Squaring the circle: lessons from the role-playing exercises on S3 regional and multi-level governance

Whilst there is widespread agreement on the importance of developing an appropriate governance structure for S3, there is little empirical evidence on the challenges this entails. The JRC, as part of its activities of Targeted Support, has developed a working group to address these issues. The working group operated in the first half of 2018, built upon an extensive background research as well as two role-playing exercises. The latter aimed at understanding and addressing key policy challenges, by enacting realistic policy scenarios. The paper explores both policy and methodological questions. As for the former, the paper investigates the main bottlenecks inhibiting the effectiveness of multi-stakeholder policy development, identifying the administrative and technical needs of those in charge of S3 governance. As for the latter, the paper provides an opportunity to reflect on role-playing as a tool for policy analysis in the context of Cohesion policy.JRC.B.3-Territorial Developmen

Outcome and Prognostic Factors of COVID-19 Infection in Swiss Cancer Patients: Final Results of SAKK 80/20 (CaSA).

PURPOSE These are the final results of a national registry on cancer patients with COVID-19 in Switzerland. METHODS We collected data on symptomatic COVID-19-infected cancer patients from 23 Swiss sites over a one-year period starting on 1 March 2020. The main objective was to assess the outcome (i.e., mortality, rate of hospitalization, ICU admission) of COVID-19 infection in cancer patients; the main secondary objective was to define prognostic factors. RESULTS From 455 patients included, 205 patients (45%) had non-curative disease, 241 patients (53%) were hospitalized for COVID-19, 213 (47%) required oxygen, 43 (9%) invasive ventilation and 62 (14%) were admitted to the ICU. Death from COVID-19 infection occurred in 98 patients, resulting in a mortality rate of 21.5%. Age ≥65 years versus <65 years (OR 3.14, p = 0.003), non-curative versus curative disease (OR 2.42, p = 0.012), ICU admission (OR 4.45, p < 0.001) and oxygen requirement (OR 20.28, p < 0.001) were independently associated with increased mortality. CONCLUSIONS We confirmed high COVID-19 severity and mortality in real-world cancer patients during the first and second wave of the pandemic in a country with a decentralized, high-quality, universal-access health care system. COVID-19-associated mortality was particularly high for those of older age in a non-curative disease setting, requiring oxygen or ICU care

Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial

<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p

New insights in the development of biological chimeras: Genomic instability and epithelial chimerism after hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans results in true biological chimeras. While circulating hematopoietic and immune cells and their tissue derivatives (e.g., Kupffer cells, Langerhans cells) become donor genotype after transplantation, other cells remain recipient in origin. This unphysiological formation of biological chimeras is not free of consequences. The first sequel which has been recognized in the development of chimerical organisms after allo-HSCT is the graft versus host reaction, in which the new developed immune cells from the graft recognize the host's epithelial cells as foreign and kill them. There is now accumulating evidence that there are also other consequences in the co-existence of two genetically distinct populations in the transplant recipient. First, epithelial cells with donor-derived genotype emerge. Second, epithelial tissues of the host acquire genomic alterations. The current chapter discusses existing data on these recently discovered phenomena and focuses on their pathogenesis, clinical significance and therapeutic implications

New insights in the development of biological chimeras: Genomic instability and epithelial chimerism after hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in humans results in true biological chimeras. While circulating hematopoietic and immune cells and their tissue derivatives (e.g. Kupffer cells, Langerhans cells) become donor genotype after transplantation, other cells remain recipient in origin. This unphysiological formation of biological chimeras is not free of consequences. The first sequel which has been recognized in the development of chimerical organisms after allo-HSCT is the graft versus host reaction, in which the new developed immune cells from the graft recognize the host's epithelial cells as foreign and kill them. There is now accumulating evidence that there are also other consequences in the co-existence of two genetically distinct populations in the transplant recipient. First, epithelial cells with donor-derived genotype emerge. Second, epithelial tissues of the host acquire genomic alterations. The current chapter discusses existing data on these recently discovered phenomena and focuses on their pathogenesis, clinical significance and therapeutic implications

Horizontal DNA and mRNA transfer between donor and recipient cells after allogeneic hematopoietic cell transplantation?

Allogeneic hematopoietic cell transplantation in humans results in true biological chimeras. There is now accumulating evidence that besides Graft versus Host Disease (GvHD), there are also other consequences in the co-existence of two genetically distinct populations in the transplant recipient. First, epithelial cells with donorderived genotype emerge. Second, epithelial tissues of the host acquire genomic alterations. The current review discusses existing data on these recently discovered phenomena and focuses on horizontal gene transfer between donor and recipient cells as a possible mechanism explaining and linking these phenomena

Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma

Introduction There is no approved second-line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off-label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD-L1). Methods Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD-L1 expression was categorized as negative (Results A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second-line treatment in 48 of 93 patients (52%). PD-L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD-L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression-free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD-L1 expression, high PD-L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. Conclusion These real-world data demonstrate similar response rates but inferior survival compared with those in early-phase trials. High PD-L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti–PD-L1 immunotherapy is a reasonable second-line therapy in patients with MPM

L'aspis

SCOPUS: re.jinfo:eu-repo/semantics/publishe

Binimetinib, pemetrexed and cisplatin, followed by maintenance of binimetinib and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC) and KRAS mutations. The phase 1B SAKK 19/16 trial.

BACKGROUND KRAS mutations are found in 20-25 % of non-squamous non-small cell lung cancer (NSCLC) and therapies targeting the RAS/MEK/ERK pathway are in development. We performed a multicenter open-label phase 1B trial to determine the recommended phase 2 dose and early antitumor activity of the MEK-inhibitor binimetinib combined with cisplatin and pemetrexed. METHODS Eligible patients (pts) had stage III-IV NSCLC unsuitable for curative treatment, KRAS exon 2 or 3 (codon 12, 13 or 61) mutations, no prior systemic therapy. Pts were enrolled into part 1: 3 + 3 design with dose escalation in 2 dose levels (DL) of binimetinib and part 2: expansion cohort at the maximum tolerated dose (MTD). Pts received 4 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2and binimetinib 30 (DL1)/45 mg (DL2) orally twice a day (bid) d1-14 q3w followed by pemetrexed and binimetinib until progressive disease (PD) or unacceptable toxicity. RESULTS From May 2017 to Dec 2019, 18 pts (13 dose escalation, 5 expansion cohort) were enrolled. Median age was 60 (48-73, range). KRAS mutations were 87.5 % at codon 12. No DLT occurred in the dose escalation cohort. Median number of cycles was 2 (1-17, range). Treatment discontinuation was mainly due to PD (33 %) or pts/physicians' decision (27 %). Together with the expansion cohort, 16 pts were evaluable for safety. Most frequent treatment-related grade 3 AEs were lung infection (25 %), fatigue (19 %), anemia (19 %). Overall response rate among 9 evaluable pts receiving binimetinib at MTD (45 mg bid) was 33 % (7-70 %, 95 % CI). Median progression-free survival was 5.7 months (1.1-14.0, 95 % CI) and overall survival 6.5 months (1.8-NR, 95 % CI). CONCLUSIONS Pts treated with combination of cisplatin, pemetrexed and binimetinib presented no unexpected toxicity. No early signal of increased antitumor activity of binimetinib added to chemotherapy was observed in our pts population