SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. PATIENTS AND METHODS: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. RESULTS: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. CONCLUSIONS: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.

PD-L1+ lung cancer stem cells modify the metastatic lymph-node immunomicroenvironment in nsclc patients.

INTRODUCTION: Cancer stem cells (CSCs) are implicated in tumor initiation and development of metastasis. However, whether CSCs also affect the immune system is not fully understood. We investigated correlations between the PD-L1+ CSCs, changes in T-cell phenotype in metastatic and non-metastatic lymph nodes (LNs) and response to treatment. METHODS: LNs' aspirates were obtained during the EBUS/TBNA procedure of 20 NSCLC patients at different stages of the disease. CSCs and T-cell characteristics were determined by flow cytometry. RESULTS: PD-L1+ CSCs positively correlated with the percentage of Tregs, PD-1+ CD4 T cells and Tim3+ CD4+ T cells, whereas PD-L1+ CSCs were negatively correlated with CD4+ T cells and CD28+ CD4+ T cells. The percentage of PD-L1+ CSCs was higher in patients with progressive disease (PD) as compared to patients with stable disease (SD) or partial response (PR). Among T cells, only PD-1+ CD4+ T cells and Tim3+ CD4+ T-cell frequencies were higher in patients with PD as compared to patients with SD or PR. CONCLUSION: The frequency of PD-L1+ CSCs associates with an altered T-cell frequency and phenotype indicating that CSCs can affect the immune system. The higher percentage of PD-L1+ CSCs in patients with PD may confirm their resistance to conventional therapy, suggesting that CSCs may be an interesting target for immunotherapy.

Assessment of the treatment efficiency of an urban stormwater pond and its impact on the natural downstream watercourse.

During the last few decades, stormwater ponds have become an alternative management practice in order to avoid flooding and to contain rainwater and runoff in urban areas where impervious land cover has increased. A second purpose of stormwater ponds is to improve the quality of runoff water that is usually contaminated with nitrogen, phosphorus, metals and organic micropollutants. Processes used are based on natural methods such as settlement and contribute to minimize the impact of these inputs to the natural aquatic system. This study aims to better understand the behavior of a wet stormwater pond, Heron Lake (33 ha) located in the city of Villeneuve d'Ascq in northern France through various indicators [trace metals, PAHs, PCBs, caffeine (CAF), carbamazepine (CBZ), nutrients and pathogens]. For that purpose, water quality was monitored for 1 year, mainly at the entrance and at the outlet of the lake. Sampling have also been done in the downstream aquatic environment, the Marque River. Sediments were sampled in the lake to evaluate the pollution trapped during sedimentation. Our results of both water and sediment sampling highlight: (i) the wastewater input into the Heron Lake is estimated to be equivalent to that of roughly 3800 inhabitants; (ii) the removal rates observed at the outlet, relative to concentrations at the entrance channel, vary as follows for these dissolved species: 24% for NO3- and PO43-, 28% for CBZ, 35% for Cu, 63% for Pb, 78% for CAF, 84% for Zn and up to 93% for NH4+; (iii) there are high levels of sediment contamination with metals, PAHs and PCBs at the entrance channel; (iv) the eutrophication of this pond is attributed to persistent high nutrient concentrations in both water and sediment, and has contributed to the development of an invasive macrophyte, the Elodea nuttallii; and (v) there appears to be only a negligible impact of the discharge from the lake to the natural watercourse, contributing annual loads of <2 up to 6% of the total amount of Cu, Pb, Zn, CAF, CBZ and nutrients measured in the Marque River, and having a slight diluting effect on concentrations in the Marque River.

Atypical B cells (CD21-CD27-IgD-) correlate with lack of response to checkpoint inhibitor therapy in NSCLC.

INTRODUCTION: Checkpoint inhibitor (CI) therapy has revolutionized treatment for non-small cell lung cancer (NSCLC). However, a proportion of patients do not respond to CI therapy for unknown reasons. Although the current paradigm in anti-tumor immunity evolves around T cells, the presence of tertiary lymphoid structures and memory B cells has been positively correlated with response to CI therapy in NSCLC. In addition, double negative (DN) (CD27- IgD-) B cells have been shown to be abundant in NSCLC compared to healthy lung tissue and inversely correlate with the intratumoral presence of memory B cells. Nonetheless, no study has correlated DN B cells to survival in NSCLC. METHODS: In this study, we evaluated the presence and phenotype of B cells in peripheral blood with flow cytometry of patients with NSCLC and mesothelioma before receiving CI therapy and correlated these with clinical outcome. RESULTS: Non-responding patients showed decreased frequencies of B cells, yet increased frequencies of antigen-experienced CD21- DN (Atypical) B cells compared to responding patients and HC, which was confirmed in patients with mesothelioma treated with CI therapy. CONCLUSIONS: These data show that the frequency of CD21- DN B cells correlates with lack of response to CI therapy in thoracic malignancies. The mechanism by which CD21- DN B cells hamper CI therapy remains unknown. Our findings support the hypothesis that CD21- DN B cells resemble phenotypically identical exhausted B cells that are seen in chronic infection or function as antigen presenting cells that induce regulatory T cells.

Nivolumab and ipilimumab in the real-world setting in patients with mesothelioma.

OBJECTIVES: Nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) is a new first-line treatment combination for patients with pleural mesothelioma. Nivolumab-ipilimumab improved the survival, however, 30.3% of the patients suffered from grade 3-4 treatment related adverse events (TRAE's) and TRAE's led to discontinuation in 23.0% of all patients. Here, we present the first real-world data of nivolumab plus ipilimumab in patients with malignant mesothelioma treated in two mesothelioma expert centers. METHODS: Clinical data of patients with mesothelioma treated with nivolumab and ipilimumab were prospectively collected. Clinical parameters were obtained every visit, CT scans were evaluated every 12 weeks and adverse events were assessed continuously during the treatment. Data on grade 2-5 TRAE's and activity (overall response rate (ORR), duration of response (DOR), disease control rate (DCR), median progression-free survival (mPFS) and median overall survival (mOS) were reported. RESULTS: Between January 2021 and August 2022, 184 patients were treated with nivolumab plus ipilimumab. The median follow-up was 12.1 months (95 %CI 11.1 - 13.1). Grade 3-4 TRAEs were seen in 27.7 % of the patients and 25.0 % discontinued immunotherapy treatment early because of TRAE's. ORR was 21.7 % (95 % CI 15.7-27.7), median DOR was 5.7 months (IQR 3.2-8.7) and DCR at 12 weeks 56.0 % (95 % CI 48.8-63.2). The mPFS was 5.5 months (95 %CI 4.1-6.9), mOS was 14.1 months (95 % CI 11.1-18.2). CONCLUSIONS: Nivolumab plus ipilimumab had an equal efficacy in a real-world comparable population but also a high risk of TRAE's, leading to discontinuation of treatment in 25% of the patients.

On inorganic tracers of wastewater treatment plant discharges along the Marque River (Northern France).

Increase of water quality in aquatic systems has become a hot button issue in recent decades. However, with the aim to implement an effective remediation strategy, the first step is to identify the sources of diffuse and point-source pollution using several tracers. In urban areas, B isotopes, Gd enrichment, Cl- or carbamazepine concentrations can be used as wastewater treatment plant tracers. In this study, a focus was made on the quantification of a wide variety of inorganic compounds (elements, ions, isotopic ratios) all along the Marque River, a small stream located in Northern France receiving effluents coming from seven wastewater treatment plants (WWTPs). The objectives were (i) to determine the importance of the WWTPs discharge during low water events, (ii) to assess the efficiency of conventional tracers in quantifying the contribution of the WWTPs and (iii) to investigate new potential tracers less commonly used. The results have shown, through statistical analyses ANOVA (Analysis Of Variance) tests, PCA (Principal Component Analysis) and contribution calculations, that the WWTPs discharges strongly impact the water composition of all the watercourse and particularly during the first 6 km. However, due to high discharges of wastewaters not always well treated, some classical indicators (e.g. B, Rb/Sr) have shown limitations when used alone. The use of a set of relevant tracers including alkali metals could therefore be one solution for overcoming such a problem. Finally, other indicators like Rb/B or Gd/Pt ratios may also be a way to tackle this issue; they are indeed promising to discriminate the source of wastewaters.

Development and validation of DGT passive samplers for the quantification of Ir, Pd, Pt, Rh and Ru: A challenging application in waters impacted by urban activities.

Platinum group elements (PGEs) are among the least abundant in the continental crust. They have become excellent tracers of anthropogenic activities, particularly due to their use in catalytic converters or in the medical industry. However, their quantification in environmental matrices is still problematic because of their low concentrations combined with the presence of interfering elements. Preconcentration methods are therefore necessary to measure accurate concentrations. In this study, the quantification of Ir, Rh, Ru, Pd and Pt was studied in depth by focusing on two resins: AG MP-1 (anion exchange) and Purolite® S-920 (chelating) with the aim of developing passive Diffusive Gradients in Thin films (DGT) samplers as in-situ pre-concentration tools. The characteristics of both resins (e.g. adsorption, elution, selectivity, etc.) were studied and the diffusion coefficients of PGEs in different matrices were determined. For the first time, carcinostatic platinum-based drugs were also studied. Better rates and percentages of adsorption were observed for S-920 while AG MP-1 was more selective with regard to spectral interferents and easier to elute. The diffusion coefficients of PGEs were resin-dependent, particularly for carcinostatic platinum-based drugs. For the first time, the applicability of these DGT samplers dedicated to PGEs was demonstrated in the field after their deployment in two wastewater treatment plants in Northern France for which concentrations were found to range from few pg L-1 (Ir, Ru) to few ng L-1 (Pt).

ETV6-NTRK3 translocation-associated low-grade mucinous bronchial adenocarcinoma: A novel bronchial salivary gland-type non-small cell lung cancer subtype.

INTRODUCTION: NTRK fusion genes have been found in several solid tumors, among which NSCLC and sarcoma. Novel NTRK translocation-related tumors are still being discovered. METHODS: We report a 49-year-old patient with a mass in the left lower lung lobe that was resected. This specimen was analyzed and sequenced using targeted DNA next generation sequencing (NGS) and anchored-multiplex-PCR (AMP) targeted RNA NGS. RESULTS: On pathological evaluation, a peribronchial mucinous neoplasm with a unique morphology was found. RNA NGS analysis showed anETV6-NTRK3 translocation in a low-grade mucinous bronchial adenocarcinoma. CONCLUSIONS: This entity represents a novel subtype of non-small cell lung cancer, which we would like to term 'ETV6-NTRK3 translocation-associated low-grade mucinous bronchial adenocarcinoma'.

Impact of the coronavirus disease 2019 pandemic on cancer treatment: the patients' perspective.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has inevitable consequences for medical care of patients without COVID-19. To assess the impact of this pandemic on oncological care, a nationwide survey was conducted among patients with cancer in the Netherlands. METHODS: The patients' perspective on oncological care was investigated using an online survey between March 29th 2020 and April 18th 2020. The survey consisted of 20 questions on four topics: patients' characteristics, contact with the hospital, consequences of the COVID-19 pandemic and concerns about COVID-19. RESULTS: Five thousand three hundred two patients with cancer completed this nationwide survey. Overall, 30% of patients reported consequences for their oncological treatment or follow-up. In the majority of cases, this resulted in conversion from hospital visit to consultation by phone or video. The most frequently adjusted treatments were chemotherapy (30%) and immunotherapy (32%). Among patients with delay and discontinuation of treatment, 55% and 63% of patients, respectively, were (very) concerned about these consequences of the COVID-19 pandemic. Consequences were independent of regional differences in COVID-19 incidence. However, patients in regions with high COVID-19 incidence were significantly more concerned. CONCLUSION: This is the first study investigating perspectives of patients with cancer during the COVID-19 pandemic. The study demonstrates the significant impact of the COVID-19 crisis on oncological care, indicating the need for psycho-oncological support during this pandemic.

Maternal adherence to guidance on breast milk collection process.

INTRODUCTION: Breast milk expression with a breast pump increases the risk of contaminating milk with pathogenic bacteria; how to decontaminate breast pumps is controversial. The aim of this study was to investigate maternal adherence to updated French guidance on the breast milk collection process, including breast pump decontamination, and to identify potential sources of increased bacterial counts in breast milk in order to improve prevention messages to mothers. METHODS: Descriptive prospective study conducted between November 2015 and April 2016 in a French tertiary perinatal center. Oral and written instructions on the breast milk collection process and breast pump decontamination were given to mothers by trained healthcare professionals. Mothers whose neonates were admitted to the neonatal care unit and expressing milk for the human milk bank were eligible if breast milk bacterial counts before pasteurization were≥106 colony-forming units (cfu)/mL for total aerobic flora or ≥104 cfu/mL for Staphylococcus aureus. Maternal adherence to the guidance was investigated with a questionnaire and a face-to-face interview. RESULTS: One hundred and fourteen mothers with neonates admitted to the neonatal care unit expressed milk for the milk bank; 44 (39%) were eligible and 29 (66%) included: most of them (76%) with increased counts of total aerobic flora in breast milk and 24% with increased counts of S. aureus. At least three divergences from the guidance provided were reported for 16 mothers (55%). The most frequent ones were inadequate storage of the breast pump collection kit (62%), ineffective decontamination of the breast pump collection kit (52%), inappropriate cleaning of the breast pump (48%), and inadequate breast milk transport from home to hospital (31%). CONCLUSION: Despite standardized instructions, mothers with increased bacterial counts in breast milk frequently declared several divergences from the guidance on the breast milk collection process. Giving mothers and any person of their choice repeated clear instructions with illustrated guidance, demonstrations, and practice may help improve the microbiological safety of expressed breast milk.

Water quality assessment of a small peri-urban river using low and high frequency monitoring.

The biogeochemical behaviors of small rivers that pass through suburban areas are difficult to understand because of the multi-origin inputs that can modify their behavior. In this context, a monitoring strategy has been designed for the Marque River, located in Lille Metropolitan area of northern France, that includes both low-frequency monitoring over a one-year period (monthly sampling) and high frequency monitoring (measurements every 10 minutes) in spring and summer. Several environmental and chemical parameters are evaluated including rainfall events, river flow, temperature, dissolved oxygen, turbidity, conductivity, nutritive salts and dissolved organic matter. Our results from the Marque River show that (i) it is impacted by both urban and agricultural inputs, and as a consequence, the concentrations of phosphate and inorganic nitrogen have degraded the water quality; (ii) the classic photosynthesis/respiration processes are disrupted by the inputs of organic matter and nutritive salts; (iii) during dry periods, the urban sewage inputs (treated or not) are more important during the day, as indicated by higher river flows and maximal concentrations of ammonium; (iv) phosphate concentrations depend on oxygen contents in the river; (v) high nutrient concentrations result in eutrophication of the Marque River with lower pH and oxygen concentrations in summer. During rainfalls, additional inputs of ammonium, biodegradable organic matter as well as sediment resuspension result in anoxic events; and finally (vi) concentrations of nitrate are approximately constant over the year, except in winter when higher inputs can be recorded. Having better identified the processes responsible for the observed water quality, a more informed remediation effort can be put forward to move this suburban river to a good status of water quality.

Active biomonitoring for assessing effects of metal polluted sediment resuspension on gammarid amphipods during fluvial traffic.

The resuspension of polluted sediments by boat traffic could release substantial amounts of metals to the water column, affecting at the same time their bioavailability. In order to characterize the impact of sediment resuspensions on biota, caged amphipods have been deployed on three different channelized watercourses in Northern France. Firstly, the biological responses of transplanted freshwater gammarid amphipods, Gammarus fossarum, described by trace metal accumulation, feeding and reproduction activities were quite similar for the three water courses despite the differences of metal contamination and navigability. Secondly, the concentrations of metals accumulated in gammarids never exceeded the contamination thresholds previously defined for Co, Cu, Cr and Zn. Values were in the same order of magnitude whatever the studied site despite: (i) large differences noticed in the sediment quality and (ii) some concentrations in the overlying waters exceeding the Environmental Quality Standards (EQS) defined by the Water Framework Directive. Conversely, Pb was highly bioaccumulated with values systematically exceeding the threshold value whatever the site. Therefore, the impact of navigation cannot be proved and the difference between the 3 monitoring periods is rather attributed to environmental variability, probably linked to the seasonality. Moreover, this study also confirms that organisms sampled from a local population in the vicinity of the three studied watercourses could be used as test organisms, leading to similar results than the ones obtained with reference gammarids initially used for developing all the biological responses. This would simplify and then promote the development of studies based on gammarid amphipod, G. fossarum, as bioindicators.

On biogeochemistry and water quality of river canals in Northern France subject to daily sediment resuspension due to intense boating activities.

In Northern France, channelized rivers facilitate greatly the waterway transport that should still increase in the coming years to replace as much as possible the road traffic, considered as a heavier source of pollution. These rivers are now subjected to the good potential status objectives required by the Water Framework Directive. The impact of the recurrent resuspension by the current boat traffic of polluted sediments (due to strong historical pollution) on the water quality is the main concern of this work. Our study reveals that the navigation seems to play a limited role on the enrichment of the water columns by dissolved metals and phosphorus, as well as on the oxygenation of surface waters. Conversely, the cycling of the phytoplankton over the year appears to partly control the physico-chemical and chemical evolutions of the overlying waters.

[Contamination of human milk with aerobic flora: Evaluation of losses for a human milk bank]. / Contamination du lait maternel par une flore aérobie : évaluation des pertes pour un lactarium.

INTRODUCTION: In France, human milk banks pasteurize milk for the mother's own hospitalized baby (personalized milk) and for donation. There is specific legislation regulating the activity of human milk banks with bacterial screening of donor milk before and after pasteurization. Milk should be tested for Staphylococcus aureus and total aerobic flora. Any sample of milk positive for aerobic flora and/or S. aureus before and/or after pasteurization should be discarded. The real pathogenicity of the total aerobic flora is actually debated as well as the usefulness of systematic postpasteurization screening. The aim of this study was to quantify milk losses related to prepasteurization contamination by total aerobic flora in a regional milk bank, to identify losses due to contamination with S. aureus or aerobic flora, and to analyze differences between centers. METHODS: This was a prospective observational study conducted in the regional human milk bank of the Nord-Pas-de-Calais area in France. Data were collected from six major centers providing 80% of the milk collected between June 2011 and June 2012. Variables were the volumes of personalized milk collected by each center, volumes of contaminated milk, and the type of bacteria identified. RESULTS: During the study period, the regional human milk bank treated 4715 L (liters) of personalized milk and 508 L (10.8%) were discarded due to bacteriological screening. Among these 508 L, 43% were discarded because of a prepasteurization contamination with aerobic flora, 55% because of a prepasteurization contamination with S. aureus, and 2% because of other pathogenic bacteria. Postpasteurization tests were positive in 25 samples (0.5%). Only five of these 25 samples were positive before pasteurization and in all cases with S. aureus. A total of 218 L were destroyed because of prepasteurization contamination with total aerobic flora, while the postpasteurization culture was sterile. There was a great difference between centers in the percentage of discarded milk and the type of contamination. The percentage of discarded milk varied from 4 to 16% (P<0.001) and the percentage of prepasteurization positive samples with aerobic flora from 0 to 70% (P<0.001). Costing 80 €/L in France, this represented an economic loss of €17,440. CONCLUSION: A significant volume of milk is discarded because of contamination with total aerobic flora found only in prepasteurization tests. Reassessment of the French regulations with regard to microbiological safety could save human milk to cover the needs of a larger group of preterm babies.

Ectopia lentis and central serous chorioretinopathy in a patient with a marfanoid habitus. A case report.

We report a case of ectopia lentis and central serous chorioretinopathy in a young female patient with several manifestations of Marfan syndrome in the skeletal, cardiovascular and dermatological systems. We can't conclude however that these two ocular abnormalities are linked.