Innovative approaches to teaching vascular access to nursing students in the COVID-19 era.

PURPOSE: For the student nurse, peripheral venous cannulation is one of the most stressful skills to be learned. Although some healthcare employers/establishments offer courses on vascular access and infusion nursing as part of their onboarding programs, ultimately educational institutions should share the responsibility to ensure that graduating nurses can provide safe infusion therapies. METHODS: An innovative vascular access and infusion nursing (VAIN) curriculum was created and mapped onto the entry to practice undergraduate nursing program at McGill University in Montréal, Québec, Canada. This presented an opportunity to implement new teaching approaches. RESULTS: Students experienced multiple new teaching approaches including multimedia and experiential learning and live simulation to ensure acquisition of knowledge and psychomotor skills. The teaching approaches had to be rapidly modified with the advent of the COVID-19 pandemic. CONCLUSIONS: The VAIN curriculum emphasizes simulation and directed practice, seeking to increase competence, confidence, and knowledge. The pandemic underscored the need for flexibility and creativity in content delivery.

Nurses' knowledge on routine care and maintenance of adult vascular access devices: A scoping review.

BACKGROUND: Vascular access devices (VAD), centrally (CVAD) or peripherally (PIV) located, are common in the nursing profession. A high proportion of admitted patients require a VAD to enable administration of intravenous treatments or diagnostic modalities. As the primary caregivers for these patients, nurses are responsible for ongoing care and maintenance of these devices. OBJECTIVE: This scoping review examines the current state of practicing nurses knowledge around routine care and maintenance of adult VADs. METHODS: In the fall of 2018, the following databases were searched: Medline-Ovid 1946 to current, Embase-Ovid 1947 to current, Ebsco CINAHL Plus with full text and ProQuest Nursing & Allied Health database, and articles were selected according to the PRISMA-ScR checklist. INCLUSION CRITERIA: original research published in peer-reviewed journals; in English or French; and focused on practising nurses' knowledge about the routine care and maintenance of adult VADs. RESULTS: Of the 4,099 abstracts identified, 36 full-text articles were included. Study characteristics are reportedin addition to themes found in the literature: the relationship between demographic data and CVAD/PIV knowledge, the state of nurses' CVAD/PIV knowledge and nurses' CVAD/PIV knowledge scores. Overall, significant gaps in nurses' knowledge on the care and maintenance of VADs are noted. CONCLUSION: The variability in nurses' knowledge around both CVAD and PIV led the authors to conclude that there is room for improvement in the educational preparation of nurses and a need for workplace training. RELEVANCE TO CLINICAL PRACTICE: This scoping review intends to highlight the knowledge gap of nurses with regard to best practices for VAD routine care and maintenance and demonstrate the need for education, both in educational and healthcare institutions, to ensure high-quality care and improved patient outcomes.

Prognostic value of health-related quality of life in patients with metastatic pancreatic adenocarcinoma: a random forest methodology.

PURPOSE: Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is currently an important parameter in the choice of treatment strategy for metastatic pancreatic adenocarcinoma (mPA) patients. However, previous research has shown that patients' self-reported health-related quality of life (HRQOL) scales provided additional prognostic information in homogeneous groups of patients with respect to ECOG-PS. The aim of this study was to identify HRQOL scales with independent prognostic value in mPA and to propose prognostic groups for these patients. METHODS: We analysed data from 98 chemotherapy-naive patients with histologically proven mPA recruited from 2007 to 2011 in the FIRGEM phase II study which aimed to compare the effectiveness of two chemotherapy regimen. HRQOL data were assessed with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. A random survival forest methodology was used to impute missing data and to identify major prognostic factors for overall survival. RESULTS: Baseline HRQOL assessment was completed by 60 % of patients (59/98). Twelve prognostic variables were identified. The three most important prognostic variables were fatigue, appetite loss, and role functioning, followed by three laboratory variables. The model's discriminative power assessed by Harrell's C statistic was 0.65. Fatigue score explained almost all the survival variability. CONCLUSION: HRQOL scores have prognostic value for mPA patients with good ECOG-PS. Moreover, the patient's fatigue, appetite loss, and self-perception of daily activities were more reliable prognostic indicators than clinical and laboratory variables. These HRQOL scores, especially the fatigue symptom, should be urgently included for prognostic assessment of mPA patients (with good ECOG-PS).

Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using (18)F-FDG PET in luminal HER2-negative breast cancer.

PURPOSE: The objective of this study was to evaluate, in the luminal human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtype, the prognostic value of tumour glucose metabolism at baseline and of its early changes during neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 61 women with hormone-sensitive HER2-negative breast cancer treated with NAC. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed at baseline. Hepatic activity was used as a reference to distinguish between low metabolic and hypermetabolic tumours. In hypermetabolic tumours, a PET exam was repeated after the first course of NAC. The relative change in the maximum standardized uptake value of the tumour (∆SUV) was calculated. RESULTS: Nineteen women had low metabolic luminal breast cancers at baseline, correlated with low proliferation indexes. Forty-two women had hypermetabolic tumours, corresponding to more proliferative breast cancers with higher Ki-67 expression (p = 0.017) and higher grade (p = 0.04). The median follow-up period was 64.2 months (range 11.5-93.2). Thirteen women developed recurrent disease, nine of whom died. Worse overall survival was associated with larger tumour size [>5 cm, hazard ratio (HR) = 6.52, p = 0.009] and with hypermetabolic tumours achieving a low metabolic response after one cycle of NAC (ΔSUV < 16%, HR = 10.63, p = 0.004). Five-year overall survival in these poor responder patients was 49.2%. Overall survival in women with low metabolic tumours or hypermetabolic/good response tumours was 100 and 96.15%, respectively. CONCLUSION: In luminal HER2-negative breast tumours, tumour metabolism at baseline and changes after the first course of NAC are early surrogate markers of patients' survival. A subgroup of women with hypermetabolic/poorly responding tumours, correlated with poor prognosis at 5 years, can be identified early. These results may guide future studies by tailoring the NAC regimen to the metabolic response.

FOLFOX as second-line chemotherapy in patients with pretreated metastatic pancreatic cancer from the FIRGEM study.

BACKGROUND: FOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study. METHODS: In this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method. RESULTS: Among 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61 years; performance status (PS) 0-1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (n = 20) or FOLFIRI.3 alternating with gemcitabine (n = 7). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3 months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0-1 versus 2-3, median PFS was 3.0 versus 1.2 months (log rank, p = 0.002), and median OS was 5.9 versus 2.6 months (log rank, p = 0.001). CONCLUSIONS: This study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS.

Best Practices to Quantify and Identify Particulate Matter on the Interior Surfaces of Single-Use Systems.

The manufacturing of a wide range of biopharmaceuticals, from antibodies and vaccines to cell-based therapies, increasingly takes place in single-use processing equipment. Manufactured in clean rooms and sealed and sterilized, single-use systems (SUSs) are ready-to-use and easily scalable. Controls in the "clean-build" manufacturing of SUSs reduce the probability of occurrence of particulate matter in SUSs. However, the size, complexity, and limited transparency of SUSs clearly limit the detectability of particulate matter on the interior (fluid-contacting) surfaces of a SUS during a visual inspection, as demonstrated in a recent study. In applications downstream of final filters or in aseptic processing, particulate matter on the surfaces of a SUS could detach and contaminate the final drug product. A realistic assessment of this risk requires reliable test methods that quantify and identify particulate matter present on the interior surfaces of SUSs. Clearly problematic is the common certification of the cleanliness of a SUS via a force-fit adaptation of the pharmacopeial standard USP <788> entitled "Particulate Matter in Injections". USP <788> does not describe a procedure for extraction of particulate matter from the interior surfaces of SUSs. In addition, application of Method 1 Light Obscuration significantly limits the probability of detection for particles in the visible size range (≥ 100 µm). In this article, we describe best practices for extracting, counting, sizing, and chemically identifying particulate matter on the interior surfaces of SUSs. Highly effective procedures for the extraction of particulate matter result from application of the qualification methodology described in a recently published ASTM standard. Filtration of the liquid extract concentrates particulate matter onto the surface of a membrane filter, allowing rapid particle counting and sizing using automated membrane microscopy, along with detailed chemical identification using infrared microscopy and/or automated confocal Raman microscopy.

Deciphering Natural Killer Cell Cytotoxicity Against Medulloblastoma in vitro and in vivo: Implications for Immunotherapy.

Purpose: Medulloblastoma (MB) is the most prevalent paediatric brain tumour. Despite improvements in patient survival with current treatment strategies, the quality of life of these patients remains poor owing to the sequelae and relapse risk. An alternative, or, in addition to the current standard treatment, could be considered immunotherapy, such as Natural Killer cells (NK). NK cells are cytotoxic innate lymphoid cells that play a major role in cancer immunosurveillance. To date, the mechanism of cytotoxicity of NK cells, especially regarding the steps of adhesion, conjugation, cytotoxic granule polarisation in the cell contact area, perforin and granzyme release in two and three dimensions, and therapeutic efficacy in vivo have not been precisely described. Materials and Methods: Each step of NK cytotoxicity against the three MB cell lines was explored using confocal microscopy for conjugation, Elispot for degranulation, flow cytometry, and luminescence assays for target cell necrosis and lysis and mediators released by cytokine array, and then confirmed in a 3D spheroid model. Medulloblastoma-xenografted mice were treated with NK cells. Their persistence was evaluated by flow cytometry, and their efficacy in tumour growth and survival was determined. In addition, their effects on the tumour transcriptome were evaluated. Results: NK cells showed variable affinities for conjugation with MB target cells depending on their subgroup and cytokine activation. Chemokines secreted during NK and MB cell co-culture are mainly associated with angiogenesis and immune cell recruitment. NK cell cytotoxicity induces MB cell death in both 2D and 3D co-culture models. NK cells initiated an inflammatory response in a human MB murine model by modulating the MB cell transcriptome. Conclusion: Our study confirmed that NK cells possess both in vitro and in vivo cytotoxic activity against MB cells and are of interest for the development of immunotherapy.

Systematic Review on CAR-T Cell Clinical Trials Up to 2022: Academic Center Input.

The development of Chimeric Antigen Receptor T cells therapy initiated by the United States and China is still currently led by these two countries with a high number of clinical trials, with Europe lagging in launching its first trials. In this systematic review, we wanted to establish an overview of the production of CAR-T cells in clinical trials around the world, and to understand the causes of this delay in Europe. We particularly focused on the academic centers that are at the heart of research and development of this therapy. We counted 1087 CAR-T cells clinical trials on ClinicalTrials.gov (Research registry ID: reviewregistry1542) on the date of 25 January 2023. We performed a global analysis, before analyzing the 58 European trials, 34 of which sponsored by academic centers. Collaboration between an academic and an industrial player seems to be necessary for the successful development and application for marketing authorization of a CAR-T cell, and this collaboration is still cruelly lacking in European trials, unlike in the leading countries. Europe, still far behind the two leading countries, is trying to establish measures to lighten the regulations surrounding ATMPs and to encourage, through the addition of fundings, clinical trials involving these treatments.

[Organizational and budgetary impacts of the implementation of CAR-T cell therapies in a French academic hospital]. / Impacts organisationnels et budgétaires de la mise en place des thérapies CAR-T cells au sein d'un centre hospitalier académique français.

Belonging to the family of advanced therapy medicinal products, CAR-T cells have changed the management of hematological malignancies. These treatments are known to involve many actors in a complex process. The quotation of hospital stays associated with this therapeutic strategy is also unusual since there is currently no specific quotation. From November 2021 to May 2022, a study was conducted at the Nancy University Hospital to evaluate the organizational impact of CAR-T cell therapy on hospital actors and the budgetary impact of stays in care centers. Through this study, we have shown significant and variable organizational impacts: from 3.12% of an additional full-time equivalent for an administrative manager to 41.5% for a clinical research associate. These times, when compared to the hourly rates of the actors, generated high costs: 6582.81 € per patient, i.e. 15.60% of the total cost of hospitalization. Taking into account the current refund of hospital stays and the costs calculated above, the balance of an average hospital stay is a deficit of 674.10 € [±10,224.79] with a median of 1334.97 €. This study highlighted the workload generated by the management of these new therapies, as well as the fragile balance of financing hospital stays. To date, it seems necessary and even essential to adapt the quotations of the acts dedicated to CAR-T cells activity and to provide adequate funding through an adapted pricing system.

Scale-Up of Academic Mesenchymal Stromal Cell Production.

BACKGROUND: Many clinical trials have reported the use of mesenchymal stromal cells (MSCs) following the indication of severe SARS-CoV-2 infection. However, in the COVID19 pandemic context, academic laboratories had to adapt a production process to obtain MSCs in a very short time. Production processes, especially freezing/thawing cycles, or culture medium have impacts on MSC properties. We evaluated the impact of an intermediate cryopreservation state during MSC culture to increase production yields. METHODS: Seven Wharton's jelly (WJ)-MSC batches generated from seven different umbilical cords with only one cryopreservation step and 13 WJ-MSC batches produced with intermediate freezing were formed according to good manufacturing practices. The identity (phenotype and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) were analyzed. RESULTS: No significant differences between MSC production processes were observed, except for the clonogenic capacity, which was decreased, although it always remained above our specifications. CONCLUSIONS: Intermediate cryopreservation allows an increase in the production yield and has little impact on the basic characteristics of MSCs.

Efficacy of Wharton Jelly Mesenchymal Stromal Cells infusions in moderate to severe SARS-Cov-2 related acute respiratory distress syndrome: a phase 2a double-blind randomized controlled trial.

Background: The COVID-19 pandemic caused a wave of acute respiratory distress syndrome (ARDS) with a high in-hospital mortality, especially in patients requiring invasive mechanical ventilation. Wharton Jelly-derived Mesenchymal Stromal Cells (WJ-MSCs) may counteract the pulmonary damage induced by the SARS-CoV-2 infection through pro-angiogenic effects, lung epithelial cell protection, and immunomodulation. Methods: In this randomized, double-blind, placebo-controlled phase 2a trial, adult patients receiving invasive mechanical ventilation for SARS-CoV-2 induced moderate or severe ARDS were assigned to receive 1 intravenous infusion of 1 × 106 WJ-MSCs/kg or placebo within 48 h of invasive ventilation followed by 2 infusions of 0.5 × 106 WJ-MSCs/kg or placebo over 5 days. The primary endpoint was the percentage of patients with a PaO2/FiO2 > 200 on day 10. Results: Thirty patients were included from November 2020 to May 2021, 15 in the WJ-MSC group and 15 in the placebo group. We did not find any significant difference in the PaO2/FiO2 ratio at day 10, with 18 and 15% of WJ-MSCs and placebo-treated patients reaching a ratio >200, respectively. Survival did not differ in the 2 groups with a 20% mortality rate at day 90. While we observed a higher number of ventilation-free days at 28 days in the WJ-MSC arm, this difference was not statistically significant (median of 11 (0-22) vs. 0 (0-18), p = 0.2). The infusions were well tolerated, with a low incidence of anti-HLA alloimmunization after 90 days. Conclusion: While treatment with WJ-MSCs appeared safe and feasible in patients with SARS-CoV2 moderate or severe ARDS in this phase 2a trial, the treatment was not associated with an increased percentage of patients with P/F > 200 at 10d, nor did 90 day mortality improve in the treated group. Clinical trial registration: https://beta.clinicaltrials.gov/study/NCT04625738, identifier NCT04625738.

Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents.

Purpose. A better identification of patients who are more likely to benefit from vascular endothelial growth factor-targeted therapy is warranted in metastatic renal cell carcinoma (mRCC). As adipose tissue releases angiogenic factors, we determined whether parameters such as visceral fat area (VFA) were associated with outcome in these patients. Experimental Design. In 113 patients with mRCC who received antiangiogenic agents (bevacizumab, sunitinib, or sorafenib) (n = 64) or cytokines (n = 49) as first-line treatment, we used computed tomography to measure VFA and subcutaneous fat area (SFA). We evaluated associations linking body mass index (BMI), SFA, and VFA to time to progression (TTP) and overall survival (OS). Results. High SFA and VFA values were significantly associated with shorter TTP and OS. By multivariate analysis, high VFA was independently associated with shorter TTP and OS. These results were internally validated using bootstrap analysis. By contrast, VFA was not associated with survival in the cytokine group. In the whole population, interaction between VFA and treatment group was significant for TTP and OS, thereby confirming the results. Conclusion. Our study provides the first evidence that high VFA could be a predictive biomarker from shorter survival in patients given first-line antiangiogenic agents for mRCC.

Natural Killer cells and monoclonal antibodies: Two partners for successful antibody dependent cytotoxicity against tumor cells.

Monoclonal antibodies targeting tumors are one of the most important discoveries in the field of cancer. Although several effective antibodies have been developed, a relapse may occur. One of their mechanisms of action is Antibody Dependent Cell Cytotoxicity (ADCC), by engaging the Fc γ receptor CD16 expressing Natural Killer cells, innate lymphoid cells involved in cancer immunosurveillance and able to kill tumor cells. A lack of NK cells observed in many cancers may therefore be a cause of the low efficacy of antibodies observed in some clinical situations. Here we review clear evidences of the essential partnership between NK cells and antibodies showed in vitro, in vivo, and in clinical trials in different indications, describe the hurdles and ways to enhance ADCC and the evolution of monoclonal antibody therapy. NK cell adoptive immunotherapy combined with monoclonal antibodies may overcome the resistance to the treatment and enhance their efficacy.

Mesenchymal Stem/Stromal Cell Production Compliant with Good Manufacturing Practice: Comparison between Bone Marrow, the Gold Standard Adult Source, and Wharton's Jelly, an Extraembryonic Source.

Many clinical trials report mesenchymal stem/stromal cells (MSCs) efficacy in various indications. Therefore, standardization of MSC production becomes necessary. MSC properties are impacted by tissue origin, especially if they are from extraembryonic tissue or adult sources. For this reason, we evaluated the impact of MSC tissue origin on production. METHODS: Three productions of MSC from Wharton's Jelly (WJ) or from bone marrow (BM) were performed according to good manufacturing practice. The identity (phenotype, differentiation, and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) of each cell batch were analyzed. RESULTS: Slight differences between MSC sources were observed for phenotype, telomerase activity, and clonogenic capacities. CONCLUSION: Both sources have made it possible to quickly and easily obtain clinical grade MSC. However, as availability of the source is thought to be essential, WJ seems more advantageous than BM.

NOX2-dependent ATM kinase activation dictates pro-inflammatory macrophage phenotype and improves effectiveness to radiation therapy.

Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the ionizing radiation-mediated activation of macrophages remain elusive. Here we show that ionizing radiation induces the expression of interferon regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. We reveal that the activation of the ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with γ-interferon, lipopolysaccharide or chemotherapeutic agent (such as cisplatin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a pro-inflammatory phenotype through the regulation of mRNA level and post-translational modifications of IRF5. We further demonstrate that NADPH oxidase 2 (NOX2)-dependent ROS production is upstream to ATM activation and is essential during this process. We also report that the inhibition of any component of this signaling pathway (NOX2, ROS and ATM) impairs pro-inflammatory activation of macrophages and predicts a poor tumor response to preoperative radiotherapy in locally advanced rectal cancer. Altogether, our results identify a novel signaling pathway involved in macrophage activation that may enhance the effectiveness of radiotherapy through the reprogramming of tumor-infiltrating macrophages.

Absolute volume of the rectum and AUC from rectal DVH between 25Gy and 50Gy predict acute gastrointestinal toxicity with IG-IMRT in prostate cancer.

BACKGROUND: To determine whether dose/volume specific endpoints (DVSE) or Area under the rectal DVH curve (rAUC) better predict acute gastrointestinal (GI) toxicity in prostate cancer patients treated with IMRT in the era of daily image guidance (IG-IMRT). METHODS: A set of DVSE was recorded from V25 to V75 (increments of 5Gy) (both in % and in cc) for 180 men. The rAUC was calculated for doses ranging between 25Gy and 50Gy (rAUC25-50). Univariate and multivariate logistic regressions were performed to determine the relationship between DVSE or rAUC25-50 and the appearance of any acute GI toxicity. RESULTS: The rates of acute grade 1 (G1), G2 and G3 GI toxicities were 53.3 %, 10.6 % and 1.1 %, respectively. No G4+ toxicity was observed. Rectal V25 to V75 expressed in % were not predictive of G ≥ 1 GI toxicity (p ≥ 0.12) whereas rectal V25 to V50 expressed in cc did correlate with GI toxicity G ≥ 1 (p ≤ 0.04). rAUC25-50 expressed in cc. Gy correlated significantly with the occurrence of any acute GI toxicity G ≥ 1 (p = 0.027). CONCLUSIONS: The absolute volume of the rectum between 25Gy and 50Gy and rAUC25-50 could significantly predict any acute rectal toxicity in prostate cancer patients treated with daily IG-IMRT.

Sequential FOLFIRI.3 + Gemcitabine Improves Health-Related Quality of Life Deterioration-Free Survival of Patients with Metastatic Pancreatic Adenocarcinoma: A Randomized Phase II Trial.

BACKGROUND: A randomized multicenter phase II trial was conducted to assess the sequential treatment strategy using FOLFIRI.3 and gemcitabine alternately (Arm 2) compared to gemcitabine alone (Arm 1) in patients with metastatic non pre-treated pancreatic adenocarcinoma. The primary endpoint was the progression-free survival (PFS) rate at 6 months. It concludes that the sequential treatment strategy appears to be feasible and effective with a PFS rate of 43.5% in Arm 2 at 6 months (26.1% in Arm 1). This paper reports the results of the longitudinal analysis of the health-related quality of life (HRQoL) as a secondary endpoint of this study. METHODS: HRQoL was evaluated using the EORTC QLQ-C30 at baseline and every two months until the end of the study or death. HRQoL deterioration-free survival (QFS) was defined as the time from randomization to a first significant deterioration as compared to the baseline score with no further significant improvement, or death. A propensity score was estimated comparing characteristics of partial and complete responders. Analyses were repeated with inverse probability weighting method using the propensity score. Multivariate Cox regression analyses were performed to identify independent factors influencing QFS. RESULTS: 98 patients were included between 2007 and 2011. Adjusting on the propensity score, patients of Arm 2 presented a longer QFS of Global Health Status (Hazard Ratio: 0.52 [0.31-0.85]), emotional functioning (0.35 [0.21-0.59]) and pain (0.50 [0.31-0.81]) than those of Arm 1. CONCLUSION: Patients of Arm 2 presented a better HRQoL with a longer QFS than those of Arm 1. Moreover, the propensity score method allows to take into account the missing data depending on patients' characteristics. TRIAL REGISTRATION INFORMATION: Eudract N° 2006-005703-34. (Name of the Trial: FIRGEM).

[The role of the expansion cohort in phase I trials in oncology: guidelines of the phase I HUB]. / Le rôle des cohortes d'expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase I.

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Production of transgenic goats by pronuclear microinjection of in vitro produced zygotes derived from oocytes recovered by laparoscopy.

Oocytes collected by laparoscopic ovum pick-up (LOPU) were successfully used to produce transgenic goats by pronuclear microinjection of in vitro zygotes. Estrus cycles of 109 donor goats were synchronized using intravaginal sponges impregnated with 60 mg of medroxyprogesterone acetate and treatment with 70 mg NIH-FSH-P1 and 300 IU eCG to stimulate follicular development. Follicles were aspirated under laparoscopic observation. In vitro maturation (IVM) of oocytes was performed in M199 supplemented with hormones, kanamycin and 10% estrus goat serum. Following IVM, oocytes were cocultured with capacitated semen in TALP supplemented with 20% estrus goat serum for 15-20 h. The resulting zygotes were microinjected with a linear DNA fragment. In total, 3293 follicles were aspirated (15.7+/-9 follicles aspirated per donor) and 2823 oocytes were recovered (13.4+/-8 oocytes per donor). A total of 1366 zygotes were microinjected and transferred into 219 recipient goats by midventral laparotomy (average 6.2 embryos per recipient). A total of 150 kids were born, of which 9 (6 M: 3 F) were confirmed to be transgenic by PCR and Southern blotting analyses. These results demonstrate that acceptable transgenesis rates can be obtained in goats by DNA microinjection of in vitro produced zygotes.