Pediatric Hospitalizations and Emergency Department Visits Related to Mental Health Conditions and Self-Harm.

Importance: Mental disorders among the pediatric population are a major area of public health concern. Little is known regarding changes in pediatric hospital resource use related to mental health (MH) long after the onset of the COVID-19 pandemic in March 2020. Objective: To assess rates and trends of hospitalizations and emergency department (ED) visits related to MH and self-harm (SH) among children before and during the 3 years following the pandemic onset. Design, Setting, and Participants: This cross-sectional study used national hospital data. The study sample included all MH- and SH-related hospitalizations and ED visits among children aged 6 to 17 years in France between January 1, 2016, to May 31, 2023. Main Outcomes and Measures: Interrupted time-series analysis of monthly rates of MH- and SH-related hospitalizations and ED visits per 100 000 children was conducted to assess changes before and every year after the pandemic onset. Rate ratios (RRs) between estimated and expected rates were calculated. Results: Overall, 583 244 hospitalizations (81.4% for MH and 18.6% for SH) and 432 725 ED visits (79.9% for MH and 20.1% for SH) were analyzed. The mean (SD) age of the children was 13.7 (2.9) and 14.8 (1.7) years for MH-related and SH-related hospitalizations, respectively, and 14.2 (2.6) and 14.6 (2.1) years for MH-related and SH-related ED visits, respectively. For MH-related hospitalizations, 52.6% were female and 47.4% were male; for SH-related hospitalizations, 83.1% were female and 16.9% were male. For MH-related ED visits, 62.8% were female and 37.2% were male; for SH-related ED visits, 77.4% were female and 22.6% were male. Before the pandemic, an increasing trend in all monthly rates, except that of MH-related hospitalizations, was observed. After an immediate decrease in hospitalization and ED visit rates during the initial pandemic period (March 1 to May 31, 2020), trends increased in the first 2 years following the pandemic onset and decreased thereafter. Overall, rates of MH-related hospitalizations and ED visits exceeded expected rates in only the second year after the pandemic onset, with increases of 6.0% (RR, 1.06 [95% CI, 1.05-1.06]) and 5.0% (RR, 1.05 [95% CI, 1.04-1.05]), respectively. However, rates of hospitalizations and ED visits for behavioral syndromes (mainly eating and sleeping disorders) persistently exceeded expected rates, with increases of 29.0% (RR, 1.29 [95% CI, 1.25-1.34]) and 26.0% (RR, 1.26 [95% CI, 1.21-1.31]) in the third year, respectively. Likewise, rates of SH-related hospitalizations and ED visits persistently rose above expected rates, with increases of 29.0% (RR, 1.29 [95% CI, 1.26-1.32]) and 43.0% (RR, 1.43 [95% CI, 1.40-1.47]) in the third year, respectively. Conclusions and Relevance: In this cross-sectional study, persistent increases in the use of hospital resources to treat eating and sleeping disorders and intentional SH among pediatric patients were observed long after the onset of the COVID-19 pandemic. These findings warrant future research to identify persistent stress factors in children.

Real-life implementation and evaluation of the e-referral system SIPILINK.

INTRODUCTION: General Practitioners (GPs) play a key role of gatekeeper, as they coordinate patients' care. However, most of them reported having difficulty to refer patients to hospital, especially in semi-urgent context. To facilitate the referral of semi-urgent patients, we implemented an e-referral platform, named SIPILINK, within 4 wards from a large public French hospital (internal medicine, diabetology, gynaecological surgery and oncology wards). Here, we aimed to evaluate the SIPILINK e-referral platform after 2 years of implementation. METHODS: The evaluation included a multidimensional assessment based on the RE-AIM framework with the analysis of implementation, requests, health professionals' satisfaction, and estimated hospital payment. RESULTS: Over 2 years of implementation, GPs sent 113 requests to hospital. Hospital respected the time of response requested by GPs in 93 % of cases and proposed a consultation or hospitalization in respectively 40.7 % and 10.6 % of cases. 100 % of GPs and 78 % of Hospital Practitioners (HPs) were satisfied with the quality of exchanges. 77 % of HPs and 100 % of Care Pathway Managers (CPMs) found that patient care pathways were improved. Nearly all practitioners would recommend this platform for patient referrals. DISCUSSION: SIPILINK shows promise in streamlining the referral process, enhancing communication, and improving patient care pathways. Further studies including the impact on the quality of care, are needed to assess its effectiveness and sustainability in healthcare settings.

A Machine Learning Approach for Predicting Biochemical Outcome After PSMA-PET-Guided Salvage Radiotherapy in Recurrent Prostate Cancer After Radical Prostatectomy: Retrospective Study.

BACKGROUND: Salvage radiation therapy (sRT) is often the sole curative option in patients with biochemical recurrence after radical prostatectomy. After sRT, we developed and validated a nomogram to predict freedom from biochemical failure. OBJECTIVE: This study aims to evaluate prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-based sRT efficacy for postprostatectomy prostate-specific antigen (PSA) persistence or recurrence. Objectives include developing a random survival forest (RSF) model for predicting biochemical failure, comparing it with a Cox model, and assessing predictive accuracy over time. Multinational cohort data will validate the model's performance, aiming to improve clinical management of recurrent prostate cancer. METHODS: This multicenter retrospective study collected data from 13 medical facilities across 5 countries: Germany, Cyprus, Australia, Italy, and Switzerland. A total of 1029 patients who underwent sRT following PSMA-PET-based assessment for PSA persistence or recurrence were included. Patients were treated between July 2013 and June 2020, with clinical decisions guided by PSMA-PET results and contemporary standards. The primary end point was freedom from biochemical failure, defined as 2 consecutive PSA rises >0.2 ng/mL after treatment. Data were divided into training (708 patients), testing (271 patients), and external validation (50 patients) sets for machine learning algorithm development and validation. RSF models were used, with 1000 trees per model, optimizing predictive performance using the Harrell concordance index and Brier score. Statistical analysis used R Statistical Software (R Foundation for Statistical Computing), and ethical approval was obtained from participating institutions. RESULTS: Baseline characteristics of 1029 patients undergoing sRT PSMA-PET-based assessment were analyzed. The median age at sRT was 70 (IQR 64-74) years. PSMA-PET scans revealed local recurrences in 43.9% (430/979) and nodal recurrences in 27.2% (266/979) of patients. Treatment included dose-escalated sRT to pelvic lymphatics in 35.6% (349/979) of cases. The external outlier validation set showed distinct features, including higher rates of positive lymph nodes (47/50, 94% vs 266/979, 27.2% in the learning cohort) and lower delivered sRT doses (<66 Gy in 57/979, 5.8% vs 46/50, 92% of patients; P<.001). The RSF model, validated internally and externally, demonstrated robust predictive performance (Harrell C-index range: 0.54-0.91) across training and validation datasets, outperforming a previously published nomogram. CONCLUSIONS: The developed RSF model demonstrates enhanced predictive accuracy, potentially improving patient outcomes and assisting clinicians in making treatment decisions.

Impact of the thresholds of surgical volume on mortality in oncological digestive surgery: A French National Cohort.

OBJECTIVE: To report the 90-day mortality benefit associated with the implementation of the new regulatory reform on oncological surgical digestive authorizations. SUMMARY BACKGROUND DATA: New thresholds in digestive cancer surgery were applied in 2023, accrediting centers for major interventions. No evidence has been provided to support their justification. METHODS: Any French adult operated for digestive cancer from January 1, 2019 to December 31, 2021 was included from the PMSI. A 90-day mortality logistic regression was performed by adjusting by age, sex, Charlson score, Frailty index, hospital-volume (<5 or ≥5 interventions/year), emergency intervention, specialty. RESULTS: 143,582 patients were identified. Of these, 64,268 underwent surgery of one of the subspecialties subject to the new thresholds (stomach N = 8283, liver N = 18,668, pancreas N = 11,220, esophagus N = 3704, rectum N = 22,393). 4808 (7.5 %) patients underwent surgery in low-volume centers, distributed as follows: stomach 1757/8283 (22.94 %), liver 970/18,668 (5.19 %), pancreas 895/11,220 (7.98 %), esophagus 672/3704 (18.14 %) and rectum 514/22,393 (2.29 %). In univariate analysis, the 90-day mortality rate was significantly lower in high-volume centers, for all subspecialties, gastric: 127/1757 (7.23 %) vs 330/6526 (5.06 %), p = 0.0004, hepatic: 64/970 (6.6 %) vs 824/17,698 (4.66 %), p = 0.006, pancreatic: 74/895 (8, 27 %) vs 608/10,325 (5.89 %), p = 0.004, esophageal: 58/672 (8.63 %) vs 195/3032 (6.43 %), p = 0.04, rectal 26/514 (5.06 %) vs 639/21,879 (2.92 %), p = 0.005. The multivariate analysis, showed a mortality reduction for high-volume centers: OR = 0.78 CI95[0.71-0.87], p < 0.001. CONCLUSION: The recent implementation of regulatory decrees appears to be justified. The enforcement of these hospital volume thresholds is likely to contribute to a reduction in postoperative mortality following digestive cancer surgery.

Evolution of minimally invasive liver surgery in France over the last decade.

BACKGROUND: Despite evidence of benefits on postoperative outcomes, minimally invasive liver surgery (MILS) had a very low diffusion up to 2014, and recent evolution is unknown. Our aim was to analyze the recent diffusion and adoption of MILS and compare the trends in indications, extent of resection, and institutional practice with open liver surgery (OLS). METHODS: We analyzed the French nationwide, exhaustive cohort of all patients undergoing a liver resection in France between January 1, 2013 and December 31, 2022. Average annual percentage changes (AAPC) in the incidence of MILS and OLS were compared using mixed-effects log-linear regression models. Time trends were analyzed in terms of extent of resection, indication, and institutional practice. RESULTS: MILS represented 25.2% of 74,671 liver resections and year incidence doubled from 16.5% in 2013 to 35.4% in 2022. The highest AAPC were observed among major liver resections [+ 22.2% (19.5; 24.9) per year], primary [+ 10.2% (8.5; 12.0) per year], and secondary malignant tumors [+ 9.9% (8.2; 11.6) per year]. The highest increase in MILS was observed in university hospitals [+ 14.7% (7.7; 22.2) per year] performing 48.8% of MILS and in very high-volume (> 150 procedures/year) hospitals [+ 12.1% (9.0; 15.3) per year] performing 19.7% of MILS. OLS AAPC decreased for all indications and institutions and accelerated over time from - 1.8% (- 3.9; - 0.3) per year in 2013-2018 to - 5.9% (- 7.9; - 3.9) per year in 2018-2022 (p = 0.013). CONCLUSIONS: This is the first reported trend reversal between MILS and OLS. MILS has considerably increased at a national scale, crossing the 20% tipping point of adoption rate as defined by the IDEAL framework.

Clinical care pathways of patients with biliary tract cancer: A French nationwide longitudinal cohort study.

BACKGROUND: Although the incidence of BTC is raising, national healthcare strategies to improve care lack. We aimed to explore patient clinical care pathways and strategies to improve biliary tract cancer (BTC) care. METHODS: We analysed the French National Healthcare database of all BTC inpatients between January 1, 2017 and December 31, 2021. Multinomial logistic regression adjusted odds ratios (aOR) were used to identify healthcare organisation factors that influenced access to curative care both overall and in a longitudinal sensibility analysis using optimal matching and hierarchical ascending classification to detect a subgroup of curative-care patients with a high survival over a two-year period. RESULTS: A total of 19,825 new BTC patients and three clinical care pathways (CCP) were identified: 'Palliative care' (PC-CCP), 'Non-curative Care' (NCC-CCP) and 'Curative Care' (CC-CCP) involving 7669 (38.7%), 7721 (38.9%) and 4435 (22.4%) patients respectively. Out of 1200 centers involved in BTC treatment, 84%, 11% and 5% were of low- (<15 patients/year), medium- (15-30 patients/year) and high-volume (>30 patients/year) respectively. Among patient, tumor and hospital factors, BTC management in academic (aOR: 2.32; 95%CI: 1.98-2.71), private (2.51; 2.22-2.83), semi-private (2.25; 1.91-2.65) and in high- (2.09; 1.81-2.42) or medium-volume (1.49; 1.33-1.68) centers increased probability to CC-CCP. These results were maintained in a longitudinal cluster of 2363 (53%) CC-CCP patients presenting a higher two-year survival compared with the rest [96.4% (95.1; 97.6) vs. 38.8% (36.3; 41.4), log-rank p < 0.001]. CONCLUSIONS: Among factors subject to healthcare policy improvement, the volume and type of centers managing BTC strongly influenced access to curative care.

Cardiovascular disease healthcare trajectories: descriptions, similarities, mortality rates of heart failure in France.

AIMS: The primary objectives of this study were to analyse the nationwide healthcare trajectories of heart failure (HF) patients in France, 2 years after their first hospitalization, and to measure sequence similarities. Secondary objectives were to identify the association between trajectories and the risk of mortality. METHODS AND RESULTS: A retrospective, observational study was conducted using data extracted from the Echantillon Généraliste des Bénéficiaires database, covering the period from 1 January 2008 to 31 December 2018. Follow-up concluded upon death or at the end of the study. We developed a methodology specific to healthcare data by extracting frequent healthcare trajectories and measuring their similarity for use in a survival machine learning analysis. In total, 11 488 HF patients were included and followed up for an average of 2.9 ± 1.3 years. The mean age of the patients was 78.0 ± 13.2 years. The first-year mortality rate was 31.7% and increased to 78.8% at 5 years. Fifty per cent of patients experienced re-hospitalization for reasons related to cardiovascular diseases. We identified 1707 hospitalization sequences, and 21 sequences were associated with survival, while 15 sequences were linked to mortality. In all our models, age and gender emerged as the most significant predictors of mortality (permutation feature importance: 0.099 ± 0.00078 and 0.0087 ± 0.00018, respectively; weights could be interpreted in relative terms). Specifically, the age at initial hospitalization for HF was positively associated with mortality. Gender (male: 49.5%) was associated with poorer prognoses. Healthcare trajectories, including non-surgical device treatments, valve replacements, and atrial fibrillation ablation, were associated with a better prognosis (permutation feature importance: 0.0047 ± 0.00011, 0.0014 ± 0.000073, and 0.00095 ± 0.000097, respectively), except in cases where these invasive treatments preceded or followed hospitalization for cardiac decompensation. The predominant negative prognosis sequences were mostly those that included HF-related hospitalizations before or after other-related hospitalizations (permutation feature importance: 0.0007 ± 0.000091 and 0.00011 ± 0.000045, respectively). CONCLUSIONS: We highlight the value of healthcare trajectories on frequent hospitalization sequences, mortality, and prognosis and indicate the necessary prognostic value of HF re-hospitalization. Our work may be an essential tool for better identification of at-risk patients in order to increase and improve personalized care in the future.

Protocol for fever control using external cooling in mechanically ventilated patients with septic shock: SEPSISCOOL II randomised controlled trial.

INTRODUCTION: Fever treatment is commonly applied in patients with sepsis but its impact on survival remains undetermined. Patients with respiratory and haemodynamic failure are at the highest risk for not tolerating the metabolic cost of fever. However, fever can help to control infection. Treating fever with paracetamol has been shown to be less effective than cooling. In the SEPSISCOOL pilot study, active fever control by external cooling improved organ failure recovery and early survival. The main objective of this confirmatory trial is to assess whether fever control at normothermia can improve the evolution of organ failure and mortality at day 60 of febrile patients with septic shock. This study will compare two strategies within the first 48 hours of septic shock: treatment of fever with cooling or no treatment of fever. METHODS AND ANALYSIS: SEPSISCOOL II is a pragmatic, investigator-initiated, adaptive, multicentre, open-label, randomised controlled, superiority trial in patients admitted to the intensive care unit with febrile septic shock. After stratification based on the acute respiratory distress syndrome status, patients will be randomised between two arms: (1) cooling and (2) no cooling. The primary endpoint is mortality at day 60 after randomisation. The secondary endpoints include the evolution of organ failure, early mortality and tolerance. The target sample size is 820 patients. ETHICS AND DISSEMINATION: The study is funded by the French health ministry and was approved by the ethics committee CPP Nord Ouest II (Amiens, France). The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04494074.

MS-CPFI: A model-agnostic Counterfactual Perturbation Feature Importance algorithm for interpreting black-box Multi-State models.

Multi-state processes (Webster, 2019) are commonly used to model the complex clinical evolution of diseases where patients progress through different states. In recent years, machine learning and deep learning algorithms have been proposed to improve the accuracy of these models' predictions (Wang et al., 2019). However, acceptability by patients and clinicians, as well as for regulatory compliance, require interpretability of these algorithms's predictions. Existing methods, such as the Permutation Feature Importance algorithm, have been adapted for interpreting predictions in black-box models for 2-state processes (corresponding to survival analysis). For generalizing these methods to multi-state models, we introduce a novel model-agnostic interpretability algorithm called Multi-State Counterfactual Perturbation Feature Importance (MS-CPFI) that computes feature importance scores for each transition of a general multi-state model, including survival, competing-risks, and illness-death models. MS-CPFI uses a new counterfactual perturbation method that allows interpreting feature effects while capturing the non-linear effects and potentially capturing time-dependent effects. Experimental results on simulations show that MS-CPFI increases model interpretability in the case of non-linear effects. Additionally, results on a real-world dataset for patients with breast cancer confirm that MS-CPFI can detect clinically important features and provide information on the disease progression by displaying features that are protective factors versus features that are risk factors for each stage of the disease. Overall, MS-CPFI is a promising model-agnostic interpretability algorithm for multi-state models, which can improve the interpretability of machine learning and deep learning algorithms in healthcare.

A systematic review and meta-analysis of the incidence of post-thrombotic syndrome, recurrent thromboembolism, and bleeding after upper extremity vein thrombosis.

BACKGROUND: Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous. METHODS: The aim of the present study was to evaluate the pooled proportions of venous thromboembolism (VTE) recurrence, bleeding, and post-thrombotic syndrome (PTS) in patients with UEVT. A systematic literature review was conducted of PubMed, Embase, and the Cochrane Library databases from January 2000 to April 2023 in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. All studies included patients with UEVT and were published in English. Meta-analyses of VTE recurrence, bleeding, and of PTS after UEVT were performed to compute pooled estimates and associated 95% confidence intervals (CIs). Subgroup analyses of cancer-associated UEVT and catheter-associated venous thrombosis were conducted. Patients with Paget-Schroetter syndrome or effort thrombosis were excluded. RESULTS: A total of 55 studies with 15,694 patients were included. The pooled proportions for VTE recurrence, major bleeding, and PTS were 4.8% (95% CI, 3.8%-6.2%), 3.0% (95% CI, 2.2%-4.0%), and 23.8% (95% CI, 17.0%-32.3%), respectively. The pooled proportion of VTE recurrence was 2.7% (95% CI, 1.6%-4.6%) for patients treated with direct oral anticoagulants (DOACs), 1.7% (95% CI, 0.8%-3.7%) for patients treated with low-molecular-weight heparin (LMWH), and 4.4% (95% CI, 1.5%-11.8%) for vitamin K antagonists (VKAs; P = .36). The pooled proportion was 6.3% (95% CI, 4.3%-9.1%) for cancer patients compared with 3.1% (95% CI, 2.1%-4.6%) for patients without cancer (P = .01). The pooled proportion of major bleeding for patients treated with DOACs, LMWH, and VKAs, was 2.1% (95% CI, 0.9%-5.1%), 3.2% (95% CI, 1.4%-7.2%), and 3.4% (95% CI, 1.4%-8.4%), respectively (P = .72). The pooled proportion of PTS for patients treated with DOACs, LMWH, and VKAs was 11.8% (95% CI, 6.5%-20.6%), 27.9% (95% CI, 20.9%-36.2%), and 24.5% (95% CI, 17.6%-33.1%), respectively (P = .02). CONCLUSIONS: The results from this study suggest that UEVT is associated with significant rates of PTS and VTE recurrence. Treatment with DOACs might be associated with lower PTS rates than treatment with other anticoagulants.

Risk factors for thromboembolic events in patients hospitalized for COVID-19 pneumonia in a general ward and requiring treatment with oxygen.

PURPOSE: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy. METHODS: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events. RESULTS: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage. CONCLUSION: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered.

Pharmacovigilance studies without a priori hypothesis: systematic review highlights inappropriate multiple testing correction procedures.

OBJECTIVES: The purpose of this study was to systematically review the statistical methods used in pharmacovigilance studies without a priori hypotheses. STUDY DESIGN AND SETTING: A systematic review was performed on studies published in the MEDLINE database between 2012 and 2021. The included studies were analyzed for database name and type, statistical methods, anatomical therapeutic chemical class for the studied drug(s), and SOC MedDRA classification for the studied adverse drug reaction. RESULTS: Ninety-two studies were included, with pharmacovigilance databases being the most used type. Disproportionality analysis using frequentist or Bayesian methods was the most common statistical method employed. The most studied drug classes were anti-infectives, nervous system drugs, and antineoplastics and immunomodulators. However, no common procedure was implemented to correct for multiple testing. CONCLUSION: This review highlights the limited number of statistical methods employed for pharmacovigilance studies without a priori hypotheses, with no established consensus-based method and a lack of interest in multiple testing correction. The establishment of guidelines is recommended to improve the performance of such studies.

Development and Validation of a Multi-institutional Nomogram of Outcomes for PSMA-PET-Based Salvage Radiotherapy for Recurrent Prostate Cancer.

Importance: Prostate-specific antigen membrane positron-emission tomography (PSMA-PET) is increasingly used to guide salvage radiotherapy (sRT) after radical prostatectomy for patients with recurrent or persistent prostate cancer. Objective: To develop and validate a nomogram for prediction of freedom from biochemical failure (FFBF) after PSMA-PET-based sRT. Design, Setting, and Participants: This retrospective cohort study included 1029 patients with prostate cancer treated between July 1, 2013, and June 30, 2020, at 11 centers from 5 countries. The initial database consisted of 1221 patients. All patients had a PSMA-PET scan prior to sRT. Data were analyzed in November 2022. Exposures: Patients with a detectable post-radical prostatectomy prostate-specific antigen (PSA) level treated with sRT to the prostatic fossa with or without additional sRT to pelvic lymphatics or concurrent androgen deprivation therapy (ADT) were eligible. Main Outcomes and Measures: The FFBF rate was estimated, and a predictive nomogram was generated and validated. Biochemical relapse was defined as a PSA nadir of 0.2 ng/mL after sRT. Results: In the nomogram creation and validation process, 1029 patients (median age at sRT, 70 years [IQR, 64-74 years]) were included and further divided into a training set (n = 708), internal validation set (n = 271), and external outlier validation set (n = 50). The median follow-up was 32 months (IQR, 21-45 months). Based on the PSMA-PET scan prior to sRT, 437 patients (42.5%) had local recurrences and 313 patients (30.4%) had nodal recurrences. Pelvic lymphatics were electively irradiated for 395 patients (38.4%). All patients received sRT to the prostatic fossa: 103 (10.0%) received a dose of less than 66 Gy, 551 (53.5%) received a dose of 66 to 70 Gy, and 375 (36.5%) received a dose of more than 70 Gy. Androgen deprivation therapy was given to 325 (31.6%) patients. On multivariable Cox proportional hazards regression analysis, pre-sRT PSA level (hazard ratio [HR], 1.80 [95% CI, 1.41-2.31]), International Society of Urological Pathology grade in surgery specimen (grade 5 vs 1+2: HR, 2.39 [95% CI, 1.63-3.50], pT stage (pT3b+pT4 vs pT2: HR, 1.91 [95% CI, 1.39-2.67]), surgical margins (R0 vs R1+R2+Rx: HR, 0.60 [95% CI, 0.48-0.78]), ADT use (HR, 0.49 [95% CI, 0.37-0.65]), sRT dose (>70 vs ≤66 Gy: HR, 0.44 [95% CI, 0.29-0.67]), and nodal recurrence detected on PSMA-PET scans (HR, 1.42 [95% CI, 1.09-1.85]) were associated with FFBF. The mean (SD) nomogram concordance index for FFBF was 0.72 (0.06) for the internal validation cohort and 0.67 (0.11) in the external outlier validation cohort. Conclusions and Relevance: This cohort study of patients with prostate cancer presents an internally and externally validated nomogram that estimated individual patient outcomes after PSMA-PET-guided sRT.

Incidence of and risk factors for local complications of peripheral venous catheters in patients older than 70 years: Empirical research quantitative.

AIMS: To assess the incidence density of local complications of peripheral venous catheters in patients aged 70 years and older, to identify risk factors for local complications of peripheral venous catheters, to describe microbiological epidemiology and to assess the impact of complications on patient outcomes. DESIGN: Prospective, observational, single-centre study. METHODS: Patients 70 years and older admitted to the geriatric department of a teaching hospital in France between December 2019 and May 2020 were considered for inclusion if they had a peripheral venous catheter during their stay. Nurses checked the catheter insertion site three times a day for local complications; physicians ensured the follow-up of complications. The STROBE checklist was used in this prospective observational study. RESULTS: A total of 322 patients were included, with 849 peripheral venous catheters; the median age was 88 years and 182 (56.5%) were women. The incidence density of local complications was 50.5/1000 peripheral venous catheter-days. Risk factors for local complications on multivariate analysis were dressing replacement (OR 1.18), furosemide (OR 1.11) and vancomycin (OR 1.60) infusion, urinary continence (OR 1.09) and hematoma at the catheter insertion site (OR 1.15). Thirteen cellulitis and three abscesses were diagnosed. Occurrence of a local complication was associated with a 3-day increased duration of hospital stay (17 vs. 14 days). CONCLUSION: Risk factors for peripheral venous catheter local complications include urinary continence, furosemide or vancomycin infusion, hematoma at the peripheral venous catheter insertion site or dressing replacement. IMPLICATION FOR THE PATIENT CARE: Closer clinical monitoring may help reduce the occurrence of local peripheral venous catheters complication in patients 70 years and older. RELEVANCE TO CLINICAL PRACTICE: Patients at greater risk of peripheral venous catheter local complications deserve closer clinical monitoring or improved preventive measures, which may be beneficial to reduce the length of hospital stay. NO PATIENT OR PUBLIC CONTRIBUTION: The study was designed to describe risk factors for local complications of peripheral venous catheters in order to reinforce surveillance in this specific population by nurses and medical staffs. Patients had their peripheral venous catheter insertion site checked thrice a day by the nurse in charge as part of usual care. They, as service users, caregivers or members of the public, were not solicited for data collection, analysis, interpretation or preparation of the manuscript.

Regulatory T cells infiltrate the tumor-induced tertiary lymphoïd structures and are associated with poor clinical outcome in NSCLC.

On one hand, regulatory T cells (Tregs) play an immunosuppressive activity in most solid tumors but not all. On the other hand, the organization of tumor-infiltrating immune cells into tertiary lymphoid structures (TLS) is associated with long-term survival in most cancers. Here, we investigated the role of Tregs in the context of Non-Small Cell Lung Cancer (NSCLC)-associated TLS. We observed that Tregs show a similar immune profile in TLS and non-TLS areas. Autologous tumor-infiltrating Tregs inhibit the proliferation and cytokine secretion of CD4+ conventional T cells, a capacity which is recovered by antibodies against Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4) and Glucocorticoid-Induced TNFR-Related protein (GITR) but not against other immune checkpoint (ICP) molecules. Tregs in the whole tumor, including in TLS, are associated with a poor outcome of NSCLC patients, and combination with TLS-dendritic cells (DCs) and CD8+ T cells allows higher overall survival discrimination. Thus, Targeting Tregs especially in TLS may represent a major challenge in order to boost anti-tumor immune responses initiated in TLS.

Plasma CD27, a Surrogate of the Intratumoral CD27-CD70 Interaction, Correlates with Immunotherapy Resistance in Renal Cell Carcinoma.

PURPOSE: CD70 is a costimulatory molecule known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). Clear-cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors; however, the clinical consequences of CD70 expression remain unclear. EXPERIMENTAL DESIGN: Tumor tissue from 25 patients with ccRCC was assessed for the expression of CD27 and CD70 in situ using multiplex immunofluorescence. CD27+ T-cell phenotypes in tumors were analyzed by flow cytometry and their gene expression profile were analyzed by single-cell RNA sequencing then confirmed with public data. Baseline sCD27 was measured in 81 patients with renal cell carcinoma (RCC) treated with immunotherapy (35 for training cohort and 46 for validation cohort). RESULTS: In the tumor microenvironment, CD27+ T cells interacted with CD70-expressing tumor cells. Compared with CD27- T cells, CD27+ T cells exhibited an apoptotic and dysfunctional signature. In patients with RCC, the intratumoral CD27-CD70 interaction was significantly correlated with the plasma sCD27 concentration. High sCD27 levels predicted poor overall survival in patients with RCC treated with anti-programmed cell death protein 1 in both the training and validation cohorts but not in patients treated with antiangiogenic therapy. CONCLUSIONS: In conclusion, we demonstrated that sCD27, a surrogate marker of T-cell dysfunction, is a predictive biomarker of resistance to immunotherapy in RCC. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be extended to other tumors.

Identifying homogeneous healthcare use profiles and treatment sequences by combining sequence pattern mining with care trajectory clustering in kidney cancer patients on oral anticancer drugs: A case study.

OBJECTIVE: We evaluated the ability of a coupled pattern-mining and clustering method to identify homogeneous groups of subjects in terms of healthcare resource use, prognosis and treatment sequences, in renal cancer patients beginning oral anticancer treatment. METHODS: Data were retrieved from the permanent sample of the French medico-administrative database. We applied the CP-SPAM algorithm for pattern mining to healthcare use sequences, followed by hierarchical clustering on principal components (HCPC). RESULTS AND CONCLUSION: We identified 127 individuals with renal cancer with a first reimbursement of an oral anticancer drug between 2010 and 2017. Clustering identified three groups of subjects, and discrimination between these groups was good. These clusters differed significantly in terms of mortality at six and 12 months, and medical follow-up profile (predominantly outpatient or inpatient care, biological monitoring, reimbursement of supportive care drugs). This case study highlights the potential utility of applying sequence-mining algorithms to a large range of healthcare reimbursement data, to identify groups of subjects homogeneous in terms of their care pathways and medical behaviors.

IDNetwork: A deep illness-death network based on multi-state event history process for disease prognostication.

Multi-state models can capture the different patterns of disease evolution. In particular, the illness-death model is used to follow disease progression from a healthy state to an intermediate state of the disease and to a death-related final state. We aim to use those models in order to adapt treatment decisions according to the evolution of the disease. In state-of-the art methods, the risks of transition between the states are modeled via (semi-) Markov processes and transition-specific Cox proportional hazard (P.H.) models. The Cox P.H. model assumes that each variable makes a linear contribution to the model, but the relationship between covariates and risks can be more complex in clinical situations. To address this challenge, we propose a neural network architecture called illness-death network (IDNetwork) that relaxes the linear Cox P.H. assumption within an illness-death process. IDNetwork employs a multi-task architecture and uses a set of fully connected subnetworks in order to learn the probabilities of transition. Through simulations, we explore different configurations of the architecture and demonstrate the added value of our model. IDNetwork significantly improves the predictive performance compared to state-of-the-art methods on a simulated data set, on two clinical trials for patients with colon cancer and on a real-world data set in breast cancer.

Overall Survival and Prognostic Factors among Older Patients with Metastatic Pancreatic Cancer: A Retrospective Analysis Using a Hospital Database.

Pre-therapeutic factors associated with overall survival (OS) among older patients ≥70 years with metastatic pancreatic cancer (mPC) are not known. This was a retrospective single-centre cohort study in Paris including 159 consecutive older patients with mPC between 2000 and 2018. Alongside geriatric parameters, specific comorbidities, cancer-related data and chemotherapy regimens were retrieved. Cox multivariate models were run to assess predictors for OS. The median age was 80 years, 52% were women, 21.5% had diabetes, and 48% had pancreatic head cancer and 72% liver metastases. 62% of the patients (n = 99) received chemotherapy, among which the gemcitabine + nab-paclitaxel (GnP) regimen was the most frequent (72%). Median OS [95%CI] was 7.40 [5.60-10.0] and 1.40 [0.90-2.20] months respectively for patients with and without chemotherapy. The GnP regimen (aHR [95%CI] = 0.47 [0.25-0.89], p = 0.02) and diabetes (aHR = 0.44 [0.24-0.77], p = 0.004) (or anti-diabetic therapy) were multivariate protective factors for death, while ECOG-PS, liver metastases, and the neutrophil cell count were multivariate risk factors for death. In the chemotherapy group, ECOG-PS, number of metastatic sites and the GnP remained significantly associated with OS. Our study confirms the feasibility and efficacy of chemotherapy and the protective effects of diabetes among older patients with mPC.