Surprising impact of stromal TIL's on immunotherapy efficacy in a real-world lung cancer study.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy. METHODS: We performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS). RESULTS: We included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and 'first-line treatment'. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively. CONCLUSIONS: This real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.

Timing of insulin basal rate reduction to reduce hypoglycemia during late post-prandial exercise in adults with type 1 diabetes using insulin pump therapy: A randomized crossover trial.

AIMS: To compare the efficacy of three timings to decrease basal insulin infusion rate to reduce exercise-induced hypoglycaemia in patients with type 1 diabetes (T1D) using pump therapy. METHODS: A single-blinded, randomized, 3-way crossover study in 22 adults that had T1D > 1 year and using insulin pump > 3 months (age, 40 ± 15 years; HbA1c, 56.3 ± 10.2 mmol/mol). Participants practiced three 45-min exercise sessions (ergocyle) at 60% VO2peak 3 hours after lunch comparing an 80% reduction of basal insulin applied 40 minutes before (T-40), 20 minutes before (T-20) or at exercise onset (T0). RESULTS: No significant difference was observed for percentage of time spent < 4.0 mmol/L (T-40: 16 ± 25%; T-20: 26 ± 27%; T0: 24 ± 29%) (main outcome) and time spent in target range 4.0-10.0 mmol/L (T-40: 63 ± 37%; T-20: 66 ± 25%; T0: 65 ± 31%). With T-40 strategy, although not significant, starting blood glucose (BG) was higher (T-40: 8.6 ± 3.6 mmol/L; T-20: 7.4 ± 2.5 mmol/L ; T0: 7.4 ± 2.7 mmol/L), fewer patients needed extra carbohydrates consumption prior to exercise for BG < 5.0 mmol/L (T-40: n = 3; T-20: n = 5; T0: n = 6) as well as during exercise for BG < 3.3 mmol/L [T-40: n = 6 (27%); T-20: n = 12 (55%); T0: n = 11 (50%)] while time to first hypoglycaemic episode was delayed (T-40: 28 ± 14 min; T-20: 24 ± 10 min; T0: 22 ± 11 min). CONCLUSION: Decreasing basal insulin infusion rate by 80% up to 40 minutes before exercise onset is insufficient to reduce exercise-induced hypoglycaemia.

Body Composition and Epicardial Fat in Type 2 Diabetes Patients Following Insulin Detemir Versus Insulin Glargine Initiation.

The aim of the study was to compare body composition and epicardial fat thickness changes in insulin-naïve inadequately controlled patients with type 2 diabetes following basal insulin initiation with detemir vs. glargine. Six-month, open-label, interventional randomized pilot study was conducted. Dual-energy X-ray absorptiometry and echocardiography were used to estimate the body composition and epicardial fat thickness respectively. Thirty-six patients in the detemir group and 20 in the glargine group completed the study. Study groups baseline characteristics were comparable. At 6 months, for similar glycemic control, those on detemir significantly gained less total weight (0.6±2.5 vs. 4.2±4.1 kg, p=0.004), total fat mass (0.9±2.2 vs. 2.9±2.4 kg, p=0.02), and truncal fat mass (0.8±1.5 vs. 2.1±1.7 kg, p=0.02), with a loss in truncal lean mass (- 0.8±1.9 kg vs. 0.3±1.7 kg; p=0.02). EFT significantly decreased from baseline in both group (detemir - 1.7±0.52-mm, glargine - 1.1±1.6-mm; p<0.05, without significant difference inter-groups). Within the detemir group, epicardial fat thickness change correlated with truncal fat and total fat mass changes (r=0.65, p=0.06 and r=0.60, p=0.07). In conclusion, detemir resulted in less fat mass gain, a trend for a more pronounced epicardial fat thickness reduction when compared with glargine.

Anomalous impurity segregation and local bonding fluctuation in l-Si.

Anomalous impurity redistribution after a laser irradiation process in group-IV elements has been reported in numerous papers. In this Letter, we correlate this still unexplained behavior with the peculiar bonding character of the liquid state of group-IV semiconductors. Analyzing the B-Si system in a wide range of experimental conditions we demonstrate that this phenomenon derives from the non-Fickian diffusion transport of B in l-Si. The proposed diffusion model relies on the balance between two impurity states in different bonding configurations: one migrating at higher diffusivity than the other. This microscopic mechanism explains the anomalous B segregation, whereas accurate comparisons between experimental chemical profiles and simulation results validate the model.

Binding of human serum albumin to silica particles by means of polymers: a liquid chromatographic study of the selectivity of resulting chiral stationary phases.

Chiral stationary phases obtained by immobilization of human serum albumin (HSA) on various polymer-coated silicas were tested to resolve DL-tryptophan, DL-NBP, RS-oxazepam and RS-warfarin racemic mixtures. HSA immobilized on anion exchangers [quaternized poly(vinylimidazole)-coated silica] was highly selective. Stable and selective chiral stationary phases were also prepared by covalent binding of HSA to silica particles via reactive-polymers. Poly(acryloyl chloride), poly(methacryloyl chloride) and poly(vinyl chloroformate) derivatives were compared. Parameters that govern the selectivity of resulting chiral supports were evaluated, especially the orientation of HSA after immobilization, the mobility of polymer chains and the number of covalent linkages between the protein and the polymer.

Structural changes of human serum albumin immobilized on chromatographic supports: a high-performance liquid chromatography and Fourier-transform infrared spectroscopy study.

Chiral stationary phases obtained by immobilization of HSA on [C8] and [C18] reversed-phases and on poly(1-vinylimidazole)-coated silica were tested to resolve DL-tryptophan, N-benzoyl-DL-phenylalanine, RS-oxazepam and RS-warfarin racemic mixtures. Parameters of enantioselectivity measured in HPLC are correlated to structural and solvation states for adsorbed HSA, evaluated by FTIR spectroscopy. HSA immobilized on [PVI]-anion-exchangers is highly selective. HSA molecules are not self-associated, only unfolded for a small hydrophobic helix. The HSA-coated reversed-phases have a lower selectivity. Unfolding is larger but the indole-benzodiazepine chiral site is preserved and remains accessible.

A 3D space-time motion evaluation for image registration in digital subtraction angiography.

In modern clinical practice, Digital Subtraction Angiography (DSA) is a powerful technique for the visualization of blood vessels in a sequence of X-ray images. A serious problem encountered in this technique is the presence of artifacts due to patient motion. The resulting artifacts frequently lead to misdiagnosis or rejection of a DSA image sequence. In this paper, a new technique for removing both global and local motion artifacts is presented. It is based on a 3D space-time motion evaluation for separating pixels changing values because of motion from those changing values because of contrast flow. This technique is proved to be very efficient to correct for patient motion artifacts and is computationally cheap. Experimental results with several clinical data sets show that this technique is very fast and results in higher quality images.

A low-protein isocaloric diet during gestation affects brain development and alters permanently cerebral cortex blood vessels in rat offspring.

In humans, low birth weight is associated with nonfatal stroke, cardiovascular disease and diabetes at adulthood. The aim of this study was to investigate in rats the effect of early protein restriction, inducing low birth weight, on brain and endocrine pancreas vascularization at birth and to study if such alterations lasted until adulthood. Pregnant rats were fed either 20 or 8% protein isocaloric diets. Control newborns were nursed by their dams fed the 20% protein diet and low protein (LP) pups by dams fed either the 8 or 20% protein diet. The diets given during lactation were maintained until adulthood. The blood vessel density of cerebral cortex analyzed by morphometry in 3-d-old pups from dams fed the 8% protein diet was lower than in control (C). It remained lower at adulthood whether a LP or a C diet was given postnatally. Reduction of vascularization at adulthood induced by the LP diet limited to fetal life seems characteristic for the brain since vascularization of islets of Langerhans was reduced in neonates but normalized at adulthood by a C diet postnatally. Body and brain weights were lower in LP pups and adults. DNA concentration was lower in forebrain and higher in cerebellum in LP pups. In brain of LP adults, DNA, protein, cholesterol and phospholipid concentrations were lower and were restored at adulthood by a normal diet after birth. In conclusion, cerebral cortex of offspring exposed to a LP isocaloric diet during fetal development showed reduced vascularization which remained throughout life.

Enantioselectivity properties of human serum albumin immobilized on anion-exchangers based on polyvinylimidazole-coated silica. Effect of protein loading on separation properties.

Chiral chromatographic supports were obtained by continuously applying solutions contained HSA to ion-exchange columns. The columns were packed with silica modified with polyvinylimidazole and a copolymer polyvinylpyrrolidone-polyvinylimidazole (75:25) respectively, quaternized and crosslinked. Small changes in the concentration of NaCl during immobilization of HSA lead to variations in the amount of HSA bound to the supports. These variations have consequences in terms of chromatographic retention (k'), selectivity (alpha) and resolution (Rs) of enantiomers. The effects of varying the pH and organic modifier of the mobile phase on the chromatographic properties were also examined.

[Gastrointestinal tuberculosis as a rare cause of perforation of the ileum]. / Die gastrointestinale Tuberkulose als seltene Ursache einer Perforation des Ileums.

The gastrointestinal tuberculosis is a rare disease and it can mimic a large variety of gastrointestinal diseases. The most common site of gastrointestinal tuberculosis is the ileocoecal region followed by the ascending colon and jejunum. Complications are an absolute indication for surgical intervention. Perforation is an extremely uncommon complication of mycobacterium tuberculosis infection.

[Non-Hodgkin's lymphoma of the digestive system. General epidemiology and epidemiological data concerning 100 Lebanese cases seen between 1965 and 1991]. / Lymphomes non hodgkiniens du tube digestif. Epidémiologie générale et données épidémiologiques sur 100 cas libanais recensés entre 1965 et 1991.

It is classical to separate gastro-intestinal non Hodgkin lymphomas into two epidemiological profiles: an "occidental" type frequently encountered in West countries (Europe and USA) and an "occidental" type which is dominant in the Middle East regions and is distinguished from the occidental type by the following features: the younger age of patients, the rarity of gastric involvement compared to the small intestinal involvement, the prevalence of Immuno Proliferative Small Intestinal Disease within the small intestinal non Hodgkin lymphomas. An epidemiological study was done on 100 cases of digestive non Hodgkin lymphomas seen in Lebanon between 1965 and 1991 in hospitals affiliated with Saint-Joseph University. The statistical analysis of our study leads to several conclusions: the ISPID is disappearing in Lebanon during the last twenty-five years; the site of gastrointestinal involvement is changing with time, the small intestinal involvement becoming more rare and the gastric involvement more frequent. So during this twenty-five years period, there was an occidentalization of the epidemiological profile. This varying pattern with time in the epidemiology of gastrointestinal non Hodgkin lymphomas could be due to changing in the environmental factors like the intestinal bacterial and parasitological infestation.

[Gastrointestinal non-hodgkin's lymphoma: general epidemiology and epidemiologic data based on 100 Lebanese cases seen between 1965 and 1991]. / Lymphomes non hodgkiniens du tube digestif: épidémiologie générale et données épidémiologiques sur 100 cas libanais recensés entre 1965 et 1991.

It is classical to separate gastro-intestinal non Hodgkin Lymphomas into two epidemiological profiles: 1--an "occidental" type frequently encountered in West countries (Europe and USA); 2--an "occidental" type which is dominant in the Middle East regions and is distinguished from the occidental type by the following features: the younger age of patients; the rarity of gastric involvement compared to the small intestinal involvement; the prevalence of Immuno Proliferative Small Intestinal Disease within the small intestinal non Hodgkin lymphomas. An epidemiological study was done on 100 cases of digestive non Hodgkin lymphomas seen in Lebanon between 1965 and 1991 in hospitals affiliated with Saint-Joseph University. The statistical analysis of our study leads to several conclusions: 1--the ISPID is disappearing in Lebanon during the last twenty-five years; 2--the site of gastrointestinal involvement is changing with time, the small intestinal involvement becoming more rare and the gastric involvement more frequent. So during this twenty-five years period, there was an occidentalization of the epidemiological profile. This varying pattern with time in the epidemiology of gastrointestinal non Hodgkin lymphomas could be due to changing in the environmental factors like the intestinal bacterial and parasitological infestation.

[Transient paraplegia of the legs after sigmoid resection--late complication after implantation of an aortic bifurcation prosthesis in arterial occlusive disease?]. / Passagere Paraplegie der Beine nach Sigmaresektion--Spätkomplikation nach Implantation einer Aorten-Bifurkationsprothese bei arterieller Verschlusserkrankung?

Ischemic spinal lesions following graft replacement of an infrarenal aortic aneurysm are rare complications. Even more rare is the development of this complication in case of aortoiliac occlusive disease. We report one further case who developed transient paraplegia following sigma resection six years after implantation of an aortobifemoral bifurcation graft because of aortoiliac occlusive disease. The abdominal vessel and the collateral situation of this site of the caudal aorta is discussed and the possibility of late ischemic spinal lesions is pointed out.

[Infections in cancer patients with granulocytopenia. Retrospective studies of 59 febrile episodes with hospitalization]. / Infections chez les cancéreux granulocytopéniques. Etudes rétrospectives de 59 épisodes fébriles hospitalisés.

A total of 59 febrile neutropenic episodes were retrospectively recorded at Hôtel-Dieu de France Hospital between August 1st 1991 and December 31st 1992. These episodes were recorded in 51 cancer patients. Median neutropenia was less than one week in 50% of the cases. The etiology of these fever was documented in 27 episodes (46%) and in 70% of the cases gram (-) rods were documented. B-Lactam and Aminoglycoside antibiotics were used in 34 episodes at the initial treatment of these patients. Success rate at this initial treatment or with a modification of the antibiotic therapy was recorded in 85% of the patients. Only 15% of the patients failed to this antibiotherapy, 2/3 of them had their disease in progression. The systemic use of Amphotericine E in those patients with prolonged febrile neutropenia and the concommitent use of growth factors in a sub-group of patients at high risk could lead to a higher success rate in these patients.

[Wilms' tumors, 12 case reports]. / Tumeurs de Wilms,à propos de douze cas.

The treatment of Wilms' tumor has shown a great success in the pediatric oncology. Our study, which includes 12 cases of nephroblastoma, between 1979 and 1987, has confirmed this results. This tumor that shows no sex prevalence, occurs in a mean age of 2.5 years. The volume of the mass is the most presenting sign in 75% of the cases, I.V.P. confirm the diagnosis in 90% of the cases. Remission occurred in 5 infants who have been in stage I, the other cases who are in stage II to V have bad prognosis. In the future, we hope more advancement in the cure of Wilms tumor, and all the remaining questions will find their answer.