Impact of G-CSF Prophylaxis on Chemotherapy Dose-Intensity,Link Between Dose-Intensity and Survival in Patients with Metastatic Pancreatic Adenocarcinoma

BackgroundIn metastatic pancreatic adenocarcinoma, few data are available on the use of granulocyte-colony stimulating factor (G-CSF) prophylaxis and its impact on dose-intensity (DI), or the link between DI and progression-free survival (PFS). This study assessed the impact of G-CSF prophylaxis on the DI received by patients and the relationship between full DI and PFS according to chemotherapy regimens.Patients and MethodsPatients from three first-line randomized phase II clinical trials were included in this retrospective cohort. G-CSF prophylaxis groups were identified and balanced according to baseline characteristics using a propensity score. Patients were classified into 2 treatment groups (FOLFIRINOX vs FOLFIRI/nab-paclitaxel (NAB)). DI was a binary variable (full/reduced). Adverse events were defined using NCI-CTCAE v4.0.ResultsOf the 498 patients, 154 (31%) were in “prophylaxis” group; 179 (36%) were treated by FOLFIRINOX and 319 (64%) by FOLFIRI/NAB. In FOLFIRINOX group, G-CSF prophylaxis was significantly associated with a higher rate of full DI (OR, 5.07; 95% CI, 1.52-16.90; P < .01) while in FOLFIRI/NAB group, it was significantly associated with a lower rate of full DI (OR, 0.23; 95% CI, 0.06-0.83; P = .03). Full DI was associated with a non-significant increase in PFS (FOLFIRINOX group: HR 0.83; 95% CI, 0.59-1.16; P = .27; FOLFIRI/NAB group: HR 0.84; 95% CI, 0.63-1.11; P = .22).ConclusionGranulocyte-colony stimulating factor prophylaxis was associated with a higher rate of full DI with FOLFIRINOX. Full DI was associated with a non-significant increase in PFS. These results need to be confirmed prospectively.     

L-454,560, a potent and selective PDE4 inhibitor with in vivo efficacy in animal models of asthma and cognition

Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast.     

One Health surveillance of West Nile and Usutu viruses: a repeated cross-sectional study exploring seroprevalence and endemicity in Southern France, 2016 to 2020

BackgroundWest Nile virus (WNV) and Usutu virus (USUV), two closely related flaviviruses, mainly follow an enzootic cycle involving mosquitoes and birds, but also infect humans and other mammals. Since 2010, their epidemiological situation may have shifted from irregular epidemics to endemicity in several European regions; this requires confirmation, as it could have implications for risk assessment and surveillance strategies.AimTo explore the seroprevalence in animals and humans and potential endemicity of WNV and USUV in Southern France, given a long history of WNV outbreaks and the only severe human USUV case in France in this region.MethodsWe evaluated the prevalence of WNV and USUV in a repeated cross-sectional study by serological and molecular analyses of human, dog, horse, bird and mosquito samples in the Camargue area, including the city of Montpellier, between 2016 and 2020.ResultsWe observed the active transmission of both viruses and higher USUV prevalence in humans, dogs, birds and mosquitoes, while WNV prevalence was higher in horses. In 500 human samples, 15 were positive for USUV and 6 for WNV. Genetic data showed that the same lineages, WNV lineage 1a and USUV lineage Africa 3, were found in mosquitoes in 2015, 2018 and 2020.ConclusionThese findings support existing literature suggesting endemisation in the study region and contribute to a better understanding of USUV and WNV circulation in Southern France. Our study underlines the importance of a One Health approach for the surveillance of these viruses.     

Cycle of the seminiferous epithelium of the bat Molossus molossus,characterized by tubular morphology and acrosomal development

ObjectiveTo describe the seminiferous epithelium cycle (SEC) by tubular morphology method, and the acrosomal development of individualizing spermatids, and to explore the distinction of the stages between two generations of spermatids.MethodsTesticular fragments were fixed in Karnovsky, embedded in glycol methacrylate and examined under light microscopy and transmission electron microscopy. Sections in 3 μm thickness were stained with toluidine blue for the characterization of the stages of the SEC by the tubular morphology method, or submitted to the PAS reaction for the visualization of the acrosomal formation. Additional details on the acrosomal formation were observed under transmission electron microscopy.ResultsThrough the eight stages described by tubular morphology method, 10 steps of acrosomal formation were observed in the spermatid development, called acrosomal steps. As the spermatids were produced in stage V of the tubular morphology method, it was at this stage from which began the steps of acrosomal development.ConclusionsWe propose association of the acrosomal steps for the first time, with the different stages by tubular morphology method. This method presents an alternative to the existent Methods, allowing interspecific comparisons of the SEC, not only among different species of bats, but also among the other mammals.     

Cholera Vaccination in Urban Haiti

Successful and sustained efforts have been made to curtail the major cholera epidemic that occurred in Haiti in 2010 with the promotion of hygiene and sanitation measures, training of health personnel and establishment of treatment centers nationwide. Oral cholera vaccine (OCV) was introduced by the Haitian Ministry of Health as a pilot project in urban and rural areas. This paper reports the successful OCV pilot project led by GHESKIO Centers in the urban slums of Port-au-Prince where 52,357 persons received dose 1 and 90.8% received dose 2; estimated coverage of the at-risk community was 75%. This pilot study demonstrated the effort, community mobilization, and organizational capacity necessary to achieve these results in a challenging setting. The OCV intervention paved the way for the recent launching of a national cholera vaccination program integrated in a long-term ambitious and comprehensive plan to address Haiti''s critical need in water security and sanitation.     

Flow cytometry thresholds of myeloperoxidase detection to discriminate between acute lymphoblastic or myeloblastic leukaemia

The World Health Organization 2008 Classification emphasizes myeloperoxidase (MPO) detection as sufficient for assigning a blast population to the myeloid lineage. Published MPO positivity thresholds are 10% for flow cytometry (FCM) but 3% for cytochemistry. Here we re‐evaluated the FCM‐MPO threshold by comparing retrospectively 128 acute lymphoblastic leukaemias and 75 acute myeloid leukaemias without maturation, all assessed by benzidine‐based cytochemistry. A 13% threshold was found to be relevant using an isotype control as background‐reference (sensitivity 95·1%, specificity 91·7%). Residual normal lymphocytes proved to be an advantageous alternative reference, a threshold of 28% yielding improved 97·4% sensitivity and 96·1% specificity.     

Hip cortical thickness assessment in postmenopausal women with osteoporosis and strontium ranelate effect on hip geometry

The aims of this study were to assess the relationship between hip geometry and the 5-yr risk of hip fractures in postmenopausal osteoporotic women and the effects of strontium ranelate on these parameters. Using the 5-yr data of a randomized placebo-controlled trial of strontium ranelate (Treatment of Peripheral Osteoporosis Study [TROPOS]), we reanalyzed the hip dual-energy X-ray absorptiometry scans to determine the role of hip geometry in the risk of hip fractures (placebo group, n=636) and to analyze the effects of strontium ranelate (n=483). The outcomes included the hip structure analysis (HSA) parameters: cross-sectional area (CSA), section modulus, cortical thickness, and buckling ratio, measured at femoral neck, intertrochanteric (IT) region, and proximal shaft. The geometric parameters associated with an increased risk of hip fracture over 5yr were IT CSA and femoral shaft cortical thickness independent of age and total-hip bone mineral density (BMD). Using Bonferroni adjustment, IT cortical thickness was associated with the risk of hip fracture. Over 5yr, significant decreases in some femoral dimensions of the placebo group contrast with significant increases in strontium ranelate group after adjustment for age and BMD. Using Bonferroni adjustment, differences between placebo and strontium ranelate groups were no longer significant after adjustment on 5-yr BMD changes. Some HSA parameters have predictive value for hip fracture risk in postmenopausal osteoporotic women. Strontium ranelate improves some HSA parameters, through the BMD increase.     

Identification of rheumatoid arthritis patients with vertebral fractures using bone mineral density and trabecular bone score

The aim of this study was to test bone mineral density (BMD), trabecular bone score (TBS), and their combination, for detection of rheumatoid arthritis (RA) patients with vertebral fractures (VFs). One hundred eighty-five women aged 56.0 ± 13.5 yr, with RA since 15.5 ± 9.9 yr were studied. Lumbar spine, total hip, and femoral neck BMD were assessed by dual-energy X-ray absorptiometry (DXA). TBS was calculated from anteroposterior image of lumbar spine BMD. VFs from T4 to L4 were evaluated using Vertebral Fracture Assessment software on DXA device. The proportions of patients with VF and T-scores ≤-2.5 were only 24.2%, 21.2%, and 33.3% at lumbar spine, total hip, and femoral neck, respectively. T-scores were significantly lower in patients with VF than in patients without VF, the largest difference being observed at femoral neck (p=0.0001). TBS was significantly lower in patients with VF vs without VF (p=0.0001). The areas under the curves were 0.621, 0.704, 0.703, 0.719, and 0.727 for lumbar spine BMD, TBS, lumbar spine BMD+TBS, total hip BMD, and femoral neck BMD, respectively. The threshold of 1.173 for TBS had the best sensitivity (63%) and specificity (74%). TBS measured at the lumbar spine has a better discrimination value than lumbar spine BMD, and similar to femoral neck BMD, for prediction of presence of VF in patients with RA. In RA subjects with osteopenia, the proportion of patients with VF was higher in the lowest tertile of TBS when compared with the highest tertile. In this population, at low risk according to BMD, TBS could help to detect patients with VF.