Attributes for a discrete-choice experiment on preferences of patients for oncology pharmacy consultations.

PURPOSE: To ensure the safe use of oral anticancer drugs, oncology pharmacy consultations (OPCs) have been established in France. They are conditioned by the needs, expectations, and involvement of the patients in their care. Thus, it is essential to elicit their preferences. The discrete-choice experiment (DCE) is a method recommended by the ISPOR for such a task. The "selection and validation of attributes and their values" step is fundamental in this process. In this context, the aim of this study was to present our research approach to identify and validate the attributes that characterize an OPC and their values. METHODS: Due to the lack of relevant published data in the literature, the focus-group method was used in accordance with good research practices for the application of conjoint-analysis of the ISPOR. The two-round Delphi method was used to validate the attributes and their values identified by the focus-group method. RESULTS: The focus-group method enabled identification of nine attributes. Thirty-seven healthcare professionals at a national level, including 30 pharmacists and seven physicians, were selected to take part in the Delphi procedure. Seven attributes (frequency, planification, operation mode, duration, content, written support, and report) and their values were thus validated. CONCLUSION: Based on these results, the next step will be to elicit patient preferences for OPCs and to then shed light on the issues of pharmaceutical support for patients by comparing their preferences with those of informal caregivers and, in particular, those of the healthcare professionals involved in their care.

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.

French healthcare students and antibiotics: are they ready to promote their appropriate use?

Objectives: French healthcare students are required to carry out primary prevention interventions as part of the Healthcare Service by Healthcare Students (HSHS). The purpose of this study was to explore students' perceptions of preparedness to address the public's concerns about antibiotic use and how their perceptions changed after implementing their intervention. Methods: A questionnaire was sent twice during the 2020-2021 academic year to 920 multidisciplinary healthcare students (nursing, medicine, physiotherapy, pharmacy and midwifery students) enrolled in the HSHS in Franche-Comté (HSHS-FC). Results: This study included 870/920 students (94.6%). Medical and pharmacy students were the most concerned about the issue of antimicrobial resistance. Before enrollment in the HSHS-FC, 463 of the 870 students included (53.2%) reported having sufficient knowledge about antibiotics to lead preventive interventions, reaching 87.9% (58/66) for pharmacy students. Despite this relative lack of knowledge, 77.2% of students felt confident to promote the appropriate use of antibiotics in the healthcare service context. This rate ranged from 68.0% (17/25) for midwifery students to 93.9% (62/66) for pharmacy students. Irrespective of the topic of the intervention, students significantly improved their knowledge and ability to promote antibiotic use after training in the HSHS-FC. Conclusions: Theoretical prerequisites and a feeling of concern vary widely depending on the curriculum. The HSHS-FC promotes multidisciplinary collaboration and can contribute to improving students' knowledge. The support of an expert in antimicrobial resistance may be necessary to validate the content of the interventions proposed by the students.

Quality of Life and Needs in Caregivers: Results From the Prospective Multicentric Open-Label Randomized Study of Informal Caregivers of Elderly Patients.

Objectives: To assess health-related quality of life (QoL) in caregivers of elderly patients with chronic disabilities receiving, or not receiving, social worker support. Methods: This multicenter open-label randomized study assigned caregivers to receive an information booklet, exclusively, or with social worker support. Caregivers completed Short Form-36 (SF-36) and Hospital Anxiety Depression Scale quarterly, and Zarit Burden Interview each semester, for 24 months. We reported caregiver QoL mean changes at 12 and 24 months (M12, M24). Longitudinal QoL analysis up to M24 used mixed models for repeated measures (MMRM). Results: Among the 179 caregivers randomized from 2015 to 2019, the SF-36 physical and mental component summary showed no significant changes at M12 and M24, in terms of neither anxiety nor burden. However, depression significantly increased (M12: 1.4 ± 4.0; M24: 1.7 ± 4.1) with significant adjusted mean increase using MMRM at M24: 3.4 [0.6-2.5] in the control group, exclusively. Conclusion: These findings call for better recognition of the social support to prevent caregiver QoL deterioration and alleviate their depression early in the course of the disease. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02626377.

Transfused Red Blood Cell Characteristics and Kidney Transplant Outcomes Among Patients Receiving Early Posttransplant Transfusion.

Importance: Red blood cell transfusion (RBCT) is frequently required in the early post-kidney transplant period, but long-term outcomes associated with RBCT is controversial. Therefore, it may be relevant to investigate the association between RBCT characteristics and transplant outcomes. Objective: To study the association between RBC storage duration and transplant outcomes. Design, Setting, and Participants: This was a nationwide retrospective cohort study based on data linking between 2 prospective French nationwide registries. Clinical transplant parameters, outcomes, and RBCT characteristics were extracted from the CRISTAL registry of the Agence de la Biomédecine and the national database of the Etablissement Français du Sang. All 12 559 patients having received a first kidney transplant in France between January 1, 2002, and December 31, 2008, were included. Patients were followed up from transplant to graft loss, death with a functional graft, or data retrieval in June 2016. Data were analyzed from April 2019 to June 2022. Exposures: Clinical outcomes of transplant recipients who underwent early RBCT were analyzed considering transfusion characteristics. Main Outcomes and Measures: Cox proportional hazards regression models were fitted to evaluate transplant failure defined as graft loss or death with a functional graft. Results: Among 12 559 patients who underwent kidney transplant, 3483 received an RBCT during the first 14 days posttransplant. The median (IQR) age of patients was 53.0 (41.5-61.2) years, and 1929 patients (55.4%) were male. Median (IQR) follow-up was 7.8 (7.6-8.0) years. In multivariable analysis, longer (vs shorter) storage duration of transfused RBC was associated with a decrease in risk of transplant failure (hazard ratio, 0.99; 95% CI, 0.98-1.00 for each additional storage day; P = .06). Patients transfused with at least 1 RBC unit stored for more than 20 days had a 5% absolute decrease in transplant failure at 3 years and 7% at 5 years compared with those who received RBC stored for less than 20 days. Conclusions and Relevance: In this study, longer RBC storage duration was associated with a decreased risk of transplant failure among patients who received kidney transplants and RBC transfusions. Preferential use of RBC with longer storage duration might improve kidney graft survival following transplant and transfusion.

Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82).

BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV+ cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. METHODS: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. DISCUSSION: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. TRIAL REGISTRATION: NCT05528952.

DCF versus doublet chemotherapy as first-line treatment of advanced squamous anal cell carcinoma: a multicenter propensity score-matching study.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38-0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39-0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324-0.521; p < 0.0001) and 0.406 (95% CI, 0.261-0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376-0.576; p < 0.0001) and 0.438 (95% CI, 0.298-0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study.

PURPOSE: Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice. PATIENTS AND METHODS: Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models. RESULTS: From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001). CONCLUSION: ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02502656.

Safety, Immunogenicity, and 1-Year Efficacy of Universal Cancer Peptide-Based Vaccine in Patients With Refractory Advanced Non-Small-Cell Lung Cancer: A Phase Ib/Phase IIa De-Escalation Study.

PURPOSE: Universal cancer peptide-based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS: A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders (P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders (P = .005), respectively. CONCLUSION: UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Prevalence and Characteristics of Sleep Apnea in Intensive Care Unit Survivors After SARS-CoV-2 Pneumonia.

Background: Sleep apnea (SA) was reported as possibly exacerbating symptoms of COVID-19, a disease induced by SARS-CoV-2 virus. The same comorbidities are common with both pathologies. This study aimed to estimate the prevalence, characteristics of SA and variation in AHI three months after severe COVID-19 requiring intensive care unit (ICU) admission. Methods: A prospective cohort of patients admitted to ICU for severe COVID-19 underwent an overnight home polygraphy 3 months after onset of symptoms, as part of a comprehensive follow-up program (pulmonary function tests, 6-minute walk tests and chest CT-scan). Patients with an apnea hypopnea index (AHI) ≥5 were considered as having SA. We performed a comparative descriptive analysis of 2 subgroups according to the existence, severity of SA and indication for effective SA treatment: patients with absent or mild SA (AHI <15) vs patients with moderate to severe SA (AHI ≥15). Results: Among 68 patients included, 62 (91%) had known comorbidities (34 hypertension, 21 obesity, 20 dyslipidemia, 16 type 2 diabetes). It has been observed a preexisting SA for 13 patients (19.1%). At 3 months, 62 patients (91%) had SA with 85.5% of obstructive events. Twenty-four patients had no or a mild SA (AHI <15) and 44 had moderate to severe SA (AHI ≥15). Ischemic heart disease exclusively affected the moderate to severe SA group. Except for thoracic CT-scan which revealed less honeycomb lesions, COVID-19 symptoms were more severe in the group with moderate to severe SA, requiring a longer curarization, more prone position sessions and more frequent tracheotomy. Conclusion: SA involved 91% of patients in our population at 3 months of severe COVID-19 and was mainly obstructive type. Although SA might be a risk factor as well as consequences of ICU care in severe COVID-19 infection, our results underline the importance of sleep explorations after an ICU stay for this disease.

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial.

Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients' survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study.

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV+ cancers. Methods: Patients with HPV+ cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific TH1 CD4 T cells sustain the quality and homing of an antigen-specific CD8+ T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based TH1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV+ cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT03946358.

Early Post-Transplant Red Blood Cell Transfusion Is Associated With an Increased Risk of Transplant Failure: A Nationwide French Study.

Background: Red blood cell (RBC) transfusions are frequently required in the early period after kidney transplantation. However, the consequences of RBC transfusions on long-term outcomes are largely unrecognized. Methods: We conducted a nationwide French cohort study involving all 31 French kidney transplant centers. Patients having received a first kidney transplant between January 1, 2002 and December 31, 2008 were identified through the national registry of the French BioMedecine Agency (Agence de BioMédecine). Number and date of RBC transfusions were collected from the national database of the French transfusion public service. The primary endpoint was transplant failure defined as graft loss or death with a functional graft. Results: Among 12,559 patients included during the study period, 3,483 (28%) were transfused during the first 14 days post-transplant. Median follow-up was 7.6 (7.5-7.8) years. Multivariable analysis determined that post-transplant RBC transfusion was associated with an increased risk in transplant failure (HR 1.650, 95%CI [1.538;1.771] p<0.0001). Both sensitivity and propension score analyses confirmed the previous result. Conclusions: Early red blood cell transfusion after kidney transplantation is associated with increased transplant failure.

Prognostic value of CD4+ T lymphopenia in non-small cell lung Cancer.

BACKGROUND: There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. MATERIALS: Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of < 500/µL and < 224/µL respectively. The prognostic value of T lymphopenia was analyzed in the whole population, in local/loco-regional (stage I-IIIB) and in advanced (stage IV) NSCLC disease, using the Kaplan-Meier method and Cox regression models for survival curves and multivariate analysis, respectively. RESULTS: Between July 2010 and January 2014, 169 evaluable patients with clinical stage I to IV NSCLC were prospectively enrolled. The prevalence of CD4+ and CD8+ T lymphopenia was similar in the study population (around 29%). Patients with CD4+ T lymphopenia showed lower overall survival than those with CD4+ T lymphocytes count > 500/µL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1-2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9-3.8], p = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065-3.817] p = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/µL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. CONCLUSION: We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage. TRIAL REGISTRATION: EUDRACT: 2009-A00642-55.

Result of one-year, prospective follow-up of intensive care unit survivors after SARS-CoV-2 pneumonia.

INTRODUCTION: Survivors of viral ARDS are at risk of long-term physical, functional and neuropsychological complications resulting from the lung injury itself, but also from potential multiorgan dysfunction, and the long stay in the intensive care unit (ICU). Recovery profiles after severe SARS-CoV-2 pneumonia in intensive care unit survivors have yet to be clearly defined. MATERIAL AND METHODS: The goal of this single-center, prospective, observational study was to systematically evaluate pulmonary and extrapulmonary function at 12 months after a stay in the ICU, in a prospectively identified cohort of patients who survived SARS-CoV-2 pneumonia. Eligible patients were assessed at 3, 6 and 12 months after onset of SARS-CoV-2. Patients underwent physical examination, pulmonary function testing, chest computed tomography (CT) scan, a standardized six-minute walk test with continuous oximetry, overnight home respiratory polygraphy and have completed quality of life questionnaire. The primary endpoint was alteration of the alveolar-capillary barrier compared to reference values as measured by DLCO, at 12 months after onset of SARS-CoV-2 symptoms. RESULTS: In total, 85 patients (median age 68.4 years, (interquartile range [IQR] = 60.1-72.9 years), 78.8% male) participated in the trial. The median length of hospital stay was 44 days (IQR: 20-60) including 17 days in ICU (IQR: 11-26). Pulmonary function tests were completed at 3 months (n = 85), 6 months (n = 80), and 12 months (n = 73) after onset of symptoms. Most patients showed an improvement in DLCO at each timepoint (3, 6, and 12 months). All patients who normalized their DLCO did not subsequently deteriorate, except one. Chest CT scans were abnormal in 77 patients (96.3%) at 3 months and although the proportion was the same at 12 months, but patterns have changed. CONCLUSION: We report the results of a comprehensive evaluation of 85 patients admitted to the ICU for SARS-CoV-2, at one-year follow-up after symptom onset. We show that most patients had an improvement in DLCO at each timepoint. TRIAL REGISTRATION: Clinical trial registration number: NCT04519320.

Is it safe to perform an anastomosis for rectal cancer after prostate cancer? A multicentre study of 126 patients from the GRECCAR group.

AIM: To determine the safety of performing an anastomosis after rectal cancer (RC) resection in patients with a previously treated prostate cancer (PC). METHODS: Patients with a previously treated PC who underwent rectal resection from 2008 to 2018 were retrospectively included. Outcomes were compared between patients who underwent rectal resection with anastomosis (restorative surgery, RS+ group) and those with a definitive stoma (RS- group). In the RS+ group, anastomotic leak (AL) rates were assessed according to the type of reconstruction. RESULTS: A total of 126 patients underwent rectal surgery for mid-low RC after a previous PC treated by radiotherapy (RT) and/or radical prostatectomy. Overall, 80 patients (63%) underwent a RS and 46 patients (37%) underwent rectal surgery with a definitive stoma. There was no statistical difference between the two groups in terms of intraoperative data, except for the type of resection with more multivisceral resection in the RS- group (p < 0.01). In the RS+group, a diverting stoma was performed in 74% of cases. No difference between the two groups in terms of overall morbidity was found. In the RS+group (n = 80), 17 patients (21%) experienced AL. Of these, none was observed when delayed coloanal anastomosis was performed (p = 0.16). Long-term permanent stoma in the RS+ group was 16% (n = 13). CONCLUSION: Restorative surgery after resection for RC in patients with a previous history of RT and/or radical prostatectomy for PC is safe without additional morbidity. In selected patients for restorative surgery, performing delayed coloanal anastomosis may represent a promising option.

Second-line treatment after docetaxel, cisplatin and 5-fluorouracil in metastatic squamous cell carcinomas of the anus. Pooled analysis of prospective Epitopes-HPV01 and Epitopes-HPV02 studies.

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line. PATIENTS AND METHODS: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol. RESULTS: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy. CONCLUSION: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options.

HPV16 Load Is a Potential Biomarker to Predict Risk of High-Grade Cervical Lesions in High-Risk HPV-Infected Women: A Large Longitudinal French Hospital-Based Cohort Study.

High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log10GE/103 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80-3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log10GE/103 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1-100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions.

Pooled analysis of 115 patients from updated data of Epitopes-HPV01 and Epitopes-HPV02 studies in first-line advanced anal squamous cell carcinoma.

AIMS: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies. PATIENTS & METHODS: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen. RESULTS: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6-16.1] [11.0 months (9.3-16.0) in -HPV02, and 15.6 months (11.2-34.5) in -HPV01, (p = 0.06)]. The median overall survival was 39.2 months (26.0-109.1) [36.3 in -HPV02 (25.2-NR), and 61.1 months (21.4-120.0) in -HPV01 (p = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF (n = 54) and mDCF (n = 58) in terms of OS (p = 0.57) and PFS (p = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed. CONCLUSION: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.

RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC). Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria may underestimate response to ICIs due to the pseudoprogression phenomenon. The GERCOR NIPICOL phase II study aimed to evaluate the frequency of pseudoprogressions in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. METHODS: Patients with MSI/dMMR mCRC previously treated with fluoropyrimidines, oxaliplatin, and irinotecan with/without targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles then nivolumab 3 mg/kg every 2 weeks until progression or a maximum of 20 cycles. Computed tomography scan tumor assessments were done every 6 weeks for 24 weeks and then every 12 weeks. The primary endpoint was disease control rate at 12 weeks according to RECIST 1.1 and iRECIST by central review. RESULTS: Of 57 patients included between December 2017 and November 2018, 48.0% received ≥3 prior lines of chemotherapy, 18.0% had BRAFV600E mutation, and 56.0% had Lynch syndrome-related cancer. Seven patients (12.0%) discontinued treatment due to adverse events; one died due to a treatment-related adverse event. The disease control rate (DCR) at 12 weeks was 86.0% with RECIST 1.1% and 87.7% with iRECIST. Two pseudoprogressions (3.5%) were observed, at week 6 and at week 36, representing 18% of patients with disease progression per RECIST 1.1 criteria. With a median follow-up of 18.4 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 72.9% with RECIST 1.1% and 76.5% with iRECIST. The 12-month OS rate was 84%. Overall response rate was 59.7% with both criteria. RAS/BRAF status, sidedness, Lynch syndrome, and other baseline parameters were not associated with PFS. CONCLUSION: Pseudoprogression is rare in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. This combined ICI therapy confirms impressive DCR and survival outcomes in these patients. TRIAL REGISTRATION NUMBER: NCT03350126.