Publications by authors named "Adrien Joseph"

30 Publications

  • Page 1 of 1

Severe infections in recipients of cancer immunotherapy: what intensivists need to know.

Curr Opin Crit Care 2022 Aug 11. Epub 2022 Aug 11.

Medical Intensive Care Unit, Saint-Louis Teaching Hospital, Public Assistance Hospitals of Paris, Paris, France.

Purpose Of Review: Given the increased number of cancer patients admitted in the ICU and the growing importance of immunotherapy in their therapeutic arsenal, intensivists will be increasingly confronted to patients treated with immunotherapies who will present with complications, infectious and immunologic.

Recent Findings: Apart from their specific immunologic toxicities, cancer immunotherapy recipients also have specific immune dysfunction and face increased infectious risks that may lead to intensive care unit admission.

Summary: Chimeric antigen receptor T-cell therapy is associated with profound immunosuppression and the risks of bacterial, fungal and viral infections vary according to the time since infusion.Immune checkpoint blockers are associated with an overall favorable safety profile but associations of checkpoint blockers and corticosteroids and immunosuppressive drugs prescribed to treat immune-related adverse events are associated with increased risks of bacterial and fungal infections.The T-cell engaging bispecific therapy blinatumomab causes profound B-cell aplasia, hypogammaglobulinemia and neutropenia, but seems to be associated with fewer infectious adverse events compared with standard intensive chemotherapy.Lastly, intravesical administration of Bacillus Calmette-Guérin (BCG) can lead to disseminated BCGitis and severe sepsis requiring a specific antibiotherapy, often associated with corticosteroid treatment.
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http://dx.doi.org/10.1097/MCC.0000000000000978DOI Listing
August 2022

Cancer cell-autonomous overactivation of PARP1 compromises immunosurveillance in non-small cell lung cancer.

J Immunother Cancer 2022 06;10(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris Cité, Sorbonne Université, Centre de Recherche des Cordeliers, INSERM UMR1138, Paris, France

Background: High activity of poly(ADP-ribose) polymerase-1 (PARP1) in non-small cell lung cancer (NSCLC) cells leads to an increase in immunohistochemically detectable PAR, correlating with poor prognosis in patients with NSCLC, as well as reduced tumor infiltration by cytotoxic T lymphocytes (CTLs). Intrigued by this observation, we decided to determine whether PARP1 activity in NSCLC cells may cause an alteration of anticancer immunosurveillance.

Methods: Continuous culture of mouse NSCLC cells in the presence of cisplatin led to the generation of cisplatin-resistant PAR clones. As compared with their parental controls, such PAR cells formed tumors that were less infiltrated by CTLs when they were injected into immunocompetent mice, suggesting a causative link between high PARP1 activity and compromised immunosurveillance. To confirm this cause-and-effect relationship, we used CRISPR/Cas9 technology to knock out PARP1 in two PAR NSCLC mouse cell lines (Lewis lung cancer [LLC] and tissue culture number one [TC1]), showing that the removal of PARP1 indeed restored cisplatin-induced cell death responses.

Results: PARP1 knockout (PARP1) cells became largely resistant to the PARP inhibitor niraparib, meaning that they exhibited less cell death induction, reduced DNA damage response, attenuated metabolic shifts and no induction of PD-L1 and MHC class-I molecules that may affect their immunogenicity. PAR tumors implanted in mice responded to niraparib irrespective of the presence or absence of T lymphocytes, suggesting that cancer cell-autonomous effects of niraparib dominate over its possible immunomodulatory action. While PAR NSCLC mouse cell lines proliferated similarly in immunocompetent and T cell-deficient mice, PARP1 cells were strongly affected by the presence of T cells. PARP1 LLC tumors grew more quickly in immunodeficient than in immunocompetent mice, and PARP1 TC1 cells could only form tumors in T cell-deficient mice, not in immunocompetent controls. Importantly, as compared with PAR controls, the PARP1 LLC tumors exhibited signs of T cell activation in the immune infiltrate such as higher inducible costimulator (ICOS) expression and lower PD-1 expression on CTLs.

Conclusions: These results prove at the genetic level that PARP1 activity within malignant cells modulates the tumor microenvironment.
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http://dx.doi.org/10.1136/jitc-2021-004280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9247697PMC
June 2022

Immune-mediated thrombotic thrombocytopenic purpura prognosis is affected by blood pressure.

Res Pract Thromb Haemost 2022 May 18;6(4):e12702. Epub 2022 May 18.

Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT) AP-HP Paris France.

Background: The prevalence, prognostic role, and diagnostic value of blood pressure in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and other thrombotic microangiopathies (TMAs) remain unclear.

Methods: Using a national cohort of iTTP ( = 368), Shigatoxin-induced hemolytic uremic syndrome ( = 86), atypical hemolytic uremic syndrome ( = 84), and hypertension-related thrombotic microangiopathy ( = 25), we sought to compare the cohort's blood pressure profile to assess its impact on prognosis and diagnostic performances.

Results: Patients with iTTP had lower blood pressure than patients with other TMAs, systolic (130 [interquartile range (IQR) 118-143] vs 161 [IQR 142-180] mmHg) and diastolic (76 [IQR 69-83] vs 92 [IQR 79-105] mmHg, both  < 0.001). The best threshold for iTTP diagnosis corresponded to a systolic blood pressure <150 mmHg. iTTP patients presenting with hypertension had a significantly poorer survival (hazard ratio 1.80, 95% confidence interval 1.07-3.04), and this effect remained significant after multivariable adjustment (hazard ratio = 1.14, 95% confidence interval 1.00-1.30). Addition of a blood pressure criterion modestly improved the French clinical score to predict a severe A disintegrin and metalloprotease with thrombospondin type 1 deficiency in patients with an intermediate score (i.e., either platelet count <30 × 10/L or serum creatinine <200 µM).

Conclusions: Elevated blood pressure at admission affects the prognosis of iTTP patients and may help discriminate them from other TMA patients. Particular attention should be paid to blood pressure and its management in these patients.
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http://dx.doi.org/10.1002/rth2.12702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115975PMC
May 2022

Improved Swiss-rolling method for histological analyses of colon tissue.

MethodsX 2022 9;9:101630. Epub 2022 Feb 9.

Centre de Recherche des Cordeliers, Inserm U1138, Team "Metabolism, Cancer & Immunity" Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, 15 rue de l'Ecole de Médecine, Paris 75006, France.

Since the introduction of the Swiss-rolling technique by Reilly and Kirsner in 1965, various methodological approaches have been developed for histological analyses of intestinal tissues. Here, we describe an improved protocol for the processing of freshly harvested murine colons that can be extended to other intestinal tissues. With simple tools, this technique allows to tightly wrap the organ throughout the whole length and to keep it in place before fixation, avoiding excessive stiffness of the tissue. Unlike the original method which relies on frozen samples, processing of the biological samples right after resection preserves epitopes integrity for subsequent immunohistochemical analyses. Ultimately, this method provides a reproducible workflow to capture the entire colon length in a unique histological section in order to assess several features such as intestinal inflammation and tumorigenesis. • Easily include freshly isolated tissues • Shorten preparation time using a few affordable tools • Prevent unrolling and preserve tissue integrity.
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http://dx.doi.org/10.1016/j.mex.2022.101630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8861817PMC
February 2022

Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects.

Cell Stress 2021 Jul 28;5(7):89-98. Epub 2021 Jun 28.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France.

Eukaryotic cells release the phylogenetically ancient protein acyl coenzyme A binding protein (ACBP, which in humans is encoded by the gene DBI, diazepam binding inhibitor) upon nutrient deprivation. Accordingly, mice that are starved for one to two days and humans that undergo voluntary fasting for one to three weeks manifest an increase in the plasma concentration of ACBP/DBI. Paradoxically, ACBP/DBI levels also increase in obese mice and humans. Since ACBP/DBI stimulates appetite, this latter finding may explain why obesity constitutes a self-perpetuating state. Here, we present a theoretical framework to embed these findings in the mechanisms of weight control, as well as a bioinformatics analysis showing that, irrespective of the human cell or tissue type, one single isoform of ACBP/DBI (ACBP1) is preponderant (~90% of all DBI transcripts, with the sole exception of the testis, where it is ~70%). Based on our knowledge, we conclude that ACBP1 is subjected to a biphasic transcriptional and post-transcriptional regulation, explaining why obesity and fasting both are associated with increased circulating ACBP1 protein levels.
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http://dx.doi.org/10.15698/cst2021.07.252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283301PMC
July 2021

Pyridoxal kinase and poly(ADP-ribose) affect the immune microenvironment of locally advanced cancers.

Oncoimmunology 2021 8;10(1):1950954. Epub 2021 Jul 8.

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.

Malignant cells adapt to the hostile tumor microenvironment by escaping from, or actively suppressing, anticancer immune responses. In the past, we reported that reduced synthesis of active vitamin B6 (due to downregulation of pyridoxal kinase) or overactivation of poly(ADP-ribose) polymerase confers resistance to chemotherapy with cisplatin. Recently, we found that these prognostically adverse alterations in oncometabolism also correlate with the rarefaction of immune effectors in the tumor bed.
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http://dx.doi.org/10.1080/2162402X.2021.1950954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274443PMC
August 2021

Metabolic features of cancer cells impact immunosurveillance.

J Immunother Cancer 2021 06;9(6)

Equipe 11 labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Paris, France

Background: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.

Methods: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PAR) and cisplatin-resistant (PAR) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.

Results: The infiltration of tumors by CD8 T and DC-LAMP cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).

Conclusions: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.
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http://dx.doi.org/10.1136/jitc-2021-002362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231002PMC
June 2021

Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index.

Cell Death Dis 2021 06 9;12(6):599. Epub 2021 Jun 9.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France.

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.
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http://dx.doi.org/10.1038/s41419-021-03864-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190068PMC
June 2021

Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.

Cell Death Differ 2021 07 11;28(7):2276-2295. Epub 2021 May 11.

Gustave Roussy Cancer Campus (GRCC), Villejuif, France.

A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFNγ-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.
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http://dx.doi.org/10.1038/s41418-021-00753-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257780PMC
July 2021

Shiga Toxin-Associated Hemolytic Uremic Syndrome: Specificities of Adult Patients and Implications for Critical Care Management.

Toxins (Basel) 2021 04 26;13(5). Epub 2021 Apr 26.

Centre de Référence des Microangiopathies Thrombotiques (CNR-MAT), Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, 75012 Paris, France.

Shiga toxin-producing -associated hemolytic uremic syndrome (STEC-HUS) is a form of thrombotic microangiopathy secondary to an infection by an enterohemorrhagic . Historically considered a pediatric disease, its presentation has been described as typical, with bloody diarrhea at the forefront. However, in adults, the clinical presentation is more diverse and makes the early diagnosis hazardous. In this review, we review the epidemiology, most important outbreaks, physiopathology, clinical presentation and prognosis of STEC-HUS, focusing on the differential features between pediatric and adult disease. We show that the clinical presentation of STEC-HUS in adults is far from typical and marked by the prevalence of neurological symptoms and a poorer prognosis. Of note, we highlight knowledge gaps and the need for studies dedicated to adult patients. The differences between pediatric and adult patients have implications for the treatment of this disease, which remains a public health threat and lack a specific treatment.
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http://dx.doi.org/10.3390/toxins13050306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145702PMC
April 2021

Efficacy and tolerance of sustained low-efficiency dialysis with calcium-free citrate-containing dialysate anticoagulation.

Clin Kidney J 2021 Mar 24;14(3):1025-1026. Epub 2020 Sep 24.

Service des Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1093/ckj/sfaa128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986335PMC
March 2021

Immune-related adverse events: a retrospective look into the future of oncology in the intensive care unit.

Ann Intensive Care 2020 Oct 16;10(1):143. Epub 2020 Oct 16.

Service de Réanimation Médicale, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Background: Immune checkpoint inhibitors have reshaped the standard of care in oncology. However, they have been associated with potentially life-threatening immune-related adverse events. With the growing indications of immune checkpoint inhibitors and their position as a pillar of cancer treatment, intensive care physicians will be increasingly confronted with their side effects. The outcome of patients with severe immune-related adverse events in the intensive care unit remains unknown. This retrospective multicentric study aims to describe the characteristics of patients admitted to the intensive care units of 4 academic hospitals in Paris area while receiving immune checkpoint inhibitor treatment between January 2013 and October 2019.

Results: Over the study period, 112 cancer patients who received immune checkpoint inhibitors were admitted to the intensive care unit within 60 days after the last dose. ICU admission was related to immune-related adverse events (n = 29, 26%), other intercurrent events (n = 39, 35%), or complications related to tumor progression (n = 44, 39%). Immune-related adverse events were pneumonitis (n = 8), colitis (n = 4), myocarditis (n = 3), metabolic disorders related to diabetes (n = 3), hypophysitis (n = 2), nephritis (n = 2), meningitis or encephalitis (n = 2), hepatitis (n = 2), anaphylaxis (n = 2) and pericarditis (n = 1). Primary tumors were mostly melanomas (n = 14, 48%), non-small-cell lung cancers (n = 7, 24%), and urothelial carcinomas (n = 5, 17%). Diagnosis of melanoma and a neutrophil/lymphocyte ratio < 10 were associated with immune-related diagnosis versus other reasons for ICU admission. During their ICU stay, immune-related adverse events patients needed vasopressors (n = 7), mechanical ventilation (n = 6), and extra-corporeal membrane oxygenation (n = 2). One-year survival was significantly higher for patients admitted for irAE compared to patients admitted for other reasons (p = 0.004).

Conclusions: Admission to the intensive care unit related to immune-related adverse event was associated with better outcome in cancer patients treated with immune checkpoint inhibitors. Our results support the admission for an intensive care unit trial for patients with suspected immune-related adverse events.
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http://dx.doi.org/10.1186/s13613-020-00761-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567777PMC
October 2020

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Blood 2020 11;136(20):2290-2295

Paris University, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR1151, Hôpital Necker-Enfants Malades, Paris, France.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.
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http://dx.doi.org/10.1182/blood.2020008423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702482PMC
November 2020

Acute kidney injury in patients with SARS-CoV-2 infection.

Ann Intensive Care 2020 Sep 3;10(1):117. Epub 2020 Sep 3.

Service de médecine Intensive et de réanimation médicale, Hôpital Saint-Louis, Assistance-Publique Hôpitaux de Paris, Paris University, 1 avenue Claude Vellefaux, 75010, Paris, France.

Background: Acute Kidney Injury (AKI) is a frequent complication of severe SARS-CoV-2 infection. Multiple mechanisms are involved in COVID-19-associated AKI, from direct viral infection and secondary inflammation to complement activation and microthrombosis. However, data are limited in critically-ill patients. In this study, we sought to describe the prevalence, risk factors and prognostic impact of AKI in this setting.

Methods: Retrospective monocenter study including adult patients with laboratory confirmed SARS-CoV-2 infection admitted to the ICU of our university Hospital. AKI was defined according to both urinary output and creatinine KDIGO criteria.

Results: Overall, 100 COVID-19 patients were admitted. AKI occurred in 81 patients (81%), including 44, 10 and 27 patients with AKI stage 1, 2 and 3 respectively. The severity of AKI was associated with mortality at day 28 (p = 0.013). Before adjustment, the third fraction of complement (C3), interleukin-6 (IL-6) and ferritin levels were higher in AKI patients. After adjustment for confounders, both severity (modified SOFA score per point) and AKI were associated with outcome. When forced in the final model, C3 (OR per log 0.25; 95% CI 0.01-4.66), IL-6 (OR per log 0.83; 95% CI 0.51-1.34), or ferritin (OR per log 1.63; 95% CI 0.84-3.32) were not associated with AKI and did not change the model.

Conclusion: In conclusion, we did not find any association between complement activation or inflammatory markers and AKI. Proportion of patients with AKI during severe SARS-CoV-2 infection is higher than previously reported and associated with outcome.
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http://dx.doi.org/10.1186/s13613-020-00734-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471244PMC
September 2020

Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI).

Cell Death Dis 2020 07 6;11(7):502. Epub 2020 Jul 6.

Fondation FondaMental, Créteil, France.

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark-light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.
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http://dx.doi.org/10.1038/s41419-020-2716-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338362PMC
July 2020

One-year survival in patients with solid tumours discharged alive from the intensive care unit after unplanned admission: A retrospective study.

J Crit Care 2020 06 30;57:36-41. Epub 2020 Jan 30.

Medical ICU, APHP Hopital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris, France. Electronic address:

Purpose: Outcomes in cancer patients after unplanned ICU admission was reassessed.

Methods: retrospective cohort of patients with solid tumours admitted to ICU over a 10 years period.

Results: 622 patients (age 62 [53-70]) were analysed. The most common primary sites of cancer were lung (n = 133; 21.4%) and digestive tract (n = 126; 20.2%) The ICU mortality rate was 22.2% (n = 138). Among 470 ICU survivors, the 1-year mortality was 41.3% (95% CI, 36-45.9) (n = 167). Factors independently associated with 1-year mortality were ICU admission after 2010 (HR 0.53 (0.37-0.76), p < .001), disease status (respectively, HR = 1.88 (1.0.2-3.45), p = .002) for locally advanced cancer and HR = 2.23 (1.35-3.67), p = .003) for metastatic cancer), poor performance status (HR = 1.58 (1.08-2.31), p = .019), newly diagnosed cancer at ICU admission (HR = 2.02 (1.28-3.20), p = .003), inability to receive oncologic treatment after ICU discharge (HR = 5.34 (3.49-8.18), p < .001) and decision to withhold life-sustaining treatment during ICU stay (HR = 2.34 (1.50-3.65), p < .001).

Conclusions: Among the factors associated with one-year mortality after ICU discharge, the possibility of receiving oncologic treatment after ICU discharge seems crucial.
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http://dx.doi.org/10.1016/j.jcrc.2020.01.027DOI Listing
June 2020

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review.

Toxins (Basel) 2020 01 21;12(2). Epub 2020 Jan 21.

Department of Renal Transplantation, Sorbonne Université, AP-HP, Hôpital Pitié Salpêtrière, F-75013 Paris, France.

The severity of human infection by one of the many Shiga toxin-producing (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.
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http://dx.doi.org/10.3390/toxins12020067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076748PMC
January 2020

Predictive factors of severe infections in patients with systemic necrotizing vasculitides: data from 733 patients enrolled in five randomized controlled trials of the French Vasculitis Study Group.

Rheumatology (Oxford) 2020 09;59(9):2250-2257

Department of Internal Medicine.

Objectives: Infections remain a major cause of morbidity and mortality in systemic necrotizing vasculitides (SNV). We aimed to identify factors predicting severe infections (SI) in SNV.

Methods: Data from five randomized controlled trials (RCTs) enrolling 733 patients were pooled. The primary end point was the occurrence of SI, defined by the need of a hospitalization and/or intravenous anti-infectious treatment and/or leading to death.

Results: After a median follow-up of 5.2 (interquartile range 3-9.7) years, 148 (20.2%) patients experienced 189 SI, and 98 (66.2%) presented their first SI within the first 2 years. Median interval from inclusion to SI was 14.9 (4.3-51.7) months. Age ≥65 years (hazard ratio (HR) 1.49 [1.07-2.07]; P=0.019), pulmonary involvement (HR 1.82 [1.26-2.62]; P=0.001) and Five Factor Score ≥1 (HR 1.21 [1.03-1.43]; P=0.019) were independent predictive factors of SI. Regarding induction therapy, the occurrence of SI was associated with the combination of GCs and CYC (HR 1.51 [1.03-2.22]; P = 0.036), while patients receiving only GCs were less likely to present SI (HR 0.69 [0.44-1.07]; P = 0.096). Finally, occurrence of SI had a significant negative impact on survival (P<0.001).

Conclusion: SI in SNV are frequent and impact mortality. Age, pulmonary involvement and Five Factor Score are baseline independent predictors of SI. No therapeutic regimen was significantly associated with SI but patients receiving glucocorticoids and CYC as induction tended to have more SI.
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http://dx.doi.org/10.1093/rheumatology/kez575DOI Listing
September 2020

Metabolic enzymes expressed by cancer cells impact the immune infiltrate.

Oncoimmunology 2019;8(6):e1571389. Epub 2019 Mar 30.

Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.

The expression of two metabolic enzymes, ., aldehyde dehydrogenase 7 family, member A1 (ALDH7A1) and lipase C, hepatic type (LIPC) by malignant cells, has been measured by immunohistochemical methods in non-small cell lung carcinoma (NSCLC) biopsies, and has been attributed negative and positive prognostic value, respectively. Here, we demonstrate that the protein levels of ALDH7A1 and LIPC correlate with the levels of the corresponding mRNAs. Bioinformatic analyses of gene expression data from 4921 cancer patients revealed that the expression of LIPC positively correlates with abundant tumor infiltration by myeloid and lymphoid cells in NSCLC, breast carcinoma, colorectal cancer and melanoma samples. In contrast, high levels of ALDH7A1 were associated with a paucity of immune effectors within the tumor bed. These data reinforce the notion that the metabolism of cancer cells has a major impact on immune and inflammatory processes in the tumor microenvironment, pointing to hitherto unsuspected intersections between oncometabolism and immunometabolism.
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http://dx.doi.org/10.1080/2162402X.2019.1571389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492976PMC
March 2019

Early Differentiation of Shiga Toxin-Associated Hemolytic Uremic Syndrome in Critically Ill Adults With Thrombotic Microangiopathy Syndromes.

Crit Care Med 2018 09;46(9):e904-e911

Medical Intensive Care Unit, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Objectives: Thrombotic microangiopathy syndromes are a heterogeneous group of severe diseases that often require ICU admission. Prompt initiation of targeted therapies is required for atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, whereas there is no specific consensus therapy for Shiga toxin-associated hemolytic uremic syndrome. We sought to compare the characteristics of Shiga toxin-associated hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura patients at admission in the ICU to allow early differentiation of Shiga toxin-associated hemolytic uremic syndrome from other thrombotic microangiopathy syndromes and help to tailor initial treatment.

Design: Retrospective cohort study.

Setting: Two ICUs part of the French reference center for thrombotic microangiopathy syndromes.

Patients: Adult patients presenting with features of thrombotic microangiopathy syndromes. Other causes than Shiga toxin-associated hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura were excluded.

Interventions: None.

Measurements And Main Results: From September 2003 to January 2017, 236 thrombotic microangiopathy syndrome patients were admitted, including 12 Shiga toxin-associated hemolytic uremic syndrome, 21 atypical hemolytic uremic syndrome, and 91 thrombotic thrombocytopenic purpura. Shiga toxin-associated hemolytic uremic syndrome patients were older than other thrombotic microangiopathy syndromes patients (64 yr [interquartile range, 50-72 yr] vs 42 yr [31-54 yr]; p = 0.007) and presented with more frequent digestive symptoms (92% vs 42%; p < 0.001), especially nonbloody diarrhea and vomiting. Biologically, Shiga toxin-associated hemolytic uremic syndrome patients displayed higher fibrinogen (490 mg/dL [460-540 mg/dL] vs 320 mg/dL [240-410 mg/dL]; p = 0.003) and creatinine levels (2.59 mg/dL [2.12-3.42 mg/dL] vs 1.26 mg/dL [0.61-1.90 mg/dL]; p < 0.001), and less marked anemia (hemoglobin level, 9.7 g/dL [8.7-11.9 g/dL] vs 7.7 g/dL [6.3-9.1 g/dL]; p < 0.001). Forty-two percent (n = 5) required renal replacement therapy, and 83% (n = 10) were treated with plasma exchange before the distinction from other thrombotic microangiopathy syndromes could be made.

Conclusions: Adult Shiga toxin-associated hemolytic uremic syndrome patients are older, present more frequently with digestive symptoms and display higher hemoglobin and fibrinogen levels than other thrombotic microangiopathy syndromes. However, overlap across the three thrombotic microangiopathy syndromes remains substantial, putting forward the need to implement early plasma therapy until thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome can be ruled out.
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http://dx.doi.org/10.1097/CCM.0000000000003292DOI Listing
September 2018

Metabolic vulnerability of cisplatin-resistant cancers.

EMBO J 2018 07 6;37(14). Epub 2018 Jun 6.

Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation and than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin-resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.
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http://dx.doi.org/10.15252/embj.201798597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043854PMC
July 2018

Renal recovery after severe acute kidney injury in critically ill myeloma patients: a retrospective study.

Clin Kidney J 2018 Feb 13;11(1):20-25. Epub 2017 Jul 13.

Medical Intensive Care Unit, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris and Paris Diderot University, Paris, France.

Background: Despite substantial improvements in the management of multiple myeloma, renal failure remains an important burden that tremendously impairs prognosis. The purpose of this study was to describe the characteristics and to establish prognostic factors of renal recovery in myeloma patients admitted to the intensive care unit (ICU) for acute kidney injury (AKI) Stage 3 treated with renal replacement therapy (RRT).

Methods: A retrospective single-centre cohort study was performed, including consecutive myeloma patients admitted to one medical ICU between 1 January 2007 and 1 September 2015 and treated with RRT. Patients were evaluated 60 days after initiation of RRT and divided into three groups: alive without dialysis, alive and dialysis-dependent or deceased. A univariate analysis was performed to identify factors associated with renal recovery (alive without dialysis 60 days after initiation of RRT).

Results: Fifty patients were included in the study. Mean age was 63 (interquartile range: 58-70) years and 32 (64%) were male. Patients were admitted to the ICU 4 (1-7) years after the diagnosis of myeloma. Twenty-one (42%) had already been treated with high-dose therapy combined with autologous stem cell transplantation. Baseline renal function evaluated by estimated glomerular filtration rate (GFR) before ICU admission was 63 (44-90) mL/min/1.73 m. The mean SOFA score at Day 1 was 7 (4-8). The three main reasons for ICU admission were AKI ( = 31, 62%), acute pulmonary oedema ( = 17, 32%) and sepsis ( = 10, 20%). During ICU stay, RRT was implemented in all patients, 16 (32%) patients required invasive mechanical ventilation and 12 (24%) received vasopressors. The mean ICU and hospital length of stay were 6 (1-7) and 28 (13-34) days, respectively. At Day 60, 23 (46%) patients were alive without dialysis, 17 (32%) had died and 10 (20%) were still undergoing dialysis. Among the 23 patients who recovered, the mean duration of dialysis was 6 (2-18) days and renal function was not significantly different from baseline [estimated GFR at baseline = 65 (25-74) mL/min/1.73 m versus 63 (56-70) mL/min/1.73 m at Day 60, P = 0.70]. By univariate analysis, two factors were associated with nonrecovery of renal function at Day 60: a history of high-dose therapy combined with autologous stem cell transplantation [odds ratio (OR) = 6.1, 95% confidence interval (CI) 1.7-21.6; P = 0.008] and a proteinuria at ICU admission >370 mg/mmol creatinine (OR = 4.2, 95% CI 1.1-17; P = 0.02). None of the other variables related to the haematological malignancy or to the ICU stay was associated with renal recovery at Day 60.

Conclusions: AKI Stage 3 in critically ill myeloma patients was associated with a lower than expected hospital mortality. Patients with a high level of proteinuria and a history of high-dose therapy combined with autologous stem cell transplantation were less likely to recover their renal function at Day 60.

Key Words: dialysis, intensive care, multiple myeloma, prognosis, proteinuria.
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http://dx.doi.org/10.1093/ckj/sfx059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798019PMC
February 2018

External validation and comparison of formulae estimating 24-h sodium intake from a fasting morning urine sample.

J Hypertens 2018 04;36(4):785-792

Physiology Department, Département Hospitalo-Universitaire FIRE, Assistance Publique - Hôpitaux de Paris, Hôpital Bichat.

Objective: The relationship between sodium intake and cardiovascular events is controversial, but most large epidemiological studies estimated sodium intake using formulae based on single urine samples, the validity of which is debated. We evaluated sodium intake estimating formulae in a large cohort of adult patients.

Design And Methods: Patients were asked to collect 24-h urine the day before admission. Validity of the 24-h urine collection was assessed by comparing creatinine clearance from this collection to the mean creatinine clearance from six fractionated urine samples. Only collections with creatinine clearance within ±15% of fractionated clearance were considered valid. The Kawasaki, INTERSALT and Tanaka formulae, using a morning fasting urine sample obtained upon admission, were compared with 24-h urine sodium excretion. The relationship between sodium intake, either measured or estimated, and blood pressure was assessed.

Results: Amongst 2278 patients referred to our physiology department between September 2006 and August 2016, 1018 had complete 24-h urine collections and were included in this analysis. Mean age was 51 ± 14 years and mean sodium excretion was 3624 ± 1614 mg/day. The intraclass correlation coefficient was higher for the Kawasaki (0.54; 95% confidence interval, 0.48-0.60), than for the INTERSALT (0.38; 0.33-0.42, P < 0.001), and Tanaka (0.42; 0.37-0.46, P < 0.001) formulae. The Kawasaki formula displayed the lowest mean bias (248; 157-339 mg/day). There was a significant positive association between measured sodium intake and blood pressure, and the Kawasaki formula yielded a similar association.

Conclusion: All formulae have poor precision and accuracy and are not suitable for estimating individual sodium intake. This does not dismiss their potential value for assessment of sodium intake in population studies.
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http://dx.doi.org/10.1097/HJH.0000000000001609DOI Listing
April 2018

Orthostatic hypotension: A review.

Nephrol Ther 2017 Apr;13 Suppl 1:S55-S67

Service de physiologie, DHU Fire, hôpital Bichat, 46, rue Henri-Huchard, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris-Cité, 46, rue Henri-Huchard, 75018 Paris, France; Inserm U1149, 46, rue Henri-Huchard, 75018 Paris, France. Electronic address:

Orthostatic hypotension, defined by a drop in blood pressure of at least 20mmHg for systolic blood pressure and at least 10mmHg for diastolic blood pressure within 3minutes of standing up, is a frequent finding, particularly in elderly patients. It is associated with a significant increase in morbidity and mortality. Although it is often multifactorial, the first favoring factor is medications. Other etiologies are divided in neurogenic orthostatic hypotension, characterized by autonomic failure due to central or peripheral nervous system disorders, and non-neurogenic orthostatic hypotension, mainly favoured by hypovolemia. Treatment always requires education of the patient regarding triggering situations and physiological countermanoeuvers. Pharmacological treatment may sometimes be necessary and mainly relies on volume expansion by fludrocortisone and/or a vasopressor agents such as midodrine. There is no predefined blood pressure target, the goal of therapy being the relief of symptoms and fall prevention.
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http://dx.doi.org/10.1016/j.nephro.2017.01.003DOI Listing
April 2017

Estimation of populational 24-h urinary sodium and potassium excretion from spot urine samples: evaluation of four formulas in a large national representative population.

J Hypertens 2017 05;35(5):1119-1120

aPhysiology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Département Hospitalo-Universitaire FIRE bParis Diderot University, Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1097/HJH.0000000000001317DOI Listing
May 2017

[Tenofovir-induced Fanconi syndrome and recovery after treatment cessation: A case report with physiological considerations].

Presse Med 2017 03 3;46(2 Pt 1):233-236. Epub 2017 Jan 3.

AP-HP, hôpital Bichat, service de physiologie, DHU Fire, 46, rue Henri-Huchard, 75722 Paris cedex 18, France; Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.lpm.2016.11.029DOI Listing
March 2017

Calcium salt during hyperkalemia.

Kidney Int 2016 08;90(2):451-452

Department of Nephrology Transplantation and Emergency, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon; Université Pierre et Marie Curie Paris 6, Paris. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2016.05.016DOI Listing
August 2016

Sodium is the secret re-agent of bicarbonate therapy during hyperkalemia.

Kidney Int 2016 08;90(2):450-451

Department of Nephrology, Transplantation and Emergency, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France; Université Pierre et Marie Curie Paris 6, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2016.05.015DOI Listing
August 2016
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