m7824 msb0011359c a bifunctional fusion protein targeting pd l1 and tgf β in patients pts with advanced scchn results from a phase i cohort

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Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open -label phase III study

Background: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. Patients and methods: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. Results: Patients were randomly assigned to receive durvalumab (n 1⁄4 240), durvalumab plus tremelimumab (n 1⁄4 247), or SoC (n 1⁄4 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72e1.08; P 1⁄4 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85e1.26; P 1⁄4 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9e43.1), 30.4% (24.7e36.3), and 30.5% (24.7 e36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade !3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Conclusion: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab

Evaluation of seven tumour markers in pleural fluid for the diagnosis of malignant effusions

Carcinoembryonic antigen (CEA), carbohydrate antigens 15–3, 19–9 and 72–4 (CA 15–3, CA 19–9 and CA 72–4), cytokeratin 19 fragments (CYFRA 21–1), neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCC) were evaluated in pleural fluid for the diagnosis of malignant effusions. With a specificity of 99%, determined in a series of 121 benign effusions, the best individual diagnostic sensitivities in the whole series of 215 malignant effusions or in the subgroup of adenocarcinomas were observed with CEA, CA 15–3 and CA 72–4. As expected, a high sensitivity was obtained with SCC in squamous cell carcinomas and with NSE in small-cell lung carcinomas. CYFRA and/or CA 15–3 were frequently increased in mesotheliomas. Discriminant analysis showed that the optimal combination for diagnosis of non-lymphomatous malignant effusions was CEA + CA 15–3 + CYFRA + NSE: sensitivity of 94.4% with an overall specificity of 95%. In malignant effusions with a negative cytology, 83.9% were diagnosed using this association. The association CYFRA + NSE + SCC was able to discriminate adenocarcinomas from small-cell lung cancers. Regarding their sensitivity and their complementarity, CEA, CA 15–3, CYFRA 21–1, NSE and SCC appear to be very useful to improve the diagnosis of malignant pleural effusions. © 1999 Cancer Research Campaig

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study

Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide, with increasing incidence.1 Approximately 10% of patients with HNSCC will be diagnosed with metastatic disease, and even when treated early, around half will have disease recurrence.2,3 The platinum-based doublet chemotherapy with cetuximab regimen has been the most widely-used therapy and considered standard of care (SoC) since it was proven effective in 2007 for recurrent/metastatic (R/M) HNSCC in the first-line setting.3,4 However, patients typically progress even after aggressive first-line therapy, and, until recently, the available options (e.g. cetuximab, methotrexate, and taxanes) have delivered limited survival benefits.3 Durvalumab is an immunotherapeutic agent that blocks the interaction between programmed cell death ligand 1 (PD-L1) and its receptors.5 Durvalumab demonstrated encouraging response rates and duration of response (DoR) with a manageable safety profile in patients with HNSCC.6 Although monotherapy agents that block the programmed cell death protein 1 (PD-1)/PD-L1 axis have shown clinical activity, immunotherapy combinations have the potential to improve upon monotherapy activity.7e9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1/PD-1 pathways have largely non-redundant roles, suggesting that blockade of both could have additive or synergistic effects.10 Indeed, the combination of durvalumab and tremelimumab, an anti-CTLA-4 monoclonal antibody, was explored based on improved efficacy over monotherapy in other solid tumor types.7 This observation, in addition to the activity demonstrated by durvalumab in earlier R/M HNSCC studies, served as the rationale to evaluate durvalumab and tremelimumab in patients with R/M HNSCC. Several studies, including the EAGLE study, were initiated to evaluate combination immunotherapy regimens in various patient groups.11,12 The EAGLE study was the first phase III study to investigate durvalumab and tremelimumab in patients with R/M HNSCC who had progressed after platinumbased therapy. During the conduct of the EAGLE study, anti-PD-1 monoclonal antibodies were approved for use for R/M HNSCC progression following a platinum-based regimen. Treatment with these immunotherapies resulted in a median overall survival (OS) of 7.5e8.4 months.13,14 These immunotherapies are now recommended for second-line treatment as monotherapies for patients with R/M HNSCC.3,13,14 More recently, immunotherapy alone or in combination with platinum-based chemotherapy has shown improvements in OS in the first-line setting, underscoring the clinical utility of immunotherapy in HNSCC.15 Here, we report the results of the randomized phase III EAGLE trial evaluating durvalumab and durvalumab plus tremelimumab versus SoC therapies in patients with R/M HNSCC who have progressed following a platinumcontaining regimen

Pneumocystis jirovecii genotypes and granulomatous pneumocystosis

International audienceThis study describes the initial data concerning molecular typing of Pneumocystis jirovecii in a patient having developed granulomatous Pneumocystis pneumonia (PCP). Three types, B(1)a(3), B(1)a(4), B(1)b(2), were identified. All three had been described in reports concerning patients with common diffuse alveolar PCP. The present data show that identical microorganisms can be involved in both granulomatous PCP and diffuse alveolar PCP and that the pathogenesis of the granulomatous response to P. jirovecii may more likely be related to host factors. = Nous présentons les premières données concernant l'identification des génotypes de Pneumocystis jirovecii chez un patient ayant développé une pneumocystose (PPC) granulomateuse. Trois génotypes, B1a3, B1a4, B1b2, ont été identifiés. Ces génotypes sont usuellement retrouvés dans la forme classique alvéolaire de la PPC. Ces résultats montrent que des micro-organismes identiques peuvent être impliqués dans ces deux formes histologiques de la PPC et suggèrent que l'étiologie de la réaction granulomateuse se rapporterait plutôt à des facteurs liés aux patients

Optimal management of renal cell carcinoma in the elderly: a review

Amandine Quivy,1,2 Amaury Daste,1 Asma Harbaoui,1 Sophie Duc,2,4 Jean-Christophe Bernhard,2,3 Marine Gross-Goupil,1 Alain Ravaud1,2 1Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France; 2University of Bordeaux 2 (Victor Ségalen), Bordeaux, France; 3Department of Urology, Hôpital Pellegrin, Bordeaux University Hospital, Bordeaux, France; 4Department of Geriatrics, Hôpital Saint-André, Bordeaux University Hospital, Bordeaux, France Abstract: Both the aging population and the incidence of renal cell carcinoma (RCC) are growing, making the question of tumor management in the elderly a real challenge. Doctors should be aware of the importance of assessing this specific subpopulation. An aggressive therapeutic approach may be balanced by the benefit of the treatment – care or cure – and the life expectancy and willingness of the patient. The treatment for local disease can be surgery (radical or partial nephrectomy) or ablative therapies (radiofrequency, cryotherapy). Even if in most cases surgery is safe, complications such as alteration of renal function may occur, especially in the elderly, with physiological renal impairment at baseline. More recently, another option has been developed as an alternative: active surveillance. In the past decade, new drugs have been approved in the metastatic setting. All the phase 3 trials have included patients without a limit on age. Nevertheless, data concerning the elderly are still poor and concern only a very selective subpopulation. The toxicity profile of targeted agents may interfere with pre-existent comorbidities. Furthermore, the metabolism of several agents via cytochrome P450 can cause drug interaction. The importance of quality of life is a major factor with regard to management of therapy. Finally, to date, there is no recommendation of systematic a priori dose reduction in the elderly. In this review we describe the various possibilities of treatment for localized RCC or metastatic RCC in an aging population. Keywords: elderly, kidney cancer, renal cell carcinoma, surgery, targeted therapy, comorbidit

Patient acceptable symptom state for burden from appearance changes in people with systemic sclerosis: A cross-sectional survey

Objective People with systemic sclerosis (SSc) often report substantial burden from appearance changes. We aimed to estimate the patient acceptable symptom state (PASS) for burden from appearance changes in people with SSc. Methods We conducted a secondary analysis of the SCISCIF II study, a cross-sectional survey of 113 patients with SSc from France enrolled in the Scleroderma Patient-centered Intervention Network Cohort. Burden from appearance changes was assessed with a self-administered numeric rating scale (0, no burden to 10, maximal burden). Acceptability of the symptom state was assessed with a specific anchoring question. Participants who answered "yes" were in the group of patients who considered their symptom state as acceptable. The PASS for the burden from appearance changes was estimated with the 75th percentile method. Results Assessments of burden from appearance changes and answers to the anchoring question were available in 82/113 (73%) participants from the SCISCIF II study. Mean age was 55.9 (14.3) years, disease duration 9.6 (6.5) years and 32/82 (40%) participants had diffuse cutaneous SSc. The PASS estimate for the burden from appearance changes was 4.8 (95% CI from 1.0 to 7.0) of 10 points. Conclusion Our study provides a PASS estimate for burden from appearance changes. Our estimate could serve as a binary response criterion to assess the efficacy of treatments targeting burden from appearance changes

The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion.

Development of the nervous system requires extensive axonal and dendritic growth during which neurons massively increase their surface area. Here we report that the endoplasmic reticulum (ER)-resident SNARE Sec22b has a conserved non-fusogenic function in plasma membrane expansion. Sec22b is closely apposed to the plasma membrane SNARE syntaxin1. Sec22b forms a trans-SNARE complex with syntaxin1 that does not include SNAP23/25/29, and does not mediate fusion. Insertion of a long rigid linker between the SNARE and transmembrane domains of Sec22b extends the distance between the ER and plasma membrane, and impairs neurite growth but not the secretion of VSV-G. In yeast, Sec22 interacts with lipid transfer proteins, and inhibition of Sec22 leads to defects in lipid metabolism at contact sites between the ER and plasma membrane. These results suggest that close apposition of the ER and plasma membrane mediated by Sec22 and plasma membrane syntaxins generates a non-fusogenic SNARE bridge contributing to plasma membrane expansion, probably through non-vesicular lipid transfer

Differences in disability perception in systemic sclerosis: A mirror survey of patients and health care providers

Differences in disability perception between patients and care providers may impact outcomes. We aimed to explore differences in disability perception between patients and care providers in systemic sclerosis (SSc). We conducted a cross-sectional internet-based mirror survey. SSc patients participating in the online SPIN Cohort and care providers affiliated with 15 scientific societies were surveyed using the Cochin Scleroderma International Classification of Functioning, Disability and Health (ICF)-65 questionnaire, including 65 items (from 0 to 10), representing 9 domains of disability. Mean differences between patients and care providers were calculated. Care providers' characteristics associated with a mean difference >= 2 of 10 points were assessed in multivariate analysis. Answers were analyzed for 109 patients and 105 care providers. The mean age of patients was 55.9 (14.7) years and the disease duration was 10.1 (7.5) years. For all domains of the ICF-65, care providers' rates were higher than those of patients. The mean difference was 2.4 (1.0) of 10 points. Care providers' characteristics associated with this difference were organ-based specialty (OR = 7.0 [2.3-21.2]), younger age (OR = 2.7 [1.0-7.1]) and following patients with disease duration >= 5 years (OR = 3.0 [1.1-8.7]). We found systematic differences in disability perception between patients and care providers in SSc

Development of a new patient-reported outcome measure to assess activities and participation in people with systemic sclerosis: The Cochin 17-item Scleroderma Functional Scale

Contains fulltext : 219549.pdf (Publisher’s version ) (Closed access)Objectives: To develop a new patient-reported outcome measure assessing activities and participation in people with systemic sclerosis (SSc). Methods: A provisional International Classification of Functioning, Disability and Health (ICF)-based 65-item questionnaire previously developed from interviews of people with SSc was sent by email to all patients followed in the internal medicine department of Cochin hospital (n=184) and enrolled in the Scleroderma Patient-centered Intervention Network Cohort. Items were reduced according to their metric properties. Dimensional structure of the questionnaire was assessed by principal component analysis, convergent and divergent validities by the Spearman correlation coefficient (ρ), internal consistency by the Cronbach alpha coefficient, and reliability by a test-retest method using intraclass correlation coefficient (ICC) and Bland and Altman analysis. Results: Overall, 113/184 (61.4%) patients completed the provisional questionnaire. The item-reduction process resulted in a 17-item questionnaire, the Cochin 17-item Scleroderma Functional scale (CSF-17). Principal component analysis extracted 2 dimensions: 10 items related to mobility (CSF-17 section A) and 7 items related to general tasks (CSF-17 section B). We observed convergent validity of the CSF-17 total score with global activity limitation, pain, depression and aesthetic burden, and divergent validity with anxiety. The Cronbach α coefficient was 0.94 for section A and 0.95 for section B. ICC (n=25 patients) was 0.92 for CSF-17 total score. Bland and Altman analysis did not reveal a systematic trend for the test-retest. Conclusions: The CSF-17 is a new patient-reported outcome assessing activities and participation specifically in people with SSc. Its content and construct validities are very good.9 p