Venetoclax-based non-intensive induction followed by allogenic stem-cell transplantation in elderly acute myeloid leukemia patients with adverse cytogenetics.

INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

Genetic deletion of JAM-C in preleukemic cells rewires leukemic stem cell gene expression program in AML.

ABSTRACT: The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether "niche anchoring" of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of "not reached" after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656.

Empirical antifungal therapy for health care-associated intra-abdominal infection: a retrospective, multicentre and comparative study.

BACKGROUND: Current guidelines recommend using antifungals for selected patients with health care-associated intra-abdominal infection (HC-IAI), but this recommendation is based on a weak evidence. This study aimed to assess the association between early empirical use of antifungals and outcomes in intensive care unit (ICU) adult patients requiring re-intervention after abdominal surgery. METHODS: A retrospective, multicentre cohort study with overlap propensity score weighting was conducted in three ICUs located in three medical institutions in France. Patients treated with early empirical antifungals for HC-IAI after abdominal surgery were compared with controls who did not receive such antifungals. The primary endpoint was the death rate at 90 days, and the secondary endpoints were the death rate at 1 year and composite criteria evaluated at 30 days following the HC-IAI diagnosis, including the need for re-intervention, inappropriate antimicrobial therapy and death, whichever occurred first. RESULTS: At 90 days, the death rate was significantly decreased in the patients treated with empirical antifungals compared with the control group (11.4% and 20.7%, respectively, p = 0.02). No differences were reported for the secondary outcomes. CONCLUSION: The use of early empirical antifungal therapy was associated with a decreased death rate at 90 days, with no effect on the death rate at 1 year, the death rate at 30 days, the rate of re-intervention, the need for drainage, and empirical antibiotic and antifungal therapy failure at 30 days.

Group sequential methods based on supremum logrank statistics under proportional and nonproportional hazards.

Despite the widespread use of Cox regression for modeling treatment effects in clinical trials, in immunotherapy oncology trials and other settings therapeutic benefits are not immediately realized thereby violating the proportional hazards assumption. Weighted logrank tests and the so-called Maxcombo test involving the combination of multiple logrank test statistics have been advocated to increase power for detecting effects in these and other settings where hazards are nonproportional. We describe a testing framework based on supremum logrank statistics created by successively analyzing and excluding early events, or obtained using a moving time window. We then describe how such tests can be conducted in a group sequential trial with interim analyses conducted for potential early stopping of benefit. The crossing boundaries for the interim test statistics are determined using an easy-to-implement Monte Carlo algorithm. Numerical studies illustrate the good frequency properties of the proposed group sequential methods.

Tripartite prehabilitation of patients with acute myeloid leukaemia and high-risk myelodysplastic syndromes during intensive chemotherapy before allogeneic haematopoietic stem cell transplantation (COHABILIT): protocol for an innovating prospective multicentre study.

OBJECTIVES: Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with intensive chemotherapy followed by allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pretransplant treatment results in a general deterioration of the patient's health and quality of life. Furthermore, allo-HSCT can be responsible for significant toxicity with risks of graft-versus-host disease (GvHD). Developing strategies to prevent physical deconditioning, undernutrition and psychological distress could help maintain a satisfactory general state of health before transplantation and thus limit these deleterious effects. This protocol evaluates the feasibility and adherence to a personalised prehabilitation programme, which can be modulated and assisted by connected objects, provided from the diagnosis to the allo-HSCT. METHODS AND ANALYSIS: This multicentre interventional study will include 50 patients treated for AML or high-risk MDS with intensive chemotherapy and eligible for allo-HSCT. The intervention consists of a coached, supervised or self-directed physical activity programme, organised during the hospitalisation phases and periods at home. At the same time, patients will receive a weekly dietary follow-up. The whole intervention is controlled and modulated through the use of a dedicated application and connected objects allowing adaptation and individualisation. The rate of participation in the prescribed physical activity sessions will assess the feasibility of this study. In addition, the evolution of physical capacities (Short Physical Performance Battery, grip and quadriceps strengths), psychosocial parameters (Functional Assessment of Cancer Therapy - Leukaemia, Functional Assessment of Cancer Therapy - Fatigue, subjective well-being, Hospital Anxiety and Depression Scale, self-efficacy, Coach-Athlete Relationship Questionnaire, interviews) and clinical status (weight, lean body mass, survival rate, number of infections, days of hospitalisation, GvHD) will be evaluated. ETHICS AND DISSEMINATION: The study procedures have been approved by the National Ethics Committee (21.00223.000003). Consent is given in person by each participant. The information collected on the participants contains only a non-identifiable study identifier. The results of this protocol will be published in a scientific paper and communicated to the medical staff of the medical centre. TRIAL REGISTRATION NUMBER: NCT03595787.

Does Breast Surgery Type Alter Incidental Axillary Irradiation? A Dosimetric Analysis of the "Sentinel Envahi et Randomisation du Curage" SERC Trial.

BACKGROUND: An incidental axillary dose of adjuvant radiotherapy using tangential beams is usually given after breast-conserving surgery for breast cancer. The goal of this sub-study was to evaluate this incidental dose in the setting of post-mastectomy radiotherapy (PMRT) according to two different radiotherapy techniques. METHODS: Patients participating in a randomized SERC trial who received PMRT in a single center were included. We collected the incidental axillary dose delivered to the Berg level 1 using different dosimetric parameters and compared two techniques using Student's t-test: three-dimensional conformal radiotherapy (3D-CRT) and volumetric arc therapy (VMAT). RESULTS: We analyzed radiotherapy plans from 52 patients who received PMRT from 2012 to 2021. The mean dose delivered to the Berg level 1 was 37.2 Gy. It was significantly higher with VMAT than with 3D-CRT-43.6 Gy (SD = 3.1 Gy) versus 34.8 Gy (SD = 8.6 Gy) p < 0.001. Eighty-four percent of the Berg level 1 was covered by 40 Gy isodose in the VMAT group versus 55.5% in the 3D-CRT group p < 0.001. CONCLUSIONS: On the Berg level 1, PMRT gives a dose at least equivalent to the one given by post-breast-conserving surgery radiotherapy, making it possible to limit completion axillary lymph node dissections in select pN1a patients treated with a mastectomy. Modern radiotherapy techniques like VMAT tend to increase this incidental dose.

Dysthyroidism during immune checkpoint inhibitors is associated with improved overall survival in adult cancers: data mining of 1385 electronic patient records.

BACKGROUND: Dysthyroidism (DT) is a common toxicity of immune checkpoint inhibitors (ICIs) and prior work suggests that dysthyroidism (DT) might be associated with ICI efficacy. PATIENTS AND METHODS: ConSoRe, a new generation data mining solution, was used in this retrospective study, to extract data from electronic patient records of adult cancer patients treated with ICI at Institut Paoli-Calmettes (Marseille, France). Every DT was verified and only ICI-induced DT was retained. Survival analyses were performed by Kaplan-Meier method (log-rank test) and Cox model. To account for immortal time bias, a conditional landmark analysis was performed (2 months and 6 months), together with a time-varying Cox model. RESULTS: Data extraction identified 1385 patients treated with ICI between 2011 and 2021. DT was associated with improved overall survival (OS) (HR 0.46, (95% CI 0.33 to 0.65), p<0.001), with a median OS of 35.3 months in DT group vs 15.4 months in non-DT group (NDT). Survival impact of DT was consistent using a 6-month landmark analysis with a median OS of 36.7 months (95% CI 29.4 to not reported) in the DT group vs 25.5 months (95% CI 22.8 to 27.8) in the NDT group. In multivariate analysis, DT was independently associated with improved OS (HR 0.49, 95% CI 0.35 to 0.69, p=0.001). After adjustment in time-varying Cox model, this association remained significant (adjusted HR 0.64, 95% CI 0.45 to 0.90, p=0.010). Moreover, patients with DT and additional immune-related adverse event had increased OS compared with patients with isolated DT, with median OS of 38.8 months vs 21.4 months, respectively. CONCLUSION: Data mining identified a large number of patients with ICI-induced DT, which was associated with improved OS accounting for immortal time bias.

Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.

BACKGROUND: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. METHODS: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. FINDINGS: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). INTERPRETATION: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. FUNDING: UK Medical Research Council and Prostate Cancer UK.

Enhanced Recovery after Surgery and Endometrial Cancers: Results from an Initial Experience Focused on Elderly Patients.

Endometrial cancer is the fifth most common cancer among French women and occurs most frequently in the over-70-year-old population. Recent years have seen a significant shift towards minimally invasive surgery and Enhanced Recovery After Surgery (ERAS) protocols in endometrial cancer management. However, the impact of ERAS on endometrial cancer has not been well-established. We conducted a prospective observational study in a comprehensive cancer center, comparing the outcomes between endometrial cancer patients who received care in an ERAS pathway (261) and those who did not (166) between 2006 and 2020. We performed univariate and multivariate analysis. Our primary objective was to evaluate the impact of ERAS on length of hospital stay (LOS), with the secondary objectives being the determination of the rates of early discharge, post-operative morbidity, and rehospitalization. We found that patients in the ERAS group had a significantly shorter length of stay, with an average of 3.18 days compared to 4.87 days for the non-ERAS group (estimated decrease -1.69, p < 0.0001). This effect was particularly pronounced among patients over 70 years old (estimated decrease -2.06, p < 0.0001). The patients in the ERAS group also had a higher chance of early discharge (47.5% vs. 14.5% in the non-ERAS group, p < 0.0001), for which there was not a significant increase in post-operative complications. Our study suggests that ERAS protocols are beneficial for the management of endometrial cancer, particularly for older patients, and could lead to the development of ambulatory pathways.

A non-inferiority randomized phase III trial of standard immunotherapy by checkpoint inhibitors vs. reduced dose intensity in responding patients with metastatic cancer: the MOIO protocol study.

BACKGROUND: Immunotherapy (IO) has become a standard of care for treating various types of metastatic cancers and has significantly improved clinical outcome. With the exception of metastatic melanoma in complete response for which treatment can be stopped at 6 months, these treatments are currently administered until either disease progression for some IO, 2 years for others, or unacceptable toxicity. However, a growing number of studies are reporting maintenance of response despite discontinuation of therapy. There is currently no evidence of a dose effect of IO in pharmacokinetic studies. Maintaining efficacy despite a reduction in treatment intensity by decreasing the frequency of administration in patients with highly selected metastatic cancer, is the hypothesis evaluated in the MOIO study. METHOD/DESIGN: This non-inferiority, randomized phase III study aims to compare the standard regimen to a 3 monthly regimen of variousIO drugs in adult patients with metastatic cancer in partial (PR) or complete response (CR) after 6 months of standard IO dosing (except melanoma in CR). This is a French national study conducted in 36 centers. The main objective is to demonstrate that the efficacy of a three-monthly administration is not unacceptably less efficacious than a standard administration. Secondary objectives are cost-effectiveness, quality of life (QOL), anxiety, fear of relapse, response rate, overall survival and toxicity. After 6 months of standard IO, patients with partial or complete response will be randomized 1:1 between standard IO or a reduced intensity dose of IO, administered every 3 months. The randomization will be stratified on therapy line,, tumor type, IO type and response status. The primary endpoint is the hazard ratio of progression-free survival. With a planned study duration of 6 years, including 36 months enrolment time, 646 patients are planned to demonstrate with a statistical level of evidence of 5% that the reduced IO regimen is non-inferior to the standard IO regimen, with a relative non-inferiority margin set at 1.3. DISCUSSION: Should the hypothesis of non-inferiority with an IO reduced dose intensity be validated, alternate scheduling could preserve efficacy while being cost-effective and allowing a reduction of the toxicity, with an increase in patient's QOL. TRIAL REGISTRATION: NCT05078047.

Is MRI-Linac helpful in SABR treatments for liver cancer?

Objective: To determine the MRI-Linac added value over conventional image-guided radiation therapy (IGRT) in liver tumors Stereotactic ablative radiation therapy (SABR). Materials and methods: We retrospectively compared the Planning Target Volumes (PTVs), the spared healthy liver parenchyma volumes, the Treatment Planning System (TPS) and machine performances, and the patients' outcomes when using either a conventional accelerator (Versa HD®, Elekta, Utrecht, NL) with Cone Beam CT as the IGRT tool or an MR-Linac system (MRIdian®, ViewRay, CA). Results: From November 2014 to February 2020, 59 patients received a SABR treatment (45 and 19 patients in the Linac and MR-Linac group, respectively) for 64 primary or secondary liver tumors. The mean tumor size was superior in the MR-Linac group (37,91cc vs. 20.86cc). PTV margins led to a median 74%- and 60% increase in target volume in Linac-based and MRI-Linac-based treatments, respectively. Liver tumor boundaries were visible in 0% and 72% of the cases when using CBCT and MRI as IGRT tools, respectively. The mean prescribed dose was similar in the two patient groups. Local tumor control was 76.6%, whereas 23.4% of patients experienced local progression (24.4% and 21.1% of patients treated on the conventional Linac and the MRIdian system, respectively). SABR was well tolerated in both groups, and margins reduction and the use of gating prevented ulcerous disease occurrence. Conclusion: The use of MRI as IGRT allows for the reduction of the amount of healthy liver parenchyma irradiated without any decrease of the tumor control rate, which would be helpful for dose escalation or subsequent liver tumor irradiation if needed.

New late-emphasis and combination tests based on infimum and supremum logrank statistics with application in oncology trials.

Immunotherapy cancer clinical trials routinely feature an initial period during which the treatment is given without evident therapeutic benefit, which may be followed by a period during which an effective therapy reduces the hazard for event occurrence. The nature of this treatment effect is incompatible with the proportional hazards assumption, which has prompted much work on the development of alternative effect measures of frameworks for testing. We consider tests based on individual and combination of early- and late-emphasis infimum and supremum logrank statistics, describe how they can be implemented, and evaluate their performance in simulation studies. Through this work and illustrative applications we conclude that this class of test statistics offers a new and powerful framework for assessing treatment effects in cancer clinical trials involving immunotherapies.

The need to tailor the omission of axillary lymph node dissection to patients with good prognosis and sentinel node micro-metastases.

BACKGROUND: Results of IBCSG-23-01-trial which included breast cancer patients with involved sentinel nodes (SN) by isolated-tumor-cells or micro-metastases supported the non-inferiority of completion axillary-lymph-node-dissection (cALND) omission. However, current data are considered insufficient to avoid cALND for all patients with SN-micro-metastases. METHODS: To investigate the impact of cALND omission on disease-free-survival (DFS) and overall survival (OS), we analyzed a cohort of 1421 patients <75 years old with SN-micro-metastases who underwent breast conservative surgery (BCS). We used inverse probability of treatment weighting (IPTW) to obtain adjusted Kaplan-Meier estimators representing the experience in the analysis cohort, based on whether all or none had been subject to cALND omission. RESULTS: Weighted log-rank tests comparing adjusted Kaplan-Meier survival curves showed significant differences in OS (p-value = 0.002) and borderline significant differences in DFS (p-value = 0.090) between cALND omission versus cALND. Cox's regression using stabilized IPTW evidenced an average increase in the risk of death associated with cALND omission (HR = 2.77, CI95% = 1.36-5.66). Subgroup analyses suggest that the rates of recurrence and death associated with cALND omission increase substantially after a large period of time in the half sample of women less likely to miss cALND. CONCLUSIONS: Using IPTW to estimate the causal treatment effect of cALND in a large retrospective cohort, we concluded cALND omission is associated with an increased risk of recurrence and death in women of <75 years old treated by BCS in the absence of a large consensus in favor of omitting cALND. These results are particularly contributive for patients treated by BCS where cALND omission rates increase over time.

EUS-guided hepaticogastrostomy in patients with obstructive jaundice after failed or impossible endoscopic retrograde drainage: A multicenter, randomized phase II Study.

Background and Objectives: Over the last two decades, EUS-guided hepaticogastrostomy (EUS-HGS) has emerged as a therapeutic alternative for patients with biliary obstruction and failed ERCP. Percutaneous transhepatic biliary drainage (PTBD) as the gold standard is associated with relevant morbidity and need for re-intervention. The aim of our work was to evaluate in a phase II study the safety and efficacy profile of EUS-HGS. A PTBD arm was considered a control group. Patients and Methods: We conducted a prospective, randomized, noncomparative phase II study in three French tertiary centers involving patients with benign or malignant obstructive jaundice after failure of ERCP. Patients were randomized to either PTBD or EUS-HGS. Results: Fifty-six patients (mean age 64 years) have been included between 2011 and 2015. Twenty-one underwent PTBD and thirty-five were drained using EUS-HGS. An interim analysis after the inclusion of 41 patients revealed an unexpected high 30-day morbidity rate for PTBD (13 out of 21 patients), justifying to stop randomization and inclusion in this control arm in 2013. The primary objective was reached with 10 out of the 35 EUS-HGS patients (28.6%) having observed complications (90%-level bilateral exact binomial confidence interval [CI] [16.4%-43.6%], left-sided exact binomial test to the objectified 50% unacceptable rate P = 0.0083). Both methods achieved comparable technical success rate (TSR) and clinical success rate (CSR) (TSR: PTBD 100% vs. EUS-HGS 94.3%, P = 0.28; CSR: PTBD 66.7% vs. EUS-HGS 80%, P = 0.35). Long-term follow-up showed EUS-HGS patients being at lower risk for re-intervention (relative risk = 0.47, 95% CI [0.27-0.83]). Conclusion: In cases of ERCP failure, EUS-HGS is a valuable alternative for biliary drainage with a high TSR and CSR. PTBD is associated with an unacceptable 30-day morbidity rate, whereas EUS-HGS seems to have a decent safety profile, suggesting that it may be the treatment of choice in appropriately selected patients.

LATE POSTPANCREATICODUODENECTOMY HEMORRHAGE: INCIDENCE, RISK FACTORS, MANAGEMENT AND OUTCOME.

ABSTRACT: Background:Postpancreaticoduodenectomy (PD) hemorrhage (PPH) is a life-threatening complication after PD. The main objective of this study was to evaluate incidence and factors associated with late PPH as well as the management strategy and outcomes. Methods: Between May 2017 and March 2020, clinical data from 192 patients undergoing PD were collected prospectively in the CHIRPAN Database (NCT02871336) and retrospectively analyzed. In our institution, all patients scheduled for a PD are routinely admitted for monitoring and management in intensive/intermediate care unit (ICU/IMC). Results: The incidence of late PPH was 17% (32 of 192), whereas the 90-day mortality rate of late PPH was 19% (6 of 32). Late PPH was associated with 90-day mortality (P = 0.001). Using multivariate analysis, independent risk factors for late PPH were postoperative sepsis (P = 0.036), and on day 3, creatinine (P = 0.025), drain fluid amylase concentration (P = 0.023), lipase concentration (P < 0.001), and C-reactive protein (CRP) concentration (P < 0.001). We developed two predictive scores for PPH occurrence, the PANCRHEMO scores. Score 1 was associated with 68.8% sensitivity, 85.6% specificity, 48.8% predictive positive value, 93.2% negative predictive value, and an area under the receiver operating characteristic curves of 0.841. Score 2 was associated with 81.2% sensitivity, 76.9% specificity, 41.3% predictive positive value, 95.3% negative predictive value, and an area under the receiver operating characteristic curve of 0.859. Conclusions: Routine ICU/IMC monitoring might contribute to a better management of these complications. Some predicting factors such as postoperative sepsis and biological markers on day 3 should help physicians to determine patients requiring a prolonged ICU/IMC monitoring.

A stratified adaptive two-stage design with co-primary endpoints for phase II clinical oncology trials.

BACKGROUND: Given the inherent challenges of conducting randomized phase III trials in older cancer patients, single-arm phase II trials which assess the feasibility of a treatment that has already been shown to be effective in a younger population may provide a compelling alternative. Such an approach would need to evaluate treatment feasibility based on a composite endpoint that combines multiple clinical dimensions and to stratify older patients as fit or frail to account for the heterogeneity of the study population to recommend an appropriate treatment approach. In this context, stratified adaptive two-stage designs for binary or composite endpoints, initially developed for biomarker studies, allow to include two subgroups whilst maintaining competitive statistical performances. In practice, heterogeneity may indeed affect more than one dimension and incorporating co-primary endpoints, which independently assess each individual clinical dimension, would therefore appear quite pertinent. The current paper presents a novel phase II design for co-primary endpoints which takes into account the heterogeneity of a population.  METHODS: We developed a stratified adaptive Bryant & Day design based on the Jones et al. and Parashar et al. algorithm. This two-stage design allows to jointly assess two dimensions (e.g. activity and toxicity) in two different subgroups. The operating characteristics of this new design were evaluated using examples and simulation comparisons with the Bryant & Day design in the context where the study population is stratified according to a pre-defined criterion. RESULTS: Simulation results demonstrated that the new design minimized the expected and maximum sample sizes as compared to parallel Bryant & Day designs (one in each subgroup), whilst controlling type I error rates and maintaining a competitive statistical power as well as a high probability of detecting heterogeneity. CONCLUSIONS: In a heterogeneous population, this two-stage stratified adaptive phase II design provides a useful alternative to classical one and allows to identify a subgroup of interest without dramatically increasing sample size. As heterogeneity is not limited to older populations, this new design may also be relevant to other study populations such as children or adolescents and young adults or the development of targeted therapies based on a biomarker.

EUS-guided hepaticogastrostomy in the management of malignant biliary obstruction: Experience and learning curve in a tertiary referral center.

BACKGROUND: EUS-guided hepaticogastrostomy (EUS-HGS) is a recognized second-line strategy for biliary drainage when endoscopic retrograde cholangiopancreatography fails or is impossible. Substantial technical and procedural progress in performing EUS-HGS has been achieved. The present study wanted to analyze whether growing experience in current practice has changed patient outcomes over time. METHODS: We retrospectively analyzed data from patients with malignant biliary obstruction treated by EUS-HGS between 2002 and 2018 at a tertiary referral center. RESULTS: A total of 205 patients were included (104 male; mean age 68 years). Clinical success was achieved in 93% of patients with available 30-days follow-up (153), and the rate of procedure-related morbidity and mortality after one month was 18% and 5%, respectively. The cumulative sum (CUSUM) learning curve suggests a slight improvement in the rate of early complications during the second learning phase (23% vs 32%; P = 0.14; including death for any cause and intensive care). However, a significant threshold of early complications could not be determined. Recurrent biliary stent occlusion is the main cause for endoscopic reintervention (47/130; 37%). CONCLUSION: The rate of procedure-related complications after EUS-HGS has improved over time. However, the overall morbidity rate remains high, emphasizing the importance of dedicated expertise, appropriate patient selection and multidisciplinary discussion.

Sentinel node involvement with or without completion axillary lymph node dissection: treatment and pathologic results of randomized SERC trial.

Based on results of clinical trials, completion ALND (cALND) is frequently not performed for patients with breast conservation therapy and one or two involved sentinel nodes (SN) by micro- or macro-metastases. However, there were limitations despite a conclusion of non-inferiority for cALND omission. No trial had included patients with SN macro-metastases and total mastectomy or with >2 SN macro-metastases. The aim of the study was too analyze treatment delivered and pathologic results of patients included in SERC trial. SERC trial is a multicenter randomized non-inferiority phase-3 trial comparing no cALND with cALND in cT0-1-2, cN0 patients with SN ITC (isolated tumor cells) or micro-metastases or macro-metastases, mastectomy or breast conservative surgery. We randomized 1855 patients, 929 to receive cALND and 926 SLNB alone. No significant differences in patient's and tumor characteristics, type of surgery, and adjuvant chemotherapy (AC) were observed between the two arms. Rates of involved SN nodes by ITC, micro-metastases, and macro-metastases were 5.91%, 28.12%, and 65.97%, respectively, without significant difference between two arms for all criteria. In multivariate analysis, two factors were associated with higher positive non-SN rate: no AC versus AC administered after ALND (OR = 3.32, p < 0.0001) and >2 involved SN versus ≤2 (OR = 3.45, p = 0.0258). Crude rates of positive NSN were 17.62% (74/420) and 26.45% (73/276) for patient's eligible and non-eligible to ACOSOG-Z0011 trial. No significant differences in patient's and tumor characteristics and treatment delivered were observed between the two arms. Higher positive-NSN rate was observed for patients with AC performed after ALND (17.65% for SN micro-metastases, 35.22% for SN macro-metastases) in comparison with AC administered before ALND.

A study of elite sport-inspired coaching for patients after allogeneic hematopoietic stem cell transplantation.

A need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being.

Endoscopic management of concomitant biliary and duodenal malignant obstruction: Impact of the timing of drainage for one vs. two procedures and the modalities of biliary drainage.

BACKGROUND AND OBJECTIVES: Concomitant biliary and duodenal malignant obstruction are a severe condition mainly managed by duodenal and biliary stenting, which can be performed simultaneously (SAMETIME) or in two distinct procedures (TWO-TIMES). We conducted a single-center retrospective study to evaluate the feasibility of a SAMETIME procedure and the impact of endoscopic ultrasound (EUS)-hepaticogastrostomy in double malignant obstructions. PATIENTS AND METHODS: From January 1, 2011, to January 1, 2018, patients with concomitant malignant bilioduodenal obstruction treated endoscopically were included. The primary endpoint was hospitalization duration. The secondary endpoints were bilioduodenal reintervention rates, adverse event rates, and overall survival. Patients were divided into groups for statistical analysis: (i) divided according to the timing of biliary drainage: SAMETIME vs. TWO-TIMES group, (ii) divided based on the biliary drainage method: EUS-HG group underwent hepaticogastrostomy, while DUODENAL ACCESS group underwent endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic drainage (PCTD) or EUS-guided choledocoduodenostomy (EUS-CD). RESULTS: Thirty-one patients were included (19 women, median age = 71 years). Stenosis was mainly related to pancreatic cancer (17 patients, 54.8%). Sixteen patients were in the SAMETIME group, and 15 were in the TWO-TIMES group. Biliary drainage was performed by EUS-HG in 11 (35.%) patients, PCTD in 11 (35.%), ERCP in 8 (25.8%) and choledoduodenostomy in 1. Thirty patients died during follow-up. The median survival was 77 days (9% confidence interval [37-140]). The mean hospitalization duration was lower in the SAMETIME group: 7.5 vs. 12.6 days, P = 0.04. SAMETIME group patients tended to have a lower complication than TWO-TIMES (26.7% vs. 56.3%, P = 0.10). The EUS-HG group tended to have a lower complication rate (5% vs. 18.2%, P = 0.07) and less biliary endoscopic revision (30% vs. 9.1%, P = 0.37) than DUODENAL ACCESS. CONCLUSIONS: SAMETIME drainage is associated with a lower hospital stay without increased morbidity. EUS-HG could provide better access because it did not exhibit a higher complication rate and showed a tendency toward better patency and fewer complications.