Publications by authors named "Arnaud François"

87 Publications

Kidney Transplant T Cell-Mediated Rejection Occurring After Anti-CD19 CAR T-Cell Therapy for Refractory Aggressive Burkitt-like Lymphoma With 11q Aberration: A Case Report.

Am J Kidney Dis 2021 Aug 27. Epub 2021 Aug 27.

Nephrology - Kidney Transplant Unit, Rouen University Hospital, Rouen, France.

Post-transplant lymphoproliferative disorder is a growing complication of kidney transplantation and is associated with a poor prognosis. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an important new treatment option modifying the outcome of refractory hematological cancers. Here, we report the case of a 40-year-old kidney transplant recipient who developed a Burkitt-like lymphoma with 11q aberration 5 years after transplantation. After 3 unsuccessful lines of chemotherapy, it was decided to treat the patient with anti-CD19 CAR T cells as a salvage therapy. Three months after CAR T-cell infusion, she experienced a grade IIB T cell-mediated rejection with severe tubulitis (T3), slight interstitial inflammation (I1), and severe intimal arteritis (V2) with blood suffusion. Among T cells infiltrating the graft, some of them expressed the anti-CD19 CAR. CAR T cells within the graft and in blood samples were also detected by droplet digital polymerase chain reaction. Function of the kidney transplant improved after corticosteroid treatment and remained stable. However, lymphoma progressed, with a massive pulmonary mass leading to the patient's death 10 months after CAR T-cell infusion.
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http://dx.doi.org/10.1053/j.ajkd.2021.07.012DOI Listing
August 2021

Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre.

BMC Nephrol 2021 07 21;22(1):267. Epub 2021 Jul 21.

Medical Intensive Care Unit, Rouen University Hospital, 37 boulevard Gambetta, 76031, Rouen Cedex, France.

Background: Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA).

Methods: This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016.

Results: Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4-44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2-22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m respectively in the eculizumab group and in the control group.

Conclusions: These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.
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http://dx.doi.org/10.1186/s12882-021-02470-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293501PMC
July 2021

Computed Tomographic Changes in Patients with Cystic Fibrosis Treated by Combination Therapy with Lumacaftor and Ivacaftor.

J Clin Med 2021 May 7;10(9). Epub 2021 May 7.

Institut Méditerranéen d'Imagerie Médicale Appliquée à la Gynécologie, la Grossesse et l'Enfance (IMAGE2), 6 rue Rocca, 13008 Marseille, France.

Background: As Cystic Fibrosis (CF) treatments drastically improved in recent years, tools to assess their efficiency need to be properly evaluated, especially cross-sectional imaging techniques. High-resolution computed tomography (HRCT) scan response to combined lumacaftor- ivacaftor therapy (Orkambi) in patients with homozygous for F508del CFTR has not yet been assessed.

Methods: We conducted a retrospective observational study in two French reference centers in CF in Marseille hospitals, including teenagers (>12 years old) and adults (>18 years) who had received lumacaftor-ivacaftor and for whom we had at disposal at least two CT scans, one at before therapy and one at least six months after therapy start. CT scoring was performed by using the modified version of the Brody score.

Results: 34 patients have been included. The mean age was 26 years (12-56 years). There was a significant decrease in the total CT score (65.5 to 60.3, = 0.049) and mucous plugging subscore (12.3 to 8.7, = 0.009). Peribronchial wall thickening (PWT) was significantly improved only in the adult group (29.1 to 27.0, = 0.04). Improvements in total score, peribronchial thickening, and mucous pluggings were significantly correlated with improvement in FEV1 (forced expiratory volume in 1 s).

Conclusions: Treatment with lumacaftor-ivacaftor was associated with a significant improvement in the total CT score, which was mainly related to an improvement in mucous pluggings.
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http://dx.doi.org/10.3390/jcm10091999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124862PMC
May 2021

Pan-TRK Immunohistochemistry Is Highly Correlated With NTRK3 Gene Rearrangements in Salivary Gland Tumors.

Am J Surg Pathol 2021 11;45(11):1487-1498

Department of Pathology, Centre Henri Becquerel.

Aims: Secretory carcinoma (SC) is characterized by ETV6 rearrangements, most often ETV6-NTRK3 fusion. Given its histologic overlap with other salivary gland tumors (SGTs), SCs can be difficult to diagnose without genetic confirmation. A recently developed pan-TRK (tropomyosin receptor kinase) antibody shows promise for identifying tumors with NTRK (neurotrophic tyrosine kinase receptor 3) fusions. The aim of this study was to evaluate the utility of pan-TRK immunohistochemistry in distinguishing SCs from mimics and selecting patients eligible for TRK inhibitor clinical trials. We examined whole-tissue sections from 111 SGTs with molecular characterization, including 26 SCs (23 with ETV6-NTRK3 fusion and 3 with ETV6-RET fusion detected by ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing and 85 non-SC SGTs (no ETV6-NTRK3 fusion). Immunohistochemistry was performed with a pan-TRK rabbit monoclonal antibody. When any pan-TRK staining (nuclear or cytoplasmic with any staining intensity) was considered to indicate positivity, 22 of 23 SCs with ETV6-NTRK3 fusion (95.7%) and 33 of 85 non-SC (38.8%) salivary neoplasms were positive, mainly basal cell adenoma, pleomorphic adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas. All SCs with ETV6-RET fusion were entirely negative. When only nuclear pan-TRK staining with any staining intensity was considered positive, 18 of 23 SCs with ETV6-NTRK3 fusion (78.3%) were positive, 11 among them with diffuse staining (>30% of cells). All non-SCs and SCs with ETV6-RET fusion were entirely negative. In comparison to molecular analysis (ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing), nuclear pan-TRK IHC has a sensitivity of 78.3% and a specificity of 100% for diagnosing SCs with ETV6-NTRK3 fusion, 69% and 100% for SCs (all fusions). Pan-TRK is a reasonable screening test for diagnosing SCs among SGTs when taking only nuclear staining into account. Although pan-TRK expression is not entirely sensitive for SCs, nuclear staining is highly specific for SCs with ETV6-NTRK3 fusion. The lack of pan-TRK immunoreactivity in a subset of SCs is suggestive of atypical exons 4 to 14 or exons 5 to 14 ETV6-NTRK3 fusion or non-NTRK alternative fusion partners such as ETV6-RET. Pan-TRK staining can serve as a strong diagnostic marker to distinguish SC from it mimics and to select patients eligible for TRK inhibitor clinical trials.
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http://dx.doi.org/10.1097/PAS.0000000000001718DOI Listing
November 2021

Intensity of de novo DSA detected by Immucor Lifecodes assay and C3d fixing antibodies are not predictive of subclinical ABMR after Kidney Transplantation.

PLoS One 2021 22;16(4):e0249934. Epub 2021 Apr 22.

EFS Normandie, Rouen, France.

De novo donor-specific antibodies (dnDSA) are associated with antibody-mediated rejection (ABMR) and allograft loss. We tested Immucor* (IM) Luminex Single-antigen beads (LSAB) assay and C3d-fixing antibodies in the setting of dnDSA and subclinical (s) ABMR. This retrospective multicentric study included 123 patients biopsied because of the presence of subclinical de novo DSA detected by One Lamda* Labscreen (MFI > 1000). In 112 patients, sera of the day of the biopsy were available and tested in a central lab with IM Lifecodes LSAB and C3d fixing antibodies assays. In 16 patients (14.3%), no DSA was detected using Immucor test. In 96 patients, at least one DSA was determined with IM. Systematic biopsies showed active sABMR in 30 patients (31.2%), chronic active sABMR in 17 patients (17.7%) and no lesions of sABMR in 49 KT recipients (51%). Intensitity criteria (BCM, BCR and AD-BCR) of DSA were not statistically different between these 3 histological groups. The proportion of patients with C3d-fixing DSA was not statistically different between the 3 groups and did not offer any prognostic value regarding graft survival. Performing biopsy for dnDSA could not be guided by the intensity criteria of IM LSAB assay. C3d-fixing DSA do not offer added value.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062066PMC
September 2021

Evolution of Non-alcoholic Fatty Liver Disease (NAFLD) Biomarkers in Response to Weight Loss 1 Year After Bariatric Surgery-a Post Hoc Analysis of the FibroTest Prospective Study.

Obes Surg 2021 08 12;31(8):3548-3556. Epub 2021 Apr 12.

Department of Digestive Surgery, Rouen University Hospital, 1 rue de Germont, 76000, Rouen, France.

Background: Bariatric surgery is among the therapeutic options for non-alcoholic fatty liver disease (NAFLD), affecting 90% of patients with obesity. The aim of this study was to evaluate the evolution of NAFLD lesions 1 year after surgery using noninvasive markers.

Methods: From November 2011 to November 2012, 253 patients with obesity undergoing bariatric surgery in three French University Hospitals were included. Histological data regarding intraoperative liver biopsy were collected at baseline, clinical, and biological data, including FibroTest®, SteatoTest®, and NASHTest®, before and after surgery.

Results: Fibrosis' prevalence was 74.2% with a positive predictive value (PPV) for FibroTest® of 78.6% and 43.4% for significant fibrosis (Kleiner ≥ F2) with a negative predictive value (NPV) of 56.1%. NAFLD's prevalence was 84% with a PPV for SteatoTest® of 85.9% and 7.7% for NASH with an NPV for NASHTest® of 93.8%. One year after bariatric surgery, mean BMI had significantly decreased from 46.5 to 31.7 kg/m (p < 0.001). Fibrosis assessed by the FibroTest® showed that 82.5% of patients were F0 after surgery compared to 90.9% before. Using SteatoTest®, the percent of patient without steatosis (S0) increased from 1.6 to 49.6% after surgery, and rate of severe steatosis (S3) improved from 43.3 to 3.9%. NASHTest® revealed that the percent of patients without NASH increased from 12.8 to 73.6% and rates of NASH improved from 12 to 0.8%.

Conclusions: Validated noninvasive biomarkers SteatoTest® and NASHTest® suggested NAFLD and steatohepatitis improvement after bariatric surgery and might be useful tools for patient follow-up. Regarding fibrosis, FibroTest® was not accurate in patients with extreme obesity.
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http://dx.doi.org/10.1007/s11695-021-05402-0DOI Listing
August 2021

Systemic efficacy on infection of aminoxanide (RM-5061), a new amino-acid ester thiazolide prodrug of tizoxanide.

Parasitology 2021 07 29;148(8):975-984. Epub 2021 Mar 29.

Laboratoire de Parasitologie-Mycologie, Rouen University Hospital and EA7510, University of Rouen, Rouen, France.

Cryptosporidiosis is a gastrointestinal illness with profuse diarrhoea. Although there are no other Food and Drug Administration (FDA)-approved alternatives for the treatment of cryptosporidiosis, nitazoxanide (NTZ) can be qualified as partially effective. In immunosuppressed conditions, severe and/or disseminated cryptosporidiosis may occur and patients should be treated parenterally. To achieve the goal of developing parenteral treatment for cryptosporidiosis, the current study was undertaken to investigate the in vitro and in vivo anticryptosporidial activity of aminoxanide. This new l-tert-leucyl thiazolide is a soluble prodrug of tizoxanide (TIZ), the main metabolite of NTZ. Confirming the good efficacy of aminoxanide in Cryptosporidium parvum-infected HCT-8 cells with a 50% inhibitory concentration of 1.55 μm (±0.21), in immunosuppressed C. parvum-infected Mongolian gerbils (Meriones unguiculatus), a 5-day treatment with a daily intramuscular dose of 100 mg kg−1 aminoxanide resulted in a 72.5% oocyst excretion inhibition, statistically equivalent to 75.5% in gerbils treated with a 4-fold lower oral dose of NTZ. Cryptosporidium parvum-induced intestinal pathology and inflammation were improved. Aminoxanide provides an injectable form of TIZ that NTZ was unable to do and is a promising drug for which optimization of the formulation should be further explored. These results represent a first promising step towards the goal of developing a parenteral treatment for cryptosporidiosis.
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http://dx.doi.org/10.1017/S0031182021000524DOI Listing
July 2021

Hemolysis induced by Left Ventricular Assist Device is associated with proximal tubulopathy.

PLoS One 2020 30;15(11):e0242931. Epub 2020 Nov 30.

Nephrology-Kidney Transplant Unit, Rouen University Hospital, Rouen, France.

Background: Chronic subclinical hemolysis is frequent in patients implanted with Left Ventricular Assist Device (LVAD) and is associated with adverse outcomes. Consequences of LVADs-induced subclinical hemolysis on kidney structure and function is currently unknown.

Methods: Thirty-three patients implanted with a Heartmate II LVAD (Abbott, Inc, Chicago IL) were retrospectively studied. Hemolysis, Acute Kidney Injury (AKI) and the evolution of estimated Glomerular Filtration Rate were analyzed. Proximal Tubulopathy (PT) groups were defined according to proteinuria, normoglycemic glycosuria, and electrolytic disorders. The Receiver Operating Characteristic (ROC) curve was used to analyze threshold of LDH values associated with PT.

Results: Median LDH between PT groups were statistically different, 688 IU/L [642-703] and 356 IU/L [320-494] in the "PT" and "no PT" groups, respectively p = 0.006. To determine PT group, LDH threshold > 600 IU/L was associated with a sensitivity of 85.7% (95% CI, 42.1-99.6) and a specificity of 84.6% (95% CI, 65.1-95.6). The ROC's Area Under Curve was 0.83 (95% CI, 0.68-0.98). In the "PT" group, patients had 4.2 [2.5-5.0] AKI episodes per year of exposure, versus 1.6 [0.4-3.7] in the "no PT" group, p = 0.03. A higher occurrence of AKI was associated with subsequent development of Chronic Kidney Disease (CKD) (p = 0.02) and death (p = 0.05).

Conclusions: LVADs-induced subclinical hemolysis is associated with proximal tubular functional alterations, which in turn contribute to the occurrence of AKI and subsequent CKD. Owing to renal toxicity of hemolysis, measures to reduce subclinical hemolysis intensity as canula position or pump parameters should be systematically considered, as well as specific nephroprotective therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703997PMC
January 2021

Major discrepancy between factual antibiotic resistance and consumption in South of France: analysis of 539,037 bacterial strains.

Sci Rep 2020 10 26;10(1):18262. Epub 2020 Oct 26.

Aix Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection, Faculté de Médecine Et de Pharmacie, 19-21 boulevard Jean Moulin, 13385, Marseille Cedex 05, France.

The burden of antibiotic resistance is currently estimated by mathematical modeling, without real count of resistance to key antibiotics. Here we report the real rate of resistance to key antibiotics in bacteria isolated from humans during a 5 years period in a large area in southeast in France. We conducted a retrospective study on antibiotic susceptibility of 539,107 clinical strains isolated from hospital and private laboratories in south of France area from January 2014 to January 2019. The resistance rate to key antibiotics as well as the proportion of bacteria classified as Difficult-to-Treat (DTR) were determined and compared with the Mann-Whitney U test, the χ test or the Fisher's exact test. Among 539,037 isolates, we did not observe any significant increase or decrease in resistance to key antibiotics for 5 years, (oxacillin resistance in Staphylococcus aureus, carbapenem resistance in enterobacteria and Pseudomonas aeruginosa and 3rd generation cephalosporin resistance in Escherichia coli and Klebsiella pneumoniae). However, we observed a significant decrease in imipenem resistance for Acinetobacter baumannii from 2014 to 2018 (24.19-12.27%; p = 0.005) and a significant increase of ceftriaxone resistance in Klebsiella pneumoniae (9.9-24.03%; p = 0.001) and Enterobacter cloacae (24.05-42.05%; p = 0.004). Of these 539,037 isolates, 1604 (0.3%) had a DTR phenotype. Over a 5-year period, we did not observe a burden of AR in our region despite a high rate of antibiotic consumption in our country. These results highlight the need for implementation of real-time AR surveillance systems which use factual data.
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http://dx.doi.org/10.1038/s41598-020-75158-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588456PMC
October 2020

Protocol Biopsies in Patients With Subclinical De Novo Donor-specific Antibodies After Kidney Transplantation: A Multicentric Study.

Transplantation 2020 08;104(8):1726-1737

Nephrology Kidney Transplantation Dialysis, CHU Rouen, Rouen, France.

Background: De novo donor-specific antibodies (DSAs) are associated with antibody-mediated rejection (AMR) and allograft loss. Whether monitoring of de novo DSA (dnDSA) paired with systematic kidney biopsy should become routine remains to be established.

Methods: A retrospective multicentric study (9 French kidney transplant units of the Spiesser group) included patients without graft dysfunction biopsied because of the presence of dnDSA (One Lambda, mean fluorescence intensity [MFI], >1000).

Results: One hundred twenty-three patients (85 male/38 female; mean age, 49.5 ± 13.1 y old) were biopsied after the detection of a dnDSA, 65.3 months (median) after kidney transplantation. Graft function was stable within 3 months before biopsy (estimated glomerular filtration rate, 55.3 ± 18.9 mL/min/1.73 m). Fifty-one subclinical AMRs (sAMRs) (41.4%) were diagnosed, of which 32 (26%) active and 19 (15.5%) chronic active sAMR. Seventy-two biopsies revealed no AMR (58.5%). Predictive factors associated with the diagnosis of active sAMR were MFI of immunodominant DSA >4000, MFI of the sum of DSA >6300, age of the recipient <45 years old, and the absence of steroids at biopsy. The presence of proteinuria >200 mg/g was predictive of chronic active sAMR. The decrease of estimated glomerular filtration rate at 5 years post-biopsy was significantly higher in patients with acute sAMR (-25.2 ± 28.3 mL/min/1.73 m) and graft survival significantly lower.

Conclusions: Performing a kidney graft biopsy for the occurrence of dnDSA without renal dysfunction leads to the diagnosis of a sAMR in over 40% of cases. Nevertheless, we did not observe any effect of standard treatment in acute sAMR.
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http://dx.doi.org/10.1097/TP.0000000000003055DOI Listing
August 2020

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology.

Mol Psychiatry 2020 May 28. Epub 2020 May 28.

Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Campus Gualtar, Minho, Portugal.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aβ) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aβ oligomer injection as well as the combined stress and Aβ i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aβ-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aβ-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.
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http://dx.doi.org/10.1038/s41380-020-0794-5DOI Listing
May 2020

Major hepatectomy decreased tumor growth in an experimental model of bilobar liver metastasis.

HPB (Oxford) 2020 10 7;22(10):1480-1489. Epub 2020 Mar 7.

Department of Hepatobiliary and Liver Transplantation - Paul Brousse University Hospital, France.

Background/purpose: Two-stage hepatectomy (TSH), is associated with a risk of drop-out due to tumoral progression following portal vein occlusion (PVO). We explored the impact of majorhepatectomy on tumor growth by objective radiological measures comparing to PVO and minor hepatectomy, using a model of bilobar colorectal liver metastasis (CLM).

Methods: CLM were induced in 48 BDIX rats by injection of DHDK12-cells. 7 days after cells injection, animals were distributed into 4 groups of equal number (n = 12): portal vein ligation (PVL), sham laparotomy (sham), minor (30%Phx) and major (70%Phx) hepatectomy. MR imaging was used for in vivo analysis of tumor implantation, growth and volumes.

Results: At POD10, tumour volumes were homogeneously distributed among the 4 groups. Lower TV were significantly observed after 70%Phx comparing to PVL at POD17 (0.63 ± 0.14cm3 vs 0.9 ± 0.16cm3, p = 0.008) and to the 3 others groups at POD24: 1.78 ± 0.38cm3 vs 3.2 ± 0.62cm3 (PVL, p = 0.019), 2.41 ± 0.74cm3 (Sham, p = 0.024) and 2.32 ± 0.59cm3 (30%PHx, p = 0.019).

Conclusion: We confirmed in a reproducible model that contrary to PVO, a major hepatectomy decreases the growth of CLM in the remnant liver. This result leads to questioning the usual TSH and justifies exploring alternative strategies. The "major hepatectomy first-approach" should be an option to be evaluated.
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http://dx.doi.org/10.1016/j.hpb.2020.02.008DOI Listing
October 2020

Reverse transcriptase multiplex ligation-dependent probe amplification in endomyocardial biopsies for the diagnosis of cardiac allograft rejection.

J Heart Lung Transplant 2020 02 26;39(2):115-124. Epub 2019 Nov 26.

Paris Translational Research Centre for Organ Transplantation, INSERM, UMR-S970, Paris, France; Pathology department, Hôpital Necker, Assistance Publique - Hôpitaux de Paris and Paris Descartes University, Paris, France; Pathology department, Nantes University, Nantes, France. Electronic address:

Background: Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation.

Methods: We performed a cross-sectional, case-control, multicenter study. After the selection of a 14-transcript panel (endothelial burden, Natural killer cells, interferon-γ pathway, effector T-cells, and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n = 113) and a validation (n = 70) series. A two-step class prediction analysis was developed (Linear prediction score-LPS1: rejection vs non-rejection; LPS2: antibody-mediated rejection [AMR] vs acute cellular rejection [ACR]). A study of the agreement between pathology and RT-MLPA was performed.

Results: Overall, 48 ACR, 82 AMR, 5 mixed rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR, and AMR). AMR was characterized by the high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by the high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation, and overall cohort, respectively. Disagreement cases were more common in the case of histologic low-grade rejection and early post-transplant EMB.

Conclusions: RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histologic diagnosis of heart allograft rejection.
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http://dx.doi.org/10.1016/j.healun.2019.11.010DOI Listing
February 2020

Ipilimumab-induced renal granulomatous arteritis: a case report.

BMC Nephrol 2019 10 11;20(1):366. Epub 2019 Oct 11.

Nephrology department, Rouen University Hospital, 147 avenue du Maréchal Juin 76230 Bois Guillaume, Rouen, France.

Background: Immune Checkpoint Inhibitors (ICPIs) are promising new drugs in treatment of advanced tumours targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD1) or its ligand (PDL-1). Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor used in treatment of metastatic melanoma. By increasing activity of the immune system, ICPIs lead to immune-related adverse events, such as dermatitis, colitis or hepatitis. ICPIs-related kidney adverse events are rare and acute tubulointerstitial nephritis with or without granuloma have mainly been reported.

Case Presentation: We report a case of acute kidney injury in a patient with melanoma treated by ipilimumab. Kidney biopsy revealed acute interlobular and juxtaglomerular granulomatous arteritis, which has not yet been reported in patients treated by ICPIs. Kidney function partially recovered after ipilimumab discontinuation and oral prednisone. Unfortunately, the patient died a few months later from progression of his melanoma.

Conclusion: This case highlights a new mechanism of acute kidney injury related to ICPIs and supports the interest of kidney biopsy in case of ICPIs related acute renal failure.
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http://dx.doi.org/10.1186/s12882-019-1552-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788031PMC
October 2019

Light chain lambda myeloma with fatal AL cardiac amyloidosis in a 21-year-old patient: A case report and review.

Clin Case Rep 2019 Jun 7;7(6):1171-1177. Epub 2019 May 7.

Inserm U1245 and Department of Hematology Centre Henri Becquerel and Normandie Univ UNIROUEN Rouen France.

Multi-organ AL amyloidosis is a therapeutic challenge because of light chain deposits severely damaging the function of concerned organs. Cardiac involvement, which leads to concentric hypertrophy of both ventricles, is particularly severe and leads to poor prognosis regardless of combination chemotherapy. This case pinpoints the relevance of combining clinical, histological, and echocardiographic information in the management of this complex and life-threatening disease.
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http://dx.doi.org/10.1002/ccr3.2165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552948PMC
June 2019

Non-proteinuric renal al amyloidosis in waldenström's macroglobulinemia.

Nephrology (Carlton) 2019 Apr;24(4):490-491

Nephrology Department, Rouen University Hospital, Normandie University, UNIROUEN, INSERM U1096, Rouen, France.

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http://dx.doi.org/10.1111/nep.13428DOI Listing
April 2019

Benefit of cetuximab addition to a platinum-fluorouracil-based chemotherapy according to KRAS-LCS6 variant in an unselected population of recurrent and/or metastatic head and neck cancers.

Eur Arch Otorhinolaryngol 2019 Feb 6;276(2):541-550. Epub 2018 Dec 6.

IRON Group, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, UNIROUEN, Inserm U1245, rue de Germont, Normandie Université, 76000, Rouen, France.

Objectives: To evaluate the benefit of cetuximab (Cx) addition to platinum-based and 5-fluorouracil chemotherapy (PFU) in unselected recurrent and/or metastatic head and neck cancer patients (R/MHNC) according to KRAS-LCS6 variant status.

Methods: All patients who received at least two PFU ± Cx cycles from 2004 to 2014 were retrospectively included into to two distinct study periods according to Cx implementation: patients treated by PFU alone before 2009 and those treated by PFU + Cx from 2009. Primary objective was to evaluate the progression-free survival (PFS) between the two groups. Secondary objectives were to analyze the overall survival (OS) between the two groups and the prognostic impact of KRAS-LCS6 variant. Factors associated with survival were determined by a Cox multivariate analysis including age, WHO performance status (PS), type of treatment, KRAS-LCS6 variant, Charlson's score and p16 status.

Results: Overall, 134 patients were included: 59 (44%) in PFU group and 75 (56%) in PFU + Cx group. Baseline characteristics were well balanced including 30% of patients with 2-3 PS. Median PFS was significantly improved in PFU + Cx group compared to PFU group (6.1 vs 4.4 months, respectively, HR 0.68, p = 0.02) and with a trend for better OS. A KRAS-LCS6 variant was found in 27 (25%) of samples without prognostic impact neither in whole population nor according to treatment. In multivariate analysis, addition of Cx to PFU was the only factor significantly associated with a better PFS (p = 0.01, HR 0.6).

Conclusion: Our results suggest that PFU + Cx combination may be effective in unselected population of R/MHNC regardless the KRAS-LCS6 variant status.
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http://dx.doi.org/10.1007/s00405-018-5235-6DOI Listing
February 2019

IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract.

Hum Pathol 2019 02 5;84:183-191. Epub 2018 Oct 5.

CHRU de Tours, Service d'Anatomie et Cytologie Pathologiques, Tours, France; Université de Tours, Faculté de Médecine, Tours, France; Laboratoire d'étude des sarcomes osseux et remodelage des tissus calcifiés, PhyOS-INSERM UMR 1238, Faculté de Médecine de Nantes, Université de Nantes, 44034 Nantes cedex 1, France. Electronic address:

Chondrosarcomas are rare primary malignant bone tumors that involve the head and neck region in 1% to 12% of cases. Central conventional chondrosarcoma is the most common subtype and is associated with isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations in 50% to 60% of cases. We aimed to define the frequency of IDH1 and IDH2 gene mutations in a multicenter series of 88 cases of chondrosarcoma of the head and neck, including tumors involving the base of the skull (n = 30), the facial skeleton (n = 11), and the laryngeal and tracheal cartilages (n = 47). Petrous bone and cricoid cartilage were the most frequently involved sites for chondrosarcomas of the skull base and laryngotracheal tract (43.3% and 31.9%, respectively). Overall, 64.9% of craniofacial chondrosarcomas featured IDH mutations, with a high rate for skull base tumors (85.7%) but no IDH mutations in tumors of the facial skeleton. This different mutational profile could be related to the type of ossification, the bones of the base of the skull mainly resulting from endochondral ossification, and those of the face from intramembranous ossification. Conversely, mutation was infrequent in chondrosarcomas involving the laryngeal and tracheal cartilages (11.8% of 47 cases). Evaluation of IDH mutation status may be a useful diagnostic tool for bone tumors of the skull base, which are most often assessable with only small biopsy samples. The low rate of IDH mutations observed in laryngotracheal chondrosarcomas suggests a different mode of tumorigenesis needing further exploration.
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http://dx.doi.org/10.1016/j.humpath.2018.09.015DOI Listing
February 2019

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy.

Kidney Int Rep 2018 Sep 8;3(5):1153-1162. Epub 2018 Jun 8.

Nephrology Department, Rouen University Hospital, Rouen, France.

Introduction: Cobalamin C (cblC) deficiency is the most common inborn error of vitamin B metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.

Methods: We performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.

Results: The histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.

Conclusion: This study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.
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http://dx.doi.org/10.1016/j.ekir.2018.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127440PMC
September 2018

Comparison of Two Luminex Single-antigen Bead Flow Cytometry Assays for Detection of Donor-specific Antibodies After Renal Transplantation.

Transplantation 2019 03;103(3):597-603

Laboratory of Histocompatibility, EFS Normandie, Rouen, France.

Background: Defining the clinical relevance of donor-specific HLA antibodies (DSA) detection by Luminex single-antigen (LSA) flow beads assay is critical in monitoring posttransplant outcome.

Methods: Sera of kidney transplanted patients were tested by LSA1 and LSA2 with One Lambda Labscreen (test 1) and Immucor Lifecodes (test 2), at the time of a graft biopsy. The first group (G1, n = 50) had a biopsy highly suggestive of humoral rejection, and the second (G2, n = 50) had no criteria of rejection. Positivity criteria for DSA was mean fluorescence intensity greater than 500 for test 1, whereas specificity assignation respected the provider's recommendations for test 2.

Results: In G1, we identified at least 1 DSA in 44 patients with test 1, and in 39 patients with test 2. In G2, test 1 identified at least 1 DSA in 16 (32%) patients and test 2 in 7 (14%) patients. Sensitivity and specificity for antibody-mediated rejection diagnosis was 88% and 68%, respectively, with One Lambda, and 78% and 86%, respectively, with Immucor. Correlation and agreement were found in class I and II between intensity parameters of the 2 manufacturers. The use of the sum of the intensity of DSA improved the sensitivity and specificity of the 2 tests.

Conclusions: We report the first comparative study of the 2 Luminex assays available for detecting DSA in the postkidney transplant setting. Although there is a good correlation and reliability between the 2 assays, significant differences exist. Positivity criteria for DSA determination differ and interpretation should take these specificities into account.
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http://dx.doi.org/10.1097/TP.0000000000002351DOI Listing
March 2019

Evaluation of voriconazole anti-Acanthamoeba polyphaga in vitro activity, rat cornea penetration and efficacy against experimental rat Acanthamoeba keratitis.

J Antimicrob Chemother 2018 07;73(7):1895-1898

EA3800 'Protozooses Transmises par l'Alimentation' - University of Rouen Normandy, Rouen, France.

Background: Acanthamoeba keratitis (AK) is a sight-threatening infectious disease. Its effective and safe medical therapy remains highly debated. Recently, voriconazole, a monotriazole with noted in vitro activity against a large variety of fungi, has been successfully used both topically and systemically to treat human AK cases.

Objectives: To measure anti-Acanthamoeba polyphaga in vitro activity, anti-rat AK efficiency and rat cornea penetration of eye-drop and oral voriconazole.

Methods: A. polyphaga was maintained in axenic cultures. In vitro, amoebicidal and cysticidal activities of voriconazole were measured using an XTT assay. AK lesions of Sprague Dawley rats were scored from grade 0 to grade 3. For 21 days, from day 7 post-infection, voriconazole (1% solution) eye drops were instilled or voriconazole was administered by gavage (60 mg/kg/day). After killing, superficial corneal epithelium scrapings were cultured and analysed by PCR, and eye-globe histology was performed. Cornea and plasma concentrations were determined using 2D HPLC separation and tandem MS.

Results: In vitro, voriconazole inhibited trophozoite proliferation with an IC50 value of 0.02 mg/L and an IC90 value of 2.86 mg/L; no cysticidal effect was found. In AK rats, eye drops reduced clinical worsening from day 7 to day 14 post-infection and oral voriconazole was not effective. Voriconazole cornea concentrations were directly dependent on the frequency of eye-drop instillations, which resulted in lower plasma concentrations, whilst oral voriconazole resulted in lower cornea concentrations.

Conclusions: Present data underline the need for high-frequency eye-drop instillation regimens for efficient AK therapy.
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http://dx.doi.org/10.1093/jac/dky094DOI Listing
July 2018

Octreotide modulates the expression of somatostatin receptor subtypes in inflamed rat jejunum induced by Cryptosporidium parvum.

PLoS One 2018 9;13(3):e0194058. Epub 2018 Mar 9.

Department of Pharmacology, XinJiang Medical University, Urumqi, XinJiang, China.

Somatostatins are proteins that are involved in gastrointestinal function. However, little is known with regard to somatostatin receptor subtype (SSTR) expression changes that occur in the jejunum during low-grade inflammation and during subsequent octreotide treatment. The aim of the present study was to investigate the expression of SSTRs in the jejunums of Cryptosporidium parvum (C. parvum)-infected rats by immunohistochemisty, reverse transcription (RT) PCR and quantitative real-time RT-PCR assays. Five-day-old suckling Sprague-Dawley rats (n = 15 for each group) were orally gavaged with 105 Nouzilly isolate (NoI) oocysts. Rats then received 50 μg/kg/day of octreotide by intraperitoneal injection from day 10 to day 17 post-infection. Animals were sacrificed on days 7 and 14 post-infection for immunohistochemical analysis and on days 14, 35 and 50 for mRNA expression analysis of SSTR subtypes. Histological analysis of jejunum tissues demonstrated infection of C. parvum along the villus brush border on day 7 post-infection and infection clearance by day 14 post-infection. Real-time PCR analysis indicated that in the inflamed jejunum, a significant increase in SSTR1 and SSTR2 expression was observed on day 14 post-infection. Octreotide therapy down-regulated the expression of SSTR2 on day 37 post-infection but significantly increased expression of SSTR1, SSTR2 and SSTR3 on day 50 post-infection. The results indicate that specific SSTRs may regulate the inflammatory pathway in the rat intestinal inflammation model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194058PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844672PMC
July 2018

Association of Neuropathological Markers in the Parietal Cortex With Antemortem Cognitive Function in Persons With Mild Cognitive Impairment and Alzheimer Disease.

J Neuropathol Exp Neurol 2017 Feb;76(2):70-88

From the Faculté de pharmacie, Université Laval, Québec, QC, Canada (CT, AF, LF, MV, FC); Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada (CT, AF, LF, MV, FC); "Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement" (RID-AGE) Research Group, University of Lille, INSERM U1167, Lille University Medical Center, Institut Pasteur de Lille, Lille, France (CD); and Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL (DAB).

The associations between cognitive function and neuropathological markers in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) remain only partly defined. We investigated relationships between antemortem global cognitive scores and β-amyloid (Aβ), tau, TDP-43, synaptic proteins and other key AD neuropathological markers assessed by biochemical approaches in postmortem anterior parietal cortex samples from 36 subjects (12 MCI, 12 AD and 12 not cognitively impaired) from the Religious Orders Study. Overall, the strongest negative correlation coefficients associated with global cognitive scores were obtained for insoluble phosphorylated tau (r2 = -0.484), insoluble Aβ42 (r2 = -0.389) and neurofibrillary tangle counts (r2 = -0.494) (all p < 0.001). Robust inverse associations with cognition scores were also established for TDP-43-positive cytoplasmic inclusions (r2 = -0.476), total insoluble tau (r2 = -0.385) and Aβ plaque counts (r2 = -0.426). Sarkosyl (SK)- or formic acid (FA)-extracted tau showed similar interrelations. On the other hand, synaptophysin (r2 = +0.335), pS403/404 TDP-43 (r2 = +0.265) and septin-3 (r2 = +0.257) proteins positively correlated with cognitive scores. This study suggests that tau and Aβ42 in their insoluble aggregated forms, synaptic proteins and TDP-43 are the markers in the parietal cortex that are most strongly associated with cognitive function. This further substantiates the relevance of investigating these markers to understand the pathogenesis of AD and develop therapeutic tools.
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http://dx.doi.org/10.1093/jnen/nlw109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526851PMC
February 2017

Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection.

Circulation 2017 Mar 1;135(10):917-935. Epub 2017 Feb 1.

From Paris Descartes University and Hôpital Necker, Assistance Publique-Hôpitaux de Paris, France (A.L., J.P.D.V.H., M.R.); Paris Translational Research Centre for Organ Transplantation, INSERM, UMR-S970, France (A.L., J.P.D.V.H., O.A., T.B., J.P.E., C.L., P.B., X.J.); Pathology Department, Necker Hospital, Paris, France (J.P.D.V.H.); Alberta Transplant Applied Genomics Centre; University of Alberta, Edmonton, AB, Canada (L.H., J.R., J.M.V., K.F., P.F.H.); Cardiology Department and Intensive Care (M.C.B.), Cardiology and Heart Transplant Department (R.G., X.J.), and Pathology Department (P.B.), Georges Pompidou Hospital, Paris, France; Pathology (P.R.) and Cardiac Surgery Departments (S.V., P.L.), La Pitié Salpétrière Hospital, Paris; Pathology (C.T.) and Thoracic and Cardiovascular Surgery Departments (S.P), Laennec Hospital, Nantes; Pathology (A.F.) and Cardiovascular Surgery Departments (A.G), Charles Nicolle Hospital, Rouen, France.

Background: Antibody-mediated rejection (AMR) contributes to heart allograft loss. However, an important knowledge gap remains in terms of the pathophysiology of AMR and how detection of immune activity, injury degree, and stage could be improved by intragraft gene expression profiling.

Methods: We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006-January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR. We characterized all patients using histopathology (ISHLT [International Society for Heart and Lung Transplantation] 2013 grades), immunostaining, and circulating anti-HLA donor-specific antibodies at the time of biopsy, together with systematic gene expression assessments of the allograft tissue, using microarrays. Effector cells were evaluated with in vitro human cell cultures. We studied a validation cohort of 98 heart recipients transplanted in Edmonton, AB, Canada, including 27 cases of AMR and 71 controls.

Results: A total of 240 heart transplant endomyocardial biopsies were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculatory inflammation by monocytes/macrophages and natural killer (NK) cells. We also observed selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and interferon-γ-inducible genes. The AMR-selective gene sets accurately discriminated patients with AMR from those without and included NK transcripts (area under the curve=0.87), endothelial activation transcripts (area under the curve=0.80), macrophage transcripts (area under the curve=0.86), and interferon-γ transcripts (area under the curve=0.84; <0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pathological AMR (pAMR) International Society for Heart and Lung Transplantation grade (<0.001) and association with donor-specific antibody levels. The unsupervised principal components analysis demonstrated a high proportion of molecularly inactive pAMR1(I+), and there was significant molecular overlap between pAMR1(H) and full-blown pAMR2/3 cases. Endothelial activation transcripts, interferon-γ, and NK transcripts showed association with chronic allograft vasculopathy. The molecular architecture and selective AMR transcripts, together with gene set discrimination capacity for AMR identified in the discovery set, were reproduced in the validation cohort.

Conclusions: Tissue-based measurements of specific pathogenesis-based transcripts reflecting NK burden, endothelial activation, macrophage burden, and interferon-γ effects accurately classify AMR and correlate with degree of injury and disease activity. This study illustrates the clinical potential of a tissue-based analysis of gene transcripts to refine diagnosis of heart transplant rejection.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022907DOI Listing
March 2017

Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.

Blood 2017 03 9;129(11):1437-1447. Epub 2017 Jan 9.

Department of Nephrology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.

The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates ( = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.
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http://dx.doi.org/10.1182/blood-2016-08-737163DOI Listing
March 2017

Old age potentiates cold-induced tau phosphorylation: linking thermoregulatory deficit with Alzheimer's disease.

Neurobiol Aging 2017 02 12;50:25-29. Epub 2016 Oct 12.

Faculté de pharmacie, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels, Québec, Québec, Canada. Electronic address:

Thermoregulatory deficits coincide with a rise in the incidence of Alzheimer's disease (AD) in old age. Lower body temperature increases tau phosphorylation, a neuropathological hallmark of AD. To determine whether old age potentiates cold-induced tau phosphorylation, we compared the effects of cold exposure (4 °C, 24 hours) in 6- and 18-month-old mice. Cold-induced changes in body temperature, brown adipose tissue activity, and phosphorylation of tau at Ser202 were not different between 6- and 18-month-old mice. However, following cold exposure, only old mice displayed a significant rise in soluble tau pThr181 and pThr231, which was correlated with body temperature. Inactivation of glycogen synthase kinase 3β was more prominent in young mice, suggesting a protective mechanism against cold-induced tau phosphorylation. These results suggest that old age confers higher susceptibility to tau hyperphosphorylation following a change in body temperature, thereby contributing to an enhanced risk of developing AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.09.024DOI Listing
February 2017
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