Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

A French community-based intervention for parents of French-Canadian children with behavior problems: The EQUIPE program.

OBJECTIVES: Behavior problems are one of the most common reasons for seeking mental health services in pediatric populations. The objectives are to evaluate the effects of the EQUIPE program (Étude Québécoise d'Intervention pour les Parents d'Enfants avec des problèmes de comportement) and to analyze the impact of the severity of behavior problems and of parental characteristics. METHODS: This program was translated from the Community Parent Education Program. The effects of EQUIPE, as compared to a control group, were evaluated by using Child Behavior Checklist and Parent Stress Index questionnaires before (T0) and after the intervention program (T1), and at 6 (T2) and 12months (T3) follow-up visits. RESULTS: In total, 533 participants were enrolled in intervention (n=465) (with "severe" or "mild" subgroups according to CBCL-T score) and a control group (n=68). In the two groups, the results showed a statistically significant decrease in Child Behavior Checklist and Parent Stress Index total scores at T1, T2 and T3, with the exception of Child Behavior Checklist total scores in the control group at T2. In the intervention group Child Behavior Checklist total scores were significantly higher in the "severe"; which was not the case for Parent Stress Index total scores at T2 and T3. DISCUSSION: Socioeconomic characteristics, family details, parental medical history and the age of the children appeared to influence changes in Child Behavior Checklist and Parent Stress Index total scores. CONCLUSION: The EQUIPE program is an effective intervention for reducing behavior problems and parents' stress in a French-Canadian population.

[Morbidity of extended pelvic lymphadenectomy during robot-assisted laparoscopic prostatectomy for localized cancer prostate]. / Morbidité du curage ganglionnaire pelvien étendu au cours de la prostatectomie totale laparoscopique robot assistée.

OBJECTIVES: To assess the morbidity specific of extended pelvic lymphadenectomy during robot-assisted laparoscopic radical prostatectomy in a 8 year retrospective study. MATERIAL: We carried out a single-center, single-surgeon retrospective study on 342 consecutive patients who underwent a robot-assisted laparoscopic radical prostatectomy and extended pelvic lymphadenectomy, from July 2010 to March 2018. Postoperative complications were recorded up to 3 months after the operation. RESULTS: Thirty (8.8%) patients had at least one complication related to lymphadenectomy including 1 vascular injury (0.3%), 7 injuries of the obturator nerve (2%), 5 venous thromboembolic complications (1.5%) including 4 pulmonary embolisms, 10 symptomatic lymphoceles (2.9%) and 8 lymphoedemas (2.3%). Of these complications, 13 were classified Clavien 1 (43.3%), 8 Clavien 2 (26.7%), 7 Clavien 3a (23.3%) and 2 Clavien 3b (6.7%). In univariate analysis a high age (P=0.04), high BMI (P<0.01) and pT stage (P=0.02) were significantly associated with complication whereas in multivariate analysis, only age (P=0.02) and BMI (P<0.01) lived were. In univariate analysis high BMI (P=0.04) and lymph node involvement (P=0.04) were associated with lymphatic complication. We did not find any other specific risk factor for the other complications. CONCLUSION: With 8.8% of overall complications related to lymphadenectomy and 5% of complication classified Clavien grade 2 or higher, extended pelvic lymphadenectomy was not very morbid. Age and BMI were risk factors for a overall complication. BMI and lymph node involvement were risk factors for lymphatic complications. LEVEL OF PROOF: 4.

Spleen route accelerates engraftment of human hematopoietic stem cells.

Intravenous injections of human hematopoietic stem cells (hHSCs) is routinely used in clinic and for modeling hematopoiesis in mice. However, unspecific dilution in vascular system and non-hematopoietic organs challenges engraftment efficiency. Although spleen is capable of extra medullar hematopoiesis, its ability to support human HSC transplantation has never been evaluated. We demonstrate that intra-splenic injection results in high and sustained engraftment of hHSCs into immune-deficient mice, with higher chimerisms than with intravenous or intra-femoral injections. Our results support that spleen microenvironment provides a niche for HSCs amplification and offers a new route for efficient HSC transplantation.

BRAF mutation is not associated with an increased risk of recurrence in patients undergoing resection of colorectal liver metastases.

BACKGROUND: BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF-mutated CRLMs. METHODS: The study included patients who underwent resection for BRAF-mutated CRLMs in 24 centres between 2012 and 2016. A case-matched comparison was made with 183 patients who underwent resection of CRLMs with wild-type BRAF during the same interval. RESULTS: Sixty-six patients who underwent resection for BRAF-mutated CRLMs in 24 centres were compared with 183 patients with wild-type BRAF. The 1- and 3-year disease-free survival (DFS) rates were 46 and 19 per cent for the BRAF-mutated group, and 55·4 and 27·8 per cent for the group with wild-type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1- and 3-year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild-type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild-type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF-mutated group (48 versus 29·8 per cent; P = 0·034). CONCLUSION: These results support surgical treatment for resectable BRAF-mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non-metastatic colorectal cancer.

European Space Agency experiments on thermodiffusion of fluid mixtures in space.

This paper describes the European Space Agency (ESA) experiments devoted to study thermodiffusion of fluid mixtures in microgravity environment, where sedimentation and convection do not affect the mass flow induced by the Soret effect. First, the experiments performed on binary mixtures in the IVIDIL and GRADFLEX experiments are described. Then, further experiments on ternary mixtures and complex fluids performed in DCMIX and planned to be performed in the context of the NEUF-DIX project are presented. Finally, multi-component mixtures studied in the SCCO project are detailed.

Molecular simulation of the water-triolein-oleic acid mixture: Local structure and thermodynamic properties.

An artificial oil-in-water emulsion analogous to those found in bioresources or food matrices is simulated and studied experimentally. It is composed of one of the major natural free fatty acids (the oleic acid, OA) and the corresponding triacylglyceride (trioleic glyceride, or triolein, GTO). Because of the large time and length scales involved, the molecular simulations are done with the Martini force field, a coarse-grained model. This allowed us to study the water-OA-GTO system at different compositions with more than 20 000 molecules and up to 2 µs. Interfacial tension was measured using the pendant drop method and compared with molecular simulation results. We observe very good agreement at high OA concentrations and deviations up to 15% at low OA concentrations. The water solubility in the lipid phase is in fair agreement with experiments, between 0.03 and 0.32 mol/l, rising with the OA content. The area occupied by OA and GTO at the interface between water and the pure product fitted with experimental data (AOA = 36.6 Å2 and AGTO = 152.1 Å2). The consistency between simulation and experimental results allowed a structural analysis of the interface. A bilayer structure of the lipids at the water/oil interface is proposed, containing preferentially oleic acid but also triolein. Through all these results, the usefulness of coarse-grained simulation for the description of water-oil interfacial organization is demonstrated. This method will be used later to bring local information on the organization of target compounds, necessary in biomass fractionation processes or food additive formulations, for example.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.

BACKGROUND: Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs. METHODS: Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression. RESULTS: We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001). CONCLUSIONS: RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted.

Classical force field for hydrofluorocarbon molecular simulations. Application to the study of gas solubility in poly(vinylidene fluoride).

A classical all-atoms force field for molecular simulations of hydrofluorocarbons (HFCs) has been developed. Lennard-Jones force centers plus point charges are used to represent dispersion-repulsion and electrostatic interactions. Parametrization of this force field has been performed iteratively using three target properties of pentafluorobutane: the quantum energy of an isolated molecule, the dielectric constant in the liquid phase, and the compressed liquid density. The accuracy and transferability of this new force field has been demonstrated through the simulation of different thermophysical properties of several fluorinated compounds, showing significant improvements compared to existing models. This new force field has been applied to study solubilities of several gases in poly(vinylidene fluoride) (PVDF) above the melting temperature of this polymer. The solubility of CH4, CO2, H2S, H2, N2, O2, and H2O at infinite dilution has been computed using test particle insertions in the course of a NpT hybrid Monte Carlo simulation. For CH4, CO2, and their mixtures, some calculations beyond the Henry regime have also been performed using hybrid Monte Carlo simulations in the osmotic ensemble, allowing both swelling and solubility determination. An ideal mixing behavior is observed, with identical solubility coefficients in the mixtures and in pure gas systems.

[Comparison of the morbidity between limited and extended pelvic lymphadenectomy during laparoscopic radical prostatectomy]. / Comparaison de la morbidité entre curage étendu et curage limité au cours de la prostatectomie radicale laparoscopique.

OBJECTIVE: To compare the morbidity of limited pelvic lymphadenectomy to extended lymphadenectomy in patients undergoing LRP (Laparoscopic Radical Prostatectomy) for clinically localized prostate cancer. PATIENTS AND METHODS: We performed a prospective monocentric study focused on 303 consecutive patients having a pelvic lymphadenectomy during LRP from June 2000 to April 2010. One hundred and seventy six patients had a limited pelvic lymphadenectomy (June 2000-June 2006, group 1). One hundred and twenty seven patients had an extended pelvis lymphadenectomy (June 2006-April 2010, group 2) including two sub-groups according to the lateral limit of the procedure i.e. with (group 2a, 60 patients) or without dissection of the lateral side of the iliac artery (group 2b, 67 patients). RESULTS: Preoperative data (age, BMI, cTNM, Gleason score and PSA) were comparable between the groups. The number of lymph nodes and the incidence of metastatic lymph nodes were lower in group 1 (6,7 lymph nodes and 5,7%) compared to group 2 (a+b) (15.6 lymph nodes and 18.9%) (P=0.001 and P=0.0004). However, there was no difference between groups 2a and 2b (15.4 and 16.7% vs 15,8 and 20.8% P=0.65 respectively). There were more complications in the extended lymphadenectomy group compared to the limited procedure (35.4% vs 14.2%, P=0.0001), in particular more lymphatic complications (27.5% vs 10.2% P=0.0001) and lymphoedema (LO) (15.7% vs 0.6% P=0.00001). However the lymphorhea (LR) and lymphocele (LC) rate was not different (P=0.11 and P=0.17). All complications were mainly of low Clavien's classification grade (1+2) whatever the group of lymphadenectomy. The hospital stay was not increased in group 2a or 2b in regard to group 1. The rate of LR and LC was higher in group 2a than in group 1 (P=0.02 and P=0.05) but not between group 2b and 1 (P=0.81 and P=0.47). CONCLUSION: Our study showed a higher rate of complications after extended pelvic lymphadenectomy but of low grade in most cases. Moreover the lateral dissection sparing the lateral side of the iliac artery reduced the risk of lymphatic complications without decreasing the number of lymph nodes removed and the rate of metastasis.

Interfacial tension in oil-water-surfactant systems: on the role of intra-molecular forces on interfacial tension values using DPD simulations.

We have computed interfacial tension in oil-water-surfactant model systems using dissipative particle dynamics (DPD) simulations. Oil and water molecules are modelled as single DPD beads, whereas surfactant molecules are composed of head and tail beads linked together by a harmonic potential to form a chain molecule. We have investigated the influence of the harmonic potential parameters, namely, the force constant K and the equilibrium distance r0, on the interfacial tension values. For both parameters, the range investigated has been chosen in agreement with typical values in the literature. Surprisingly, we observe a large effect on interfacial tension values, especially at large surfactant concentration. We demonstrate that, due to a subtle balance between intra-molecular and inter-molecular interactions, the local structure of surfactants at the oil-water interface is modified, the interfacial tension is changed and the interface stability is affected.

Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study.

BACKGROUND: Influenza vaccination is recommended to cancer patients undergoing chemotherapy, but vaccine coverage remains low. During the 2009 influenza pandemic, French recommendations were to vaccinate immunocompromised patients with two doses of adjuvanted vaccine. This study aimed to evaluate vaccine immunogenicity in cancer patients receiving chemotherapy. PATIENTS AND METHODS: VACANCE is a prospective open-label study that evaluated the immunogenicity and safety of two doses of AS03A-adjuvanted H1N1v vaccine in cancer patients receiving cytotoxic and/or targeted therapies. Serum haemagglutination-inhibited antibody titres against influenza A H1N1v were measured at days 1, 21, and 42, to estimate the proportion of participants with antibody titres ≥ 1 : 40 [seroprotection rate (SPR)], the efficacy of seroconversion, and factors that increased the geometric mean titre. RESULTS: Sixty-five patients were included. At baseline, 5% of patients had vaccine strain titres of specific haemagglutination inhibition antibodies that were ≥ 1 : 40. After one and two doses of vaccine, SPRs were 48% and 73%, respectively, and seroconversion rates were 44% and 73%, respectively. Vaccine-related adverse events were mild to moderate. CONCLUSIONS: A single dose of AS03-adjuvanted A/H1N1 vaccine triggered a low immune response in cancer patients on chemotherapy depending on their treatment type and frequency. Two doses are needed for these cancer patients.

[Urinary continence following laparoscopic radical prostatectomy: qualitative analysis]. / Étude qualitative de la continence urinaire après prostatectomie radicale laparoscopique.

PURPOSE: The main purpose of this study was to report urinary continence after laparoscopic radical prostatectomy (LRP) for localised prostate cancer and the return to baseline rate for urinary continence. The minor purpose was to determine the risk factors, which influence return to baseline urinary continence after radical prostatectomy. METHODS: Prospective evaluation of urinary continence with self-administered questionnaire in 300 consecutive LRP for localized prostate cancer. RESULTS: After LRP, at 3, 6 and 12 months, respectively 12.5%, 23% and 33.7% of patients recover baseline urinary continence. Fifty-four percent, 72.3% and 78.4% of patients did not wear pads 3, 6 and 12 months after LRP. In patients without pad, 43 % recovered baseline continence one year after radical prostatectomy. In univariate analysis, age older than 60 years (P=0.003, P=0.003, P=0.02, 3, 6 and 12 months after LRP) and no sparing of neurovascular bundles (P=0.01, P=0.08 at 3 and 6 months after LRP) were risks factors of urinary incontinence. In multivariate analysis, only age older than 60 years (P=0.018, P=0.01 and P=0.01 at 3, 6 and 12 months after LRP) was a risk factor of urinary incontinence. CONCLUSION: One year after LRP, 66.3% of patients had urinary incontinence according to our evaluation using stringent criteria, i.e. return to baseline continence status. However, only 21.6% of patients wore pads and less than 2% wore more than two pads per day.

Correction of the VIR-visible dataset from the Dawn mission at Vesta.

This work describes the correction method applied to the dataset acquired at the asteroid (4) Vesta by the visible channel of the visible and infrared mapping spectrometer. The rising detector temperature during data acquisitions in the visible wavelengths leads to a spectral slope increase over the whole spectral range. This limits the accuracy of the studies of the Vesta surface in this wavelength range. Here, we detail an empirical method to correct for the visible detector temperature dependency while taking into account the specificity of the Vesta dataset.

Correction of the VIR-visible data set from the Dawn mission.

Data acquired at Ceres by the visible channel of the Visible and InfraRed mapping spectrometer (VIR) on board the NASA Dawn spacecraft are affected by the temperatures of both the visible (VIS) and the infrared (IR) sensors, which are, respectively, a charged coupled device and a HgCdTe array. The variations of the visible channel temperatures measured during the sessions of acquisitions are correlated with the variations in the spectral slope and shape for all the mission phases. The IR channel temperature is more stable during the acquisitions; nonetheless, it is characterized by a bimodal distribution whether the cryocooler (and, therefore, the IR channel) is used or not during the visible channel operations. When the infrared channel temperature is high (175 K, i.e., not in use and with the cryocooler off), an additional negative slope and a distortion are observed in the spectra of the visible channel. We developed an empirical correction based on a reference spectrum for the whole dataset; it is designed to correct the two issues related to the sensor temperatures that we have identified. The reference spectrum is calculated to be representative of the global Ceres' surface. It is also made of the data acquired when the visible and infrared channel temperatures are equal to the ones measured during an observation of the Arcturus star by VIR, which is consistent with several ground-based observations. The developed correction allows reliable analysis and mapping to be performed by minimizing the artifacts induced by fluctuations of the VIS temperature. Thanks to this correction, a direct comparison between different mission phases during which the VIR experienced different visible and infrared channel temperatures is now possible.