Study design and rationale for IFCT- 2203 TAXIO: A study that aims to evaluate the effectiveness of a first-line chemotherapy regimen without etoposide, combined with durvalumab, for patients with extensive disease small cell lung cancer.

BACKGROUND: Studies have shown improvement in overall survival with anti-PD1/PD-L1 molecules in combination with cisplatin/carboplatin and etoposide as a first-line treatment for Small Cell Lung Cancer (SCLC). However, first-line efficacy remains limited and well below that observed in Non-Small Cell Lung Cancer (NSCLC). Etoposide may have a detrimental effect on lymphocyte activation, which could explain the limited benefit of immunotherapy in the first line and the lack of benefit in the second line for patients previously exposed to high levels of etoposide. METHODS: We initiated a multicenter, single-arm, open-label phase II study of a chemotherapy regimen with durvalumab, combined with carboplatin and paclitaxel for extensive disease SCLC. Eligible patients will receive durvalumab plus carboplatin and paclitaxel every 3 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. A total of 67 patients will be enrolled in this study, with a 12-month enrollment period and 36-month follow-up. The primary endpoint is Overall Survival (OS) rate at 12 months. Secondary endpoints are best response rate, OS, OS at 24- and 36 months, progression free survival (PFS), duration of response, quality of life and safety. RESULTS: This study aims to establish the efficacy of durvalumab combined with carboplatin and paclitaxel in patients with extensive disease Small Cell Lung Cancer. CLINICAL TRIAL REGISTRATION: EU CT: 2023-504670-38-00.

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study.

BACKGROUND: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials. METHODS: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments. RESULTS: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news. CONCLUSIONS: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression.

Behavior of general physicians about lung cancer screening in a French region hosting a pilot study.

INTRODUCTION: Lung cancer is the leading cause of cancer-related death in France and has a 5-year survival rate of 20%. Recent prospective randomized controlled trials revealed that lung cancer-specific mortality decreased in patients who underwent screening using low-dose chest computed tomography (low-dose CT). The DEP KP80 pilot study conducted in 2016 showed that an organized lung cancer screening campaign involving general practitioners was feasible. MATERIAL AND METHOD: We conducted a descriptive observational study of screening practices by sending a self-reported questionnaire to 1013 general practitioners practicing in the Hauts-de-France region. Our study's primary aim was to investigate the knowledge and practices of general practitioners in the Hauts-de-France region of France regarding lung cancer screening using low-dose CT. The secondary endpoint was to compare practices between general practitioners in the Somme department who had experience of experimental screening and their colleagues in the rest of the region. RESULTS: The response rate was 18.8% (190 completed questionnaires). Even though 69.5% of the physicians were unaware of the potential benefits of organized low-dose CT screening for lung cancer, 76% proposed screening tests for individual patients. Despite its proven ineffectiveness, chest radiography was still the most widely recommended screening modality. Half of the physicians stated that they had already prescribed chest CT to screen for lung cancer. Additionally, only 36.3% proposed chest CT screening for patients aged over 50 years with a history of more than 30 pack-years. The physicians working in the Somme department (61% had participated in the DEP KP80 pilot study) were more aware of low-dose CT as a screening modality, and offered it significantly more than their colleagues in the other departments (61.1% vs 13.4% p<0.01). All the physicians were in favor of an organized screening program. CONCLUSION: More than a third of general practitioners in the Hauts-de-France region offered for lung cancer screening using chest CT, although only 18% specified low-dose CT. Before an organized screening program can be set up, good practice guidelines must be made available about lung cancer screening.

Implementing Lung Cancer Screening in Europe: Taking a Systems Approach.

Lung cancer is the leading cause of cancer death in Europe. Screening by means of low-dose computed tomography (LDCT) can shift detection to an earlier stage and reduce lung cancer mortality in high-risk individuals. However, to date, Poland, Croatia, Italy, and Romania are the only European countries to commit to large-scale implementation of targeted LDCT screening. Using a health systems approach, this article evaluates key factors needed to enable the successful implementation of screening programs across Europe. Recent literature on LDCT screening was reviewed for 10 countries (Belgium, Croatia, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, and United Kingdom) and complemented by 17 semistructured interviews with local experts. Research findings were mapped against a health systems framework adapted for lung cancer screening. The European policy landscape is highly variable, but potential barriers to implementation are similar across countries and consistent with those reported for other cancer screening programs. While consistent quality and safety of screening must be ensured across all screening centers, system factors are also important. These include appropriate data infrastructure, targeted recruitment methods that ensure equity in participation, sufficient capacity and workforce training, full integration of screening with multidisciplinary care pathways, and smoking cessation programs. Stigma and underlying perceptions of lung cancer as a self-inflicted condition are also important considerations. Building on decades of implementation research, governments now have a unique opportunity to establish effective, efficient, and equitable lung cancer screening programs adapted to their health systems, curbing the impact of lung cancer on their populations.

Epidemiological impact of lung cancer screening by low dose CT scan in the French Department of the SOMME.

CONTEXT: Lung cancer is the leading cause of cancer death worldwide. In recent years, screening using low-dose CT scan has shown a reduction in lung cancer-related mortality and in all-cause mortality. The DEP KP80 study was implemented in the French department of the Somme with the aim of investigating lung cancer screening in practice. The results of the first round showed a prevalence of 2.7% for lung cancer, with the majority at localized stages (77%). The primary objective of our study was to compare the stage at diagnosis of patients with lung cancer screened as part of DEP KP80 and those who were not screened. The secondary objectives were to describe the epidemiological characteristics of lung cancer in the French department of the Somme for the period in question and to compare survival rates in screened and unscreened patients. METHODS: This retrospective cohort study compared from May 2016 to December 2017 the characteristics of patients with lung cancer screened as part of DEP KP80 and those who were not screened, using data from the Somme Cancer Registry. RESULTS: In total, 644 patients with lung cancer were included (18 in the screened group and 626 in the unscreened group). There was a significant inversion in the stage distribution at diagnosis, with a predominance of metastatic or locally advanced stages (69%) and a minority of early stages (31%) in unscreened patients, and a majority of early stages (77.8%) and a lower proportion of locally advanced or disseminated stages (22.2%) in screened patients (p < 0.01). In the screened group, there was a significant improvement in survival, a higher rate of surgical resection, and a longer time interval between first contact and treatment initiation. CONCLUSION: Lung cancer screening by low-dose CT scan in the French department of the Somme showed an impact on stage at diagnosis, with a majority of early stages in screened patients, allowing for curative treatment with a significant improvement in survival.

Results of Second Round Lung Cancer Screening by Low-Dose CT scan - French Cohort Study (DEP-KP80).

INTRODUCTION: Over the last few years, lung cancer screening by low-dose CT scan has demonstrated a decrease in lung cancer mortality. While this method has been in use since 2013 in the United States of America, no European country has yet implemented a systematic screening program. We hereby report the results from the second round of screening from a French cohort study. PATIENTS AND METHODS: DEP KP80 is a prospective study evaluating lung cancer screening by means of three low-dose computer tomography (CT) scans at 1-year intervals in 1,307 participants, aged 55 to 74 years old, all smokers or former smokers, having quit within the last 15 years, with over 30 pack years. The results of the first round demonstrated it was possible to conduct effective screening in real-life situations. RESULTS: Participation was lower in this second round than in the first (35.3% vs. 73.1%, P < .001). The rate of negative results was significantly higher and that of undetermined results lower than those produced in the first round. Overall, 75% of cancers revealed were Stage 1 and 87.5% benefitted from surgical treatment. The incidence of cancer in the second round was 2.43%. CONCLUSION: As with the first round, the results of this second round confirm the feasibility and efficacy of lung cancer screening. The lower participation rate for this second round is proof of the need to improve awareness among participants and healthcare professionals of the relevance of committing to an annual screening program.

Intergroupe francophone de cancérologie thoracique, Société de pneumologie de langue française, and Société d'imagerie thoracique statement paper on lung cancer screening.

Following the American National Lung Screening Trial results in 2011 a consortium of French experts met to edit a statement. Recent results of other randomized trials gave the opportunity for our group to meet again in order to edit updated guidelines. After literature review, we provide here a new update on lung cancer screening in France. Notably, in accordance with all international guidelines, the experts renew their recommendation in favor of individual screening for lung cancer in France as per the conditions laid out in this document. In addition, the experts recommend the very rapid organization and funding of prospective studies, which, if conclusive, will enable the deployment of lung cancer screening organized at the national level.

Lung Cancer Screening by Low-Dose CT Scan: Baseline Results of a French Prospective Study.

BACKGROUND: Lung cancer mortality has been found to decrease significantly with low-dose (LD) computed tomographic (CT) screening among current or former smokers. However, such a screening program is not implemented in France. This study assessed the feasibility of a lung cancer screening program using LD CT scan in a French administrative territory. We report here the results of the first screening round. PATIENTS AND METHODS: DEP KP80 was a single-arm prospective study initiated in May 2016. Participants aged 55 to 74 years, current or former smokers of ≥ 30 pack-years, were recruited. An annual LD CT scan was scheduled. Our algorithms considered nodules < 5 mm as negative findings and nodules > 10 mm as positive; for intermediate nodules between 5 and 10 mm, 3-month CT scan with doubling time measurement was recommended. All general practitioners, pulmonologists, and radiologists from the Somme department were solicited to participate. Subjects were selected by general practitioners or pulmonologists who checked the inclusion criteria and prescribed the CT scan. RESULTS: Over a 2.5-year period, 1307 subjects were recruited. Screening was negative in 733 cases (77.2%), positive in 54 (5.7%), and indeterminate in 162 (17.1%). After the 3-month scans, 57 subjects screened positive: 26 patients exhibited 31 lung cancers (67.7% of stage 0 to I), of whom 76.9% underwent surgical resection, and 29 had no cancer (false-positive rate = 3.1%). The prevalence of lung cancer was 2.7%. CONCLUSION: This study demonstrated the feasibility of organized lung cancer screening using LD CT scan within a real-life context in the general population.

Nitrate signaling and the two component high affinity uptake system in Arabidopsis.

Nitrate transporters are important for nitrogen acquisition by plants and in algae some require two gene products, NRT2 and NAR2, for function. The NRT2 family was already described and the recent identification of a family of the NAR2-type genes in higher plants showed that there was a homologue in Arabidopsis, AtNAR2.1. Using heterologous expression in yeast and oocytes we showed that the two Arabidopsis AtNRT2.1 and AtNAR2.1 proteins interacted to give a functional high affinity nitrate transport system (HATS). The gene knock out mutant atnar2.1-1 is deficient specifically for HATS activity and the resulting growth phenotype on low nitrate concentration is more severe than for the atnrt2.1-1 knock out mutant. Physiological characterisation of the plant N status and gene expression revealed a pattern that was characteristic of severe nitrogen deficiency. Consistent with the down regulation of AtNRT2.1 expression, the atnar2.1-1 plants also displayed the same phenotype as atnrt2.1 mutants in lateral root (LR) response to low nitrate supply. Using atnar2.1-1 plants constitutively expressing the NpNRT2.1 gene, we now show a specific role for AtNAR2.1 in LR response to low nitrate supply. AtNAR2.1 is also involved in the repression of LR initiation in response to high ratios of sucrose to nitrogen in the medium. Therefore the two component system itself is likely to be involved in the signaling pathway integrating nutritional cues for LR architecture regulation. Using a green fluorescent protein-NRT2.1 protein fusion we show the essential role of AtNAR2.1 for the presence of AtNRT2.1 to the plasma membrane.

Characterization of a two-component high-affinity nitrate uptake system in Arabidopsis. Physiology and protein-protein interaction.

The identification of a family of NAR2-type genes in higher plants showed that there was a homolog in Arabidopsis (Arabidopsis thaliana), AtNAR2.1. These genes encode part of a two-component nitrate high-affinity transport system (HATS). As the Arabidopsis NRT2 gene family of nitrate transporters has been characterized, we tested the idea that AtNAR2.1 and AtNRT2.1 are partners in a two-component HATS. Results using the yeast split-ubiquitin system and Xenopus oocyte expression showed that the two proteins interacted to give a functional HATS. The growth and nitrogen (N) physiology of two Arabidopsis gene knockout mutants, atnrt2.1-1 and atnar2.1-1, one for each partner protein, were compared. Both types of plants had lost HATS activity at 0.2 mm nitrate, but the effect was more severe in atnar2.1-1 plants. The relationship between plant N status and nitrate transporter expression revealed a pattern that was characteristic of N deficiency that was again stronger in atnar2.1-1. Plants resulting from a cross between both mutants (atnrt2.1-1 x atnar2.1-1) showed a phenotype like that of the atnar2.1-1 mutant when grown in 0.5 mm nitrate. Lateral root assays also revealed growth differences between the two mutants, confirming that atnar2.1-1 had a stronger phenotype. To show that the impaired HATS did not result from the decreased expression of AtNRT2.1, we tested if constitutive root expression of a tobacco (Nicotiana plumbaginifolia) gene, NpNRT2.1, previously been shown to complement atnrt2.1-1, can restore HATS to the atnar2.1-1 mutant. These plants did not recover wild-type nitrate HATS. Taken together, these results show that AtNAR2.1 is essential for HATS of nitrate in Arabidopsis.

Physiological characterisation of Arabidopsis mutants affected in the expression of the putative regulatory protein PII.

The PII signal transducing protein is involved in carbon/nitrogen (C/N) sensing in bacteria and cyanobacteria. In higher plants the function of the PII homolog GLB1 is not known. GLB1 transcripts were found in all plant organs tested, while in Arabidopsis leaves GLB1 expression and PII protein levels were not significantly affected by either the day/night cycle or N-nutrition. Its putative regulatory role in plants has been studied by analysing Arabidopsis thaliana T-DNA insertion lines in the GLB1 gene. These PII mutants showed an 80% (PIIV1 mutant) and 100% (PIIS2 mutant) reduced AtGLB1 transcript level and no detectable PII protein. They did not display an altered growth or developmental phenotype when grown under non-limiting conditions suggesting that the PII protein does not play a crucial role in plants. However, in vitro grown PII mutants did show a higher sensitivity to nitrite (NO (2) (-) ) compared to the wild-type plants. This observation is reminiscent of the role of PII in the regulation of NO (2) (-) metabolism in cyanobacteria. Furthermore, when grown hydroponically, the PII mutants displayed a slight increase in carbohydrate (starch and sugars) levels in response to N starvation and a slight decrease in the levels of ammonium (NH (4) (+) ) and amino acids (mainly Gln) in response to NH (4) (+) resupply. Although the phenotypic changes are rather small in the mutant lines, these data support the hypothesis of a subtle involvement of the PII protein in the regulation of some steps of primary C and N metabolism.

GeneFarm, structural and functional annotation of Arabidopsis gene and protein families by a network of experts.

Genomic projects heavily depend on genome annotations and are limited by the current deficiencies in the published predictions of gene structure and function. It follows that, improved annotation will allow better data mining of genomes, and more secure planning and design of experiments. The purpose of the GeneFarm project is to obtain homogeneous, reliable, documented and traceable annotations for Arabidopsis nuclear genes and gene products, and to enter them into an added-value database. This re-annotation project is being performed exhaustively on every member of each gene family. Performing a family-wide annotation makes the task easier and more efficient than a gene-by-gene approach since many features obtained for one gene can be extrapolated to some or all the other genes of a family. A complete annotation procedure based on the most efficient prediction tools available is being used by 16 partner laboratories, each contributing annotated families from its field of expertise. A database, named GeneFarm, and an associated user-friendly interface to query the annotations have been developed. More than 3000 genes distributed over 300 families have been annotated and are available at http://genoplante-info.infobiogen.fr/Genefarm/. Furthermore, collaboration with the Swiss Institute of Bioinformatics is underway to integrate the GeneFarm data into the protein knowledgebase Swiss-Prot.

Unusual regulatory nitrate reductase activity in cotyledons of Brassica napus seedlings: enhancement of nitrate reductase activity by ammonium supply.

The effect of supplying either nitrate or ammonium on nitrate reductase activity (NRA) was investigated in Brassica napus seedlings. In roots, nitrate reductase activity (NRA) increased as a function of nitrate content in tissues and decreased when ammonium was the sole nitrogen source. Conversely, in the shoots (comprising the cotyledons and hypocotyl), NRA was shown to be independent of nitrate content. Moreover, when ammonium was supplied as the sole nitrogen source, NRA in the shoots was surprisingly higher than under nitrate supply and increased as a function of the tissue ammonium content. Under 15 mM of exogenous ammonium, the NRA was up to 2.5-fold higher than under nitrate supply after 6 d of culture. The NR mRNA accumulation under ammonium nutrition was 2-fold higher than under nitrate supply. The activation state of NR in shoots was especially high compared with roots: from nearly 80% under nitrate supply it reached 94% under ammonium. This high NR activation state under ammonium supply could be the consequence of the slight acidification observed in the shoot tissue. The effect of ammonium on NRA was only observed in cotyledons and when more than 3 mM ammonium was supplied. No such NRA increase was evident in the roots or in foliar discs. Addition of 1 mM nitrate under ammonium nutrition halved NRA and decreased the ammonium content in shoots. Thus, this unusual NRA was restricted to seedling cotyledons when nitrate was lacking in the nitrogen source.