Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial.

BACKGROUND: Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas. METHODS: AcSé Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSé Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620. FINDINGS: Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13·1 months (range 0·1-52·8; IQR 4·3-19·7). At week 12, objective response rate was 6·2% (95% CI 2·3-13·0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause). INTERPRETATION: Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer. FUNDING: The Ligue contre le cancer, INCa, MSD. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Platform trials.

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities.

Safety and efficacy of nivolumab, an anti-PD1 immunotherapy, in patients with advanced basal cell carcinoma, after failure or intolerance to sonic Hedgehog inhibitors: UNICANCER AcSé NIVOLUMAB trial.

BACKGROUND: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived. METHODS: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%). RESULTS: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction). CONCLUSION: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial.

BACKGROUND: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. METHODS: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. FINDINGS: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. INTERPRETATION: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. FUNDING: The French National Cancer Institute.

Cost-effectiveness of acupuncture versus standard care for pelvic and low back pain in pregnancy: A randomized controlled trial.

OBJECTIVE: To assess the cost-effectiveness of acupuncture for pelvic girdle and low back pain (PGLBP) during pregnancy. DESIGN: Pragmatic-open-label randomised controlled trial. SETTING: Five maternity hospitals. POPULATION: Pregnant women with PGLBP. METHOD: 1:1 randomization to standard care or standard care plus acupuncture (5 sessions by an acupuncturist midwife). MAIN OUTCOME MEASURE: Efficacy: proportion of days with self-assessed pain by numerical rating scale (NRS) ≤ 4/10. Cost effectiveness (societal viewpoint, time horizon: pregnancy): incremental cost per days with NRS ≤ 4/10. Indirect non-healthcare costs included daily compensations for sick leave and productivity loss caused by absenteeism or presenteeism. RESULTS: 96 women were allocated to acupuncture and 103 to standard care (total 199). The proportion of days with NRS ≤ 4/10 was greater in the acupuncture group than in the standard care group (61% vs 48%, p = 0.007). The mean Oswestry disability score was lower in the acupuncture group than with standard care alone (33 versus 38, Δ = 5, 95% CI: 0.8 to 9, p = 0.02). Average total costs were higher in the control group (€2947) than in the acupuncture group (€2635, Δ = -€312, 95% CI: -966 to +325), resulting from the higher indirect costs of absenteeism and presenteeism. Acupuncture was a dominant strategy when both healthcare and non-healthcare costs were included. Costs for the health system (employer and out-of-pocket costs excluded) were slightly higher for acupuncture (€1512 versus €1452, Δ = €60, 95% CI: -272 to +470). CONCLUSION: Acupuncture was a dominant strategy when accounting for employer costs. A 100% probability of cost-effectiveness was obtained for a willingness to pay of €100 per days with pain NRS ≤ 4.

Are elderly patients presenting with squamous cell carcinoma of the oral cavity given the appropriate treatment?

OBJECTIVES: There is no consensus for the specific management of elderly patients presenting with oral cavity squamous cell carcinomas (OC SCC). We report our findings in the treatment of primary OC SCC, for patients of 70 years of age or more, in a French university hospital center. PATIENTS AND METHODS: One hundred and twenty five patients diagnosed between 2000 and 2010, were included retrospectively. Independent risk factors of post-operative complications were identified using a logistic regression. The overall survival (OS) was estimated using the Kaplan Meier method. Independent factors of survival were calculated using a Cox model. RESULTS: The patient's median age was 78. Women presented significantly more premalignant lesions, less alcohol intoxication, and less tobacco consumption. Half of the population sample was staged T4 in the TNM classification. Eighty eight percent of the patients received a curative treatment. The independent risk factors for post-operative complications were T3/T4 stages (OR 4.3 [1.3-14.4]), lymph node metastasis (OR 6.9 [2.1-22.7]), and alcohol abuse (OR 3.5 [1.1-11.0]). The median OS was 14.0 months. The independent negative prognostic factors for OS for patients treated curatively were: age >79 years (HR 1.9 [1.2-3.2]), stage T2/T3/T4 tumor vs. T1 (HR = 3.0 [1.5-6.0], P = 0.001) and substandard surgery (HR = 1.8 [1.1-2.9], P = 0.03). CONCLUSIONS: The management of OC SCC in elderly patients is complex and requires collaboration among gerontologists, surgeons and oncologists. The treatment choice is related to the disease extent and preoperative morbid conditions.

Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation.

BACKGROUND: Increased left ventricular afterload during peripheral venoarterial-extracorporeal membrane oxygenation (VA-ECMO) support frequently causes hydrostatic pulmonary oedema. Because physiological studies demonstrated left ventricular afterload decrease during VA-ECMO assistance combined with the intra-aortic balloon pump (IABP), we progressively changed our standard practice systematically to associate an IABP with VA-ECMO. This study aimed to evaluate IABP efficacy in preventing pulmonary oedema in VA-ECMO-assisted patients. METHODS: A retrospective single-centre study. RESULTS: Among 259 VA-ECMO patients included, 104 received IABP. Weinberg radiological score-assessed pulmonary oedema was significantly lower in IABP+ than IABP- patients at all times after ECMO implantation. This protection against pulmonary oedema persisted when death and switching to central ECMO were used as competing risks (subhazard ratio 0.49, 95% confidence interval (CI) 0.33-0.75; P<0.001). Multivariable analysis retained IABP as being independently associated with a lower risk of radiological pulmonary oedema (odds ratio (OR) 0.4, 95% CI 0.2-0.7; P=0.001) and a trend towards lower mortality (OR 0.54, 95% CI 0.29-1.01; P=0.06). Finally, the time on ECMO free from mechanical ventilation increased in IABP+ patients (2.2±4.3 vs. 0.7±2.0 days; P=0.0003). Less frequent pulmonary oedema and more days off mechanical ventilation were also confirmed in 126 highly comparable IABP+ and IABP- patients, propensity score matched for receiving an IABP. CONCLUSIONS: Associating an IABP with peripheral VA-ECMO was independently associated with a lower frequency of hydrostatic pulmonary oedema and more days off mechanical ventilation under ECMO.

A Fully Automated Web-Based Program Improves Lifestyle Habits and HbA1c in Patients With Type 2 Diabetes and Abdominal Obesity: Randomized Trial of Patient E-Coaching Nutritional Support (The ANODE Study).

BACKGROUND: The prevalence of abdominal obesity and type 2 diabetes mellitus (T2DM) is a public health challenge. New solutions need to be developed to help patients implement lifestyle changes. OBJECTIVE: The objective of the study was to evaluate a fully automated Web-based intervention designed to help users improve their dietary habits and increase their physical activity. METHODS: The Accompagnement Nutritionnel de l'Obésité et du Diabète par E-coaching (ANODE) study was a 16-week, 1:1 parallel-arm, open-label randomized clinical trial. Patients with T2DM and abdominal obesity (n=120, aged 18-75 years) were recruited. Patients in the intervention arm (n=60) had access to a fully automated program (ANODE) to improve their lifestyle. Patients were asked to log on at least once per week. Human contact was limited to hotline support in cases of technical issues. The dietetic tool provided personalized menus and a shopping list for the day or the week. Stepwise physical activity was prescribed. The control arm (n=60) received general nutritional advice. The primary outcome was the change of the dietary score (International Diet Quality Index; DQI-I) between baseline and the end of the study. Secondary endpoints included changes in body weight, waist circumference, hemoglobin A1c (HbA1c) and measured maximum oxygen consumption (VO2 max). RESULTS: The mean age of the participants was 57 years (standard deviation [SD] 9), mean body mass index was 33 kg/m² (SD 4), mean HbA1c was 7.2% (SD 1.1), and 66.7% (80/120) of participants were women. Using an intention-to-treat analysis, the DQI-I score (54.0, SD 5.7 in the ANODE arm; 52.8, SD 6.2 in the control arm; P=.28) increased significantly in the ANODE arm compared to the control arm (+4.55, SD 5.91 vs -1.68, SD 5.18; between arms P<.001). Body weight, waist circumference, and HbA1c changes improved significantly in the intervention. CONCLUSIONS: Among patients with T2DM and abdominal obesity, the use of a fully automated Web-based program resulted in a significant improvement in dietary habits and favorable clinical and laboratory changes. The sustainability of these effects remains to be determined. TRIAL REGISTRATION: ClinicalTrials.gov NCT02343107; http://clinicaltrials.gov/ct2/show/NCT02343107 (Archived by WebCite at http://www.webcitation.org/6uVMKPRzs).

The European "clinical trial" regulation; relationship with the Jardé Act: a Giens workshop.

In May 2014, the European Union Parliament and Council published a new regulation on clinical trials on medicinal products for human use, which is designed to replace Directive 2001/20/EC. It will not come into effect until 2016. Nevertheless, it is essential to examine its relationship with national legislation, i.e. the Jardé Act, whose implementation has been delayed pending publication of the European regulation. The Giens workshop identified and examined the various issues that this relationship is bound to raise. In particular, it looked at trial methodology assessment procedures, the working relationship between the French National Agency of Drug Safety and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM) and ethics committees during the authorization application evaluation phase, review of post-authorization/registration studies on medicinal products and medical devices, and data transparency.

Evaluation of an integrated multidisciplinary approach in multiple sclerosis care: A prospective, randomized, controlled study.

BACKGROUND: Disabled multiple sclerosis (MS) patients often need intervention of multiple specialists, resulting in a complex organization of care. How this multidisciplinary care should be organized and structured has not been studied. OBJECTIVE: The objective of this article is to address the effectiveness of an integrated multidisciplinary approach versus usual care in MS patients. METHODS: This is a prospective, randomized, controlled, monocentric clinical trial in MS patients. Two treatment strategies were compared: (i) an integrated multidisciplinary (IMD) approach, consisting of a half-day individually tailored comprehensive assessment in the MS clinic; and (ii) a standard care. The primary outcome was the impact of the strategy on quality of life (QoL) measured using the MSIS-29 scale at inclusion and after six months. RESULTS: Fifty MS patients were included. Median MSIS 29 score decreased over six months in the control group (-4.89) and increased in the IMD group (+2.00), with a significant difference between the two groups (p = 0.03). However, in the multivariate analysis, after adjustment of HAD-D and INTERMED score, this difference was no longer significant. CONCLUSIONS: This prospective, randomized study is the first attempt to evaluate the multidisciplinary approach in MS patients. The results show that, contrary to our expectations, an integrated multidisciplinary approach is not superior to usual care on QoL.

Promoting the place of the allied health professions in clinical research.

Clinical research is of major importance to today's society, as scientific evidence is increasingly demanded as a basis for progress, whether this involves developing new healthcare products, improving clinical practice and care protocols or progress in prevention. Clinical research therefore requires professionals who are both experienced and increasingly well trained. Against this background, allied health professionals are becoming involved more and more, both as team members supporting clinical research projects and as managers or coordinators of projects in their own field. Clinical research activities provide an ideal opportunity for continuing professional development. All of this means that the professional skills of the allied health professions and clinical research support professions must be enhanced, their role promoted in the context of lecturer status and in the longer term, their status recognised by the supervisory authorities.

How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed?

The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription.

Clinical significance and prognostic value of chromatin assembly factor-1 overexpression in human solid tumours.

AIMS: Chromatin assembly factor-1 (CAF-1), whose function is critical for maintaining chromatin stability during DNA replication and repair, has been identified as a proliferation marker in breast cancer. The aim was to investigate CAF-1 as a proliferation marker in a wide variety of solid tumours, and to assess its potential value in predicting clinical outcome. METHODS AND RESULTS: Using immunocytochemistry on paraffin-embedded tissue sections, the CAF-1 labelling index was compared with known proliferation markers Ki-67 and minichromosome maintenance (MCM), and its association with clinicopathological data and patients' outcome analysed. CAF-1 expression showed a strong positive correlation with Ki-67, used routinely to detect proliferating cells, while it generally displayed weaker correlations with MCM markers, known to label cells with replicative potential. CAF-1 expression was associated significantly with histological grade in breast, cervical, endometrial and renal cell carcinomas, and with disease stage in endometrial and renal carcinomas. Furthermore, high expression of CAF-1 was an independent predictor of adverse clinical outcome in renal, endometrial and cervical carcinomas. CONCLUSIONS: CAF-1 is a proliferation marker in various malignant tumours with prognostic value in renal, endometrial and cervical carcinomas, which supports the value of CAF-1 as a clinical marker of cancer progression.

Takayasu arteritis in France: a single-center retrospective study of 82 cases comparing white, North African, and black patients.

We conducted a single-center retrospective study to compare the characteristics of Takayasu arteritis (TA) among white, North African, and black patients in a French tertiary care center (Hospital Pitié-Salpêtrière, Paris). Eighty-two patients were studied (82.9% female) during a median follow-up of 5.1 years (range, 1 mo to 30 yr). Among these 82 patients, 39 (47.6%) were white, 20 (24.4%) were North African, and 20 (24.4%) were black patients. Median age at diagnosis was 39.3 years (range, 14-70 yr) in white patients vs. 28.4 years (range, 12-54 yr) in North African (p = 0.02), and 28.0 years (range, 13-60 yr) in black patients (p = 0.08). Patients aged >40 years at TA onset were more frequently white than non-white (40.0% vs. 18.6%, p = 0.03). North African patients had more frequent occurrence of ischemic stroke (p = 0.03) and poorer survival (p = 0.01) than white patients. Type V of the Hata classification was the most frequent type among white (38.5%), North African (65.0%), and black patients (40.0%). Corticosteroids were used in 96.1% of patients. Fifty-three percent of white and North African patients, and 44% of black patients required a second line of immunosuppressive treatment (p = 0.60). Vascular surgical procedures were respectively performed in 46.1%, 50.0%, and 55.0% of white, North African, and black patients, p = 0.81. The 5-year and 10-year survival rates were 100% and 95.0%, respectively, in white patients; 67.4% at both 5 years and 10 years in North African patients; and 100% at both 5 years and 10 years in black patients. This study is one of the first direct comparisons of TA profiles among patients of distinct ethnic backgrounds. Our data support the idea that late-onset TA or an overlap between TA and large-vessel giant cell arteritis may be observed in white patients. North African patients have a higher occurrence of ischemic stroke and poorer survival than white patients.

[Patients' perception of information received when a complementary medical examination is prescribed]. / Perception par les patients de l'information reçue lors d'un examen complémentaire.

Medical doctors are required to provide information to their patients regarding their medical procedures according to the law on patient information enacted on March 4, 2002. The objective of this study was to assess patients' awareness and satisfaction with respect to their perception of information obtained prior to or during a medical examination. A self-descriptive patient survey was conducted at the Groupe Hospitalier of Pitié-Salpêtrière in 2005 for this purpose. Data were collected at three distinct moments using a standard questionnaire. 147 patients were interviewed (101 had received and MRI and 46 a bronchoscopy). Twenty percent of the participants reported that they had not been provided with any specific medical or paramedical information before the examination and 4% had received no information at all. Health professionals must ensure that information is given to their patients in a manner that takes into account their expectations and responds to their concerns before a medical procedure is performed in order to improve its delivery and its intrinsic quality.