitus in Republic of Ireland.

AIM: Report the outcomes of pregnant women with type 1 and type 2 diabetes and to identify modifiable and non-modifiable factors associated with poor outcomes. METHODS: Retrospective analysis of pregnancy preparedness, pregnancy care and outcomes in the Republic of Ireland from 2015 to 2020 and subsequent multivariate analysis. RESULTS: In total 1104 pregnancies were included. Less than one third attended pre-pregnancy care (PPC), mean first trimester haemoglobin A1c was 7.2 ± 3.6% (55.5 ± 15.7 mmol/mol) and 52% received pre-conceptual folic acid. Poor preparation translated into poorer pregnancy outcomes. Livebirth rates (80%) were comparable to the background population however stillbirth rates were 8.7/1000 (four times the national rate). Congenital anomalies occurred in 42.5/1000 births (1.5 times the background rate). More than half of infants were large for gestational age and 47% were admitted to critical care. Multivariate analyses showed strong associations between non-attendance at PPC, poor glycaemic control and critical care admission (adjusted odds ratio of 1.68 (1.48-1.96) and 1.61 (1.43-1.86), p < 0.05 respectively) for women with type 1 diabetes. Smoking and teratogenic medications were also associated with critical care admission and hypertensive disorders of pregnancy. CONCLUSION: Pregnancy outcomes in women with diabetes are suboptimal. Significant effort is needed to optimize the modifiable factors identified in this study.

Adenoid cystic carcinoma of the prostate - A rare case of genitourinary malignancy.

A 72 year old was referred to the Urology department with lower urinary tract symptoms (LUTS), an abnormal prostate on digital examination and a serum prostate specific antigen (PSA) level within normal limits. A flexible cystoscopy revealed no abnormality of the urethra and an obstructive prostate. Magnetic resonance imaging (MRI) revealed a 4.3× 4cm soft tissue mass on the posterior corpus spongiosum encasing the bulbar urethra with tumour abutting the prostate. Transperineal prostate biopsies confirmed adenoid cystic carcinoma. Cross-sectional imaging arranged for staging, revealed multiple pulmonary metastastis. The patient is currently being treated with tyrosine kinase inhibitor medication.