Publications by authors named "Jean-Philippe Jais"

137 Publications

Economic burden in non-Hodgkin lymphoma survivors: The French Lymphoma Study Association SIMONAL cross-sectional study.

Cancer 2021 Oct 4. Epub 2021 Oct 4.

Onco-Hematology Unit, l'Archet Hospital, Nice University Hospital Center, University of Côte d'Azur, Nice, France.

Background: No study has focused on the economic burden in non-Hodgkin lymphoma (NHL) survivors, even though this knowledge is essential. This study reports on health care resource use and associated health care costs as well as related factors in a series of 1671 French long-term NHL survivors.

Methods: Health care costs were measured from the payer perspective. Only direct medical costs (medical consultations, outpatient treatments, hospitalizations, and medical transport) in the past 12 months were included (reference year 2015). Multiple linear regression was used to search for explanatory factors of health care costs.

Results: In total, 1100 survivors (66%) reported having used at least 1 health care resource, and 867 (52%) reported having used at least 1 outpatient treatment. After the authors accounted for missing data, the mean health care cost was estimated at €702 ± €2221. Hospitalizations and outpatient treatments were the main cost drivers. Sensitivity analyses confirmed the robustness of the results. For the 1100 survivors who reported using at least 1 health care resource, the mean health care cost was €1067 ± €2268. Several factors demonstrated statistically significant relationships with health care costs. For instance, cardiovascular disorders increased costs by 66% ± 16%. In contrast, rituximab or autologous stem cell transplantation as initial therapy had no effect on health care costs.

Conclusions: The consideration of economic constraints in health care is now a reality. This retrospective study reports on a better understanding of health care resource use and associated health care costs as well as related factors. It may help health care professionals in their ongoing efforts to design person-centered health care pathways.
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http://dx.doi.org/10.1002/cncr.33938DOI Listing
October 2021

The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma.

Blood 2021 07 7. Epub 2021 Jul 7.

Université de Paris, NF-kappaB, Différenciation et Cancer, Paris, France

Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. NF-kB transcription factor family is activated by two main pathways, the canonical and the alternative NF-kB activation pathways with different functions. The alternative NF-kB pathway leads to the activation of the transcriptionally active RelB NF-kB subunit. Alternative NF-kB activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their ABC or GCB subtypes. RelB activity defines a new subset of DLBCL patients with a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for ABC tumors carrying MYD88L265P and CD79B mutations that cooperatively activate canonical NF-kB, thus indicating that current genetic tools to evaluate NF-kB activity in DLBCL do not provide information on the alternative NF-kB activation. Further, the newly defined RelB-positive subgroup of DLBCL patients exhibits a dismal outcome following immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA-damage induced apoptosis in response to doxorubicin, a genotoxic agent used in front-line treatment for DLBCL. We also show that RelB positivity is associated with high expression of cIAP2. Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of DLBCL patients.
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http://dx.doi.org/10.1182/blood.2020010039DOI Listing
July 2021

Continuous positive airway pressure improves work of breathing in pediatric chronic heart failure.

Sleep Med 2021 07 19;83:99-105. Epub 2021 Apr 19.

Pediatric Noninvasive Ventilation and Sleep Unit, Hôpital Necker-Enfants Malades F-75015, Paris, France; Université de Paris, VIFASOM F-75004, Paris, France.

Background: Sleep disordered breathing (SDB) is common in adults with chronic heart failure (CHF), but its prevalence in children remains unclear. Continuous positive airway pressure (CPAP) is the treatment of SDB but deleterious hemodynamic effects have been reported.

Methods: We prospectively analyzed SDB in children with CHF and the effect of CPAP on work of breathing (WOB) and cardiac index (CI). Children aged 6 months to 18 years old with CHF due to: 1) dilated cardiomyopathy (DM) with an ejection fraction < 45%, 2) functional single ventricle (SV) or 3) aortic or mitral valve disease awaiting surgery (VD) were eligible for the study. A polysomnography (PSG), measurement of WOB and CI during spontaneous breathing (SB) and CPAP (6, 8 and 10 cmHO) were performed.

Results: Thirty patients with mean age of 6.4 ± 5 years were included (16 DM 16, 10 SV, 4 LV). Twenty (73%) patients had a normal sleep efficiency. Median apnoeas hypopnea index (IAH) was within normal range at 1.6 events/h (0, 14) events/hour. Only one patient had central sleep apnoeas, none had Cheyne-Stokes respiration, and 3 patients had an obstructive AHI between 5 and 10 events/hour. Optimal CPAP level decreased WOB (p = 0.05) and respiratory rate (p = 0.01).

Conclusions: Severe SDB was uncommon in children with CHF. However, CPAP may be beneficial by decreasing WOB and respiratory rate without deleterious effects on CI.
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http://dx.doi.org/10.1016/j.sleep.2021.04.003DOI Listing
July 2021

c-Rel Is the Pivotal NF-κB Subunit in Germinal Center Diffuse Large B-Cell Lymphoma: A LYSA Study.

Front Oncol 2021 20;11:638897. Epub 2021 Apr 20.

CNRS UMR-7276, INSERM U1262, CRIBL, University of Limoges, and Hematology Laboratory of Dupuytren Hospital University Center (CHU) of Limoges, Limoges, France.

Relationships between c-Rel and GCB-DLBCLs remain unclear. We found that strong c-Rel DNA-binding activity was mostly found in GCBs on two independent series of 48 DLBCLs and 66 DLBCLs, the latter issued from the GHEDI series. c-Rel DNA-binding activity was associated with increased mRNA expression. Extending the study to the whole GHEDI and Lenz DLBCL published series of 202 and 233 cases, it was found that the c-Rel gene expression profile (GEP) overlapped partially (12%) but only with the GCB GEP and not with the GEP of ABC-DLBCLs. Cases with both overexpression of mRNA and c-Rel GEP were defined as those having a c-Rel signature. These cases were GCBs in 88 and 83% of the GHEDI or Lenz's DLBCL series respectively. The c-Rel signature was also associated with various recurrent GCB-DLBCL genetic events, including gains, translocation, , , , and mutations and with the EZB GCB genetic subtype. By CGH array, the c-Rel signature was specifically correlated with 2p15-16.1 amplification that includes XPO1, BCL11A, and USP34 and with the 22q11.22 deletion that covers IGLL5 and PRAME. The total number of gene copy number aberrations, so-called genomic imbalance complexity, was decreased in cases with the c-Rel signature. These cases exhibited a better overall survival. Functionally, overexpression of c-Rel induced its constitutive nuclear localization and protected cells against apoptosis while its repression tended to increase cell death. These results show that, clinically and biologically, c-Rel is the pivotal NF-B subunit in the GCB-DLBCL subgroup. Functionally, c-Rel overexpression could directly promote DLBCL tumorigenesis without need for further activation signals.
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http://dx.doi.org/10.3389/fonc.2021.638897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095348PMC
April 2021

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Am J Hematol 2021 07 3;96(7):834-845. Epub 2021 May 3.

Department of Hematology, Inserm U1163, IMAGINE Institute, Paris University, Necker Hospital, Paris, France.

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.
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http://dx.doi.org/10.1002/ajh.26200DOI Listing
July 2021

The use of biofeedback for children with fecal incontinence secondary to retentive constipation: Experience of a French Pediatric Center.

Clin Res Hepatol Gastroenterol 2021 May 22;45(3):101550. Epub 2020 Oct 22.

Department of Pediatric Gastroenterology, Hepatology, and Nutrition, APHP, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France; Université de Paris, Faculté de Médecine, 2 rue de l'Ecole de Médecine, 75006, Paris, France.

Background: Fecal incontinence (FI) secondary to chronic retentive constipation is a frequent demand in pediatric gastroenterology clinics. The management of constipation in children includes laxatives (polyethylene glycol, PEG), enhanced toilet training, and dietary advice. Biofeedback is a possible treatment for children above the age of 7 years with resistant FI.

Aim: To analyze any changes in volume to trigger defecation (VTD) and envy score over the course of biofeedback sessions according to clinical response.

Methods: In this retrospective study, we reviewed the medical records of 23 children diagnosed with FI according to the Rome IV criteria and treated with biofeedback. For each biofeedback session, a mean VTD by subject was measured. At the end, therapy was considered a success if soiling disappeared and a failure if any persisted. The need to defecate expressed by the child was described as an envy score. A 0-10 visual analog scale was used to express the intensity of this sensation. Follow-up involved calling the parents 12 months after the biofeedback sessions had ended to assess symptoms remotely.

Results: The study included 19 boys and 4 girls with a median age of 10 years. Patients' ages ranged between 7 and 17 years. None of them had any associated neurological disorders. All children had FI for >1 year. The median number of soiling episodes per week was 7. The average number of biofeedback sessions was 3 (range 1-5). At the end of the rehabilitation sessions, 12 children (52%) were in the "success" group. In the latter, median VTD decreased from 97 ml to 70 ml between the first and last session. In the "failure" group, VTD decreased from 120 ml to 100 ml. The between-group difference in the median VTD at the first session was not statistically significant. The last observation carried forward (LOCF) VTD was significantly lower in the "success" group compared to the "failure" group (70 ml versus 100 ml, p = 0.03). Median envy scores decreased during the biofeedback sessions with no statistical difference between the groups at the last session. Follow-up of children in the "success" group one year after the last biofeedback session revealed that 10 patients had no relapse (83%) and 2 were lost to follow-up.

Conclusions: Biofeedback might be an effective tool for the management of FI resistant to medical treatment in children.
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http://dx.doi.org/10.1016/j.clinre.2020.09.011DOI Listing
May 2021

Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA.

Blood 2021 Apr;137(17):2307-2320

Department of Hematology, University Hospital F. Mitterrand, Dijon, France; and.

Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2-/PET4-) received immunochemotherapy. Responders after only cycle 4 (PET2+/4-) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2-/4- and PET2+/4- had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.
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http://dx.doi.org/10.1182/blood.2020008750DOI Listing
April 2021

Predictors of low exercise cardiac output in patients with severe pulmonic regurgitation.

Heart 2021 02 16;107(3):223-228. Epub 2020 Nov 16.

Unité Médico-Chirurgicale de Cardiologie Congénitale Adulte, Hopital Europeen Georges Pompidou, Paris, Île-de-France, France

Background And Objectives: Chronic pulmonic regurgitation (PR) following repair of congenital heart disease (CHD) impairs right ventricular function that impacts peak exercise cardiac index (pCI). We aimed to estimate in a non-invasive way pCI and peak oxygen consumption (pVO) and to evaluate predictors of low pCI in patients with significant residual pulmonic regurgitation after CHD repair.

Method: We included 82 patients (median age 19 years (range 10-54 years)) with residual pulmonic regurgitation fraction >40%. All underwent cardiac MRI and cardiopulmonary testing with measurement of pCI by thoracic impedancemetry. Low pCI was defined <7 L/min/m.

Results: Low pCI was found in 18/82 patients. Peak indexed stroke volume (pSVi) tended to compensate chronotropic insufficiency only in patients with normal pCI (r=-0.31, p=0.01). Below 20 years of age, only 5/45 patients had low pCI but near-normal (≥6.5 L/min/m). pVO (mL/kg/min) was correlated with pCI (r=0.58, p=0.0002) only in patients aged >20 years. Left ventricular stroke volume in MRI correlated with pSVi only in the group of patients with low pCI (r=0.54, p=0.02). No MRI measurements predicted low pCI. In multivariable analysis, only age predicted a low pCI (OR=1.082, 95% CI 1.035 to 1.131, p=0.001) with continuous increase of risk with age.

Conclusions: In patients with severe PR, pVO is a partial reflection of pCI. Risk of low pCI increases with age. No resting MRI measurement predicts low haemodynamic response to exercise. Probably more suitable to detect ventricular dysfunction, pCI measurement could be an additional parameter to take into account when considering pulmonic valve replacement.
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http://dx.doi.org/10.1136/heartjnl-2020-317550DOI Listing
February 2021

TEDIS, a Comprehensive Data Model for In-Depth Clinical Assessment of Patients Affected with Neuro-Developmental Disorders Including Autism.

Stud Health Technol Inform 2020 Jun;270:1401-1402

Paris Descartes University, Faculty of Medicine, Biostatistics Unit, Necker Hospital, APHP - Paris, France.

TEDIS, an information system dedicated to patients affected with neuro-developmental disorders including autism, focuses on patient data generated during in-depth clinical assessment in nine expert centers in Ile-de-France region. Long term partnership involving methodologists and domain experts is necessary to support quality data production and analyses and to guarantee quality data and information governance in a domain characterized by frequent evolutions in clinical assessment instruments and in diagnostic criteria and classification.
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http://dx.doi.org/10.3233/SHTI200462DOI Listing
June 2020

The Surface Microbiome of Clinically Unaffected Skinfolds in Hidradenitis Suppurativa: A Cross-Sectional Culture-Based and 16S rRNA Gene Amplicon Sequencing Study in 60 Patients.

J Invest Dermatol 2020 09 25;140(9):1847-1855.e6. Epub 2020 Apr 25.

Normandie Univ, UNICAEN, UNIROUEN, CHU de Caen Normandie, Department of Microbiology, Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0, EA 2656), Caen, France. Electronic address:

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin associated with specific lesional dysbiotic features. We studied the microbiome of clinically unaffected typical HS sites (armpits, inguinal folds, and gluteal clefts) in 60 patients with HS and 17 healthy controls. A total of 192 samples obtained by swabbing were analyzed by bacterial cultures. Of these, 116 randomly selected samples were studied by 16S rRNA gene amplicon sequencing. Patients and controls showed similar characteristics, except for smoking (87% vs. 6%, respectively). HS skinfolds were characterized by an increased abundance of anaerobes, predominantly Prevotella, but also Actinomyces, Campylobacter ureolyticus, and Mobiluncus, contrasting with a lower abundance of skin commensals such as Staphylococcus epidermidis, a major component of the skin microbiome; Kocuria; and Micrococcus luteus. The following three independent factors were associated with an abundance of high anaerobes by multivariate analysis: samples originating from patients with HS patients (P = 2.1 × 10); body mass index (P = 5 × 10); and the sampling site, the gluteal cleft being the most anaerobic area, followed by inguinal folds and axilla (P = 3 × 10). The microbiome of clinically unaffected HS skinfolds is reminiscent, albeit to a minor extent, of the microbiome of chronic suppurative HS lesions and may fuel inflammation at a preclinical stage of the disease.
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http://dx.doi.org/10.1016/j.jid.2020.02.046DOI Listing
September 2020

Insights into the variability of nasal potential difference, a biomarker of CFTR activity.

J Cyst Fibros 2020 07 4;19(4):620-626. Epub 2019 Nov 4.

Centre Maladies Rares Mucoviscidose, Hôpital Universitaire Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, Paris, France; Université Paris Sorbonne, Paris, France; Institut Necker-Enfants Malades. INSERM U1151, Paris, France. Electronic address:

Background: Nasal potential difference (NPD) is used to evaluate CFTR function in vivo. We aimed to evaluate the intrasubject and intersubject variability of NPD measurements.

Methods: We reviewed NPD tracings of 116 patients with CF enrolled in the placebo arm of a multicenter study. Patients carried at least one nonsense mutation and underwent repeated NPD tests every 16 weeks. NPD parameters included basal potential difference (basal PD), inhibition of sodium absorption by amiloride (Δ Amiloride), chloride (Cl) transport in response to a Cl-free solution (Δ Low Cl), isoproterenol (Δ Isoproterenol), the sum of Δ Low Cl and Δ Isoproterenol (Δ Low Cl-Isoproterenol) and ATP (Δ ATP).

Results: Basal PD and Δ Amiloride displayed the highest variabilities, mainly stemming from intercenter and intrasubject effect. Δ Low Cl, Δ Isoproterenol and Δ Low Cl-Isoproterenol demonstrated a large intrasubject variability but a smaller intersubject variability. The intrasubject measurement variability for Δ Low Cl-Isoproterenol, was within ± 7.2 mV with 95% probability. It was greater in patients reporting ongoing pulmonary exacerbations.

Conclusions: The large intercenter variability of basal PD and Δ Amiloride highlights the operator-dependent aspect of these measurements. A difference greater than 7.2 mV in Δ Low Cl-Isoproterenol in a given patient on CFTR modulator can be attributed, with 95% probability, to a treatment effect rather than to the variability inherent in the measurement.
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http://dx.doi.org/10.1016/j.jcf.2019.09.015DOI Listing
July 2020

Refining diffuse large B-cell lymphoma subgroups using integrated analysis of molecular profiles.

EBioMedicine 2019 Oct 21;48:58-69. Epub 2019 Oct 21.

Inserm U1245, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France. Electronic address:

Background: Gene expression profiling (GEP), next-generation sequencing (NGS) and copy number variation (CNV) analysis have led to an increasingly detailed characterization of the genomic profiles of DLBCL. The aim of this study was to perform a fully integrated analysis of mutational, genomic, and expression profiles to refine DLBCL subtypes. A comparison of our model with two recently published integrative DLBCL classifiers was carried out, in order to best reflect the current state of genomic subtypes.

Methods: 223 patients with de novo DLBCL from the prospective, multicenter and randomized LNH-03B LYSA clinical trials were included. GEP data was obtained using Affymetrix GeneChip arrays, mutational profiles were established by Lymphopanel NGS targeting 34 key genes, CNV analysis was obtained by array CGH, and FISH and IHC were performed. Unsupervised independent component analysis (ICA) was applied to GEP data and integrated analysis of multi-level molecular data associated with each component (gene signature) was performed.

Findings: ICA identified 38 components reflecting transcriptomic variability across our DLBCL cohort. Many of the components were closely related to well-known DLBCL features such as cell-of-origin, stromal and MYC signatures. A component linked to gain of 19q13 locus, among other genomic alterations, was significantly correlated with poor OS and PFS. Through this integrated analysis, a high degree of heterogeneity was highlighted among previously described DLBCL subtypes.

Interpretation: The results of this integrated analysis enable a global and multi-level view of DLBCL, as well as improve our understanding of DLBCL subgroups.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838437PMC
October 2019

Regional Professionals Network to Support the Renal Epidemiology and Information Registry in Ile-de-France.

Stud Health Technol Inform 2019 Aug;264:1425-1426

Paris Descartes University, Faculty of Medicine, Biostatistics Unit, APHP - Necker Enfants Malades Hospital, Paris, France.

We present the regional professional network to support the Renal Epidemiology Information Network (REIN) registry in maintaining high quality data production and information analyses in Ile-De-France region. The network is based on a long term partnership between the nephrologists and a regional methodology support unit. It integrates clinical research assistants for data quality control. We also present organizational methods on maintaining the registry and enhancing information analyses and automating analyses reports.
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http://dx.doi.org/10.3233/SHTI190466DOI Listing
August 2019

A 1-Year Prospective French Nationwide Study of Emergency Hospital Admissions in Children and Adults with Primary Immunodeficiency.

J Clin Immunol 2019 10 10;39(7):702-712. Epub 2019 Aug 10.

Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France.

Purpose: Patients with primary immunodeficiency (PID) are at risk of serious complications. However, data on the incidence and causes of emergency hospital admissions are scarce. The primary objective of the present study was to describe emergency hospital admissions among patients with PID, with a view to identifying "at-risk" patient profiles.

Methods: We performed a prospective observational 12-month multicenter study in France via the CEREDIH network of regional PID reference centers from November 2010 to October 2011. All patients with PIDs requiring emergency hospital admission were included.

Results: A total of 200 admissions concerned 137 patients (73 adults and 64 children, 53% of whom had antibody deficiencies). Thirty admissions were reported for 16 hematopoietic stem cell transplantation recipients. When considering the 170 admissions of non-transplant patients, 149 (85%) were related to acute infections (respiratory tract infections and gastrointestinal tract infections in 72 (36%) and 34 (17%) of cases, respectively). Seventy-seven percent of the admissions occurred during winter or spring (December to May). The in-hospital mortality rate was 8.8% (12 patients); death was related to a severe infection in 11 cases (8%) and Epstein-Barr virus-induced lymphoma in 1 case. Patients with a central venous catheter (n = 19, 13.9%) were significantly more hospitalized for an infection (94.7%) than for a non-infectious reason (5.3%) (p = 0.04).

Conclusion: Our data showed that the annual incidence of emergency hospital admission among patients with PID is 3.4%. The leading cause of emergency hospital admission was an acute infection, and having a central venous catheter was associated with a significantly greater risk of admission for an infectious episode.
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http://dx.doi.org/10.1007/s10875-019-00658-9DOI Listing
October 2019

Effect of acute and chronic aldosterone exposure on the retinal pigment epithelium-choroid complex in rodents.

Exp Eye Res 2019 10 5;187:107747. Epub 2019 Aug 5.

INSERM, UMRS 1138, Team 17, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, 75006, Paris, France; Department of Ophthalmology, Ophthalmopole, Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, 75014, Paris, France. Electronic address:

Preclinical and clinical evidences show that aldosterone and/or mineralocorticoid receptor (MR) over-activation by glucocorticoids can be deleterious to the retina and to the retinal pigment epithelium (RPE)-choroid complex. However, the exact molecular mechanisms driving these effects remain poorly understood and pathological consequences of chronic exposure of the retina and RPE/choroid to aldosterone have not been completely explored. We aimed to decipher the transcriptomic regulation in the RPE-choroid complex in rats in response to acute intraocular aldosterone injection and to explore the consequences of systemic chronic aldosterone exposure on the morphology and the gene regulation in RPE/choroid in mice. High dose of aldosterone (100 nM) was intravitreously injected in Lewis rat eyes in order to yield an aldosterone dose able to induce a molecular response at the apical side of the RPE-choroid complex. The posterior segment morphology was evaluated in vivo using optical coherence tomography (OCT) before and 24 h after aldosterone injection. Rat RPE-choroid complexes were used for RNA sequencing and analysis. Uninephrectomy/aldosterone/salt (NAS) model was created in wild-type C57BL/6 mice. After 6 weeks, histology of mouse posterior segments were observed ex vivo. Gene expression in the RPE-choroid complex was analyzed using quantitative PCR. Acute intravitreous injection of aldosterone induced posterior segment inflammation observed on OCT. RNA sequencing of rat RPE-choroid complexes revealed up-regulation of pathways involved in inflammation, oxidative stress and RNA procession, and down-regulation of genes involved in synaptic activity, muscle contraction, cytoskeleton, cell junction and transporters. Chronic aldosterone/salt exposure in NAS model induces retinal edema, choroidal vasodilation and RPE cell dysfunction and migration. Quantitative PCR showed deregulation of genes involved in inflammatory response, oxidative stress, particularly the NOX pathway, angiogenesis and cell contractility. Both rodent models share some common phenotypes and molecular regulations in the RPE-choroid complex that could contribute to pachychoroid epitheliopathy in humans. The difference in inflammatory status relies on different intraocular or systemic route of aldosterone administration and on the different doses of aldosterone exposed to the RPE-choroid complex.
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http://dx.doi.org/10.1016/j.exer.2019.107747DOI Listing
October 2019

Mycobacterium bolletii Lung Disease in Cystic Fibrosis.

Chest 2019 08 29;156(2):247-254. Epub 2019 Mar 29.

Centre de Ressources et de Compétences pour la Mucoviscidose, Pneumologie et Allergologie Pédiatriques, Hôpital Necker Enfants Malades, Paris, France. Electronic address:

Background: The cystic fibrosis (CF) pathogen, Mycobacterium abscessus complex, covers three subspecies: M. abscessus, M. massiliense, and M. bolletii. There are no clinical outcome data concerning M. bolletii. Our aim was to characterize M. bolletii lung infections in patients with CF.

Methods: We included patients with M. bolletii lung infection recorded between 1994 and 2012 in France. Data were collected from the CF registry, medical records, and questionnaires submitted to the CF primary physician. Strains were typed by multilocus sequence typing analysis.

Results: Fifteen cases were identified in nine CF centers. Nine patients (60%) presented with nontuberculous mycobacterial pulmonary disease. Follow-up of 13 patients showed a trend to more rapid decline in FEV in the first year of colonization (-9.4%; SD 19.3) in comparison with noninfected control subjects (-2.3%; SD 12.1) (P = .16). Twelve patients were treated, and 11 received oral macrolides. Treatment-induced eradication occurred in five patients (41.7%). Four patients died (26.7%), including one patient with fatal nontuberculous mycobacterial pulmonary disease. Inducible macrolide resistance was demonstrated in all strains. Patients always harbored unique strains.

Conclusions: Our study reports the largest study cohort of CF patients infected with M. bolletii. M. bolletii infection affects both children and young adults, is most often symptomatic, and may be fatal. Macrolide-based therapies have poor effectiveness. There is no evidence of patient-to-patient transmission.
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http://dx.doi.org/10.1016/j.chest.2019.03.019DOI Listing
August 2019

Long-term fatigue in survivors of non-Hodgkin lymphoma: The Lymphoma Study Association SIMONAL cross-sectional study.

Cancer 2019 07 22;125(13):2291-2299. Epub 2019 Mar 22.

French Center on eHealth, North-West Region Data Processing Center and French National League Against Cancer Clinical Research Platform, Caen, France.

Background: Long-term survivors of non-Hodgkin lymphoma (NHL) must cope with treatment complications and late toxicities that affect their health-related quality of life. Little is known about the risk-to-benefit ratio of new agents like rituximab. The impact of treatment regimens and health disorders on long-term fatigue levels was investigated in a cross-sectional study.

Methods: Two self-administered questionnaires, the 20-item Multidimensional Fatigue Inventory (MFI-20) and a Life Situation Questionnaire, were mailed in 2015 to NHL survivors enrolled onto 12 successive clinical studies (1993-2010) conducted by the Lymphoma Study Association. Private addresses were obtained for 3317 survivors, of whom 1671 (50%) returned the questionnaires. Severe fatigue was defined as MFI-20 scores ≥60 on dimension scales scored from 0 to 100. Linear regression models were used to assess factors that were linked to increased fatigue levels.

Results: The study population included 906 men and 765 women, and the median age was 64 years (age range, 24-95 years). Overall, 811 survivors had received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy, 518 had received high-dose CHOP, and 342 had undergone upfront autologous stem cell transplantation; 829 survivors also had received rituximab. In total, 1100 survivors (66%) reported 1 or more late health disorders. Severe fatigue was reported by 602 survivors (37%). Increased fatigue levels were associated (P < .001) with increased age, obesity, and the presence of health disorders, but not with initial treatment or rituximab.

Conclusions: The survey confirms that high proportions long-term NHL survivors have severe fatigue. The results suggest that initial treatment and the receipt of rituximab have no influence on the development of long-term fatigue.
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http://dx.doi.org/10.1002/cncr.32040DOI Listing
July 2019

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

BJU Int 2019 11 25;124(5):849-861. Epub 2019 Mar 25.

Department of Urology, Strasbourg University Hospital, Strasbourg University, Strasbourg, France.

Objective: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.

Patients And Methods: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.

Results: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001).

Conclusion: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.
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http://dx.doi.org/10.1111/bju.14721DOI Listing
November 2019

Idiopathic, heritable and veno-occlusive pulmonary arterial hypertension in childhood: computed tomography angiography features in the initial assessment of the disease.

Pediatr Radiol 2019 05 16;49(5):575-585. Epub 2019 Jan 16.

M3C-Necker, Congenital and Pediatric Cardiology, Hôpital Universitaire Necker-Enfants malades, Paris, France.

Background: In children, idiopathic and heritable pulmonary arterial hypertension present echocardiographic and heart catheterization findings similar to findings in pulmonary veno-occlusive disease.

Objective: To provide a systematic analysis of CT angiography anomalies in children with idiopathic or heritable pulmonary arterial hypertension, or pulmonary veno-occlusive disease. We also sought to identify correlations between CT findings and patients' baseline characteristics.

Materials And Methods: We retrospectively analyzed CT features of children with idiopathic and heritable pulmonary arterial hypertension or pulmonary veno-occlusive disease and 30 age-matched controls between 2008 and 2014. We compared CT findings and patient characteristics, including gene mutation type, and disease outcome until 2017.

Results: The pulmonary arterial hypertension group included idiopathic (n=15) and heritable pulmonary arterial hypertension (n=11) and pulmonary veno-occlusive disease (n=4). Median age was 6.5 years. Children with pulmonary arterial hypertension showed enlargement of pulmonary artery and right cardiac chambers. A threshold for the ratio between the pulmonary artery and the ascending aorta of ≥1.2 had a sensitivity of 90% and a specificity of 100% for pulmonary arterial hypertension. All children with pulmonary veno-occlusive disease had thickened interlobular septa, centrilobular ground-glass opacities, and lymphadenopathy. In children with idiopathic and heritable pulmonary arterial hypertension, presence of intrapulmonary neovessels and enlargement of the right atrium were correlated with higher mean pulmonary artery pressure (P=0.011) and pulmonary vascular resistance (P=0.038), respectively. Mediastinal lymphadenopathy was associated with disease worsening within the first 2 years of follow-up (P=0.024).

Conclusion: CT angiography could contribute to early diagnosis and prediction of severity in children with pulmonary arterial hypertension.
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http://dx.doi.org/10.1007/s00247-018-04331-yDOI Listing
May 2019

Genetic diagnosis of primary immunodeficiencies: A survey of the French national registry.

J Allergy Clin Immunol 2019 04 9;143(4):1646-1649.e10. Epub 2019 Jan 9.

French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Pediatric Immuno-Haematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Imagine Institute, INSERM UMR 1163, Paris, France; Collège de France, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.12.994DOI Listing
April 2019

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial.

JAMA 2018 08;320(6):557-565

Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France.

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated.

Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.

Design, Setting, And Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.

Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.

Main Outcomes And Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.

Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).

Conclusions And Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.

Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.
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http://dx.doi.org/10.1001/jama.2018.9396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583003PMC
August 2018

The impact of three discharge coding methods on the accuracy of diagnostic coding and hospital reimbursement for inpatient medical care.

Int J Med Inform 2018 07 27;115:35-42. Epub 2018 Mar 27.

Wessex Institute of Health & Research, Faculty of Medicine, University of Southampton, SO16 7NS, United Kingdom. Electronic address:

Background: Coding of diagnoses is important for patient care, hospital management and research. However coding accuracy is often poor and may reflect methods of coding. This study investigates the impact of three alternative coding methods on the inaccuracy of diagnosis codes and hospital reimbursement.

Methods: Comparisons of coding inaccuracy were made between a list of coded diagnoses obtained by a coder using (i)the discharge summary alone, (ii)case notes and discharge summary, and (iii)discharge summary with the addition of medical input. For each method, inaccuracy was determined for the primary, secondary diagnoses, Healthcare Resource Group (HRG) and estimated hospital reimbursement. These data were then compared with a gold standard derived by a consultant and coder.

Results: 107 consecutive patient discharges were analysed. Inaccuracy of diagnosis codes was highest when a coder used the discharge summary alone, and decreased significantly when the coder used the case notes (70% vs 58% respectively, p < 0.0001) or coded from the discharge summary with medical support (70% vs 60% respectively, p < 0.0001). When compared with the gold standard, the percentage of incorrect HRGs was 42% for discharge summary alone, 31% for coding with case notes, and 35% for coding with medical support. The three coding methods resulted in an annual estimated loss of hospital remuneration of between £1.8 M and £16.5 M.

Conclusion: The accuracy of diagnosis codes and percentage of correct HRGs improved when coders used either case notes or medical support in addition to the discharge summary. Further emphasis needs to be placed on improving the standard of information recorded in discharge summaries.
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http://dx.doi.org/10.1016/j.ijmedinf.2018.03.015DOI Listing
July 2018

Categorical state sequence analysis and regression tree to identify determinants of care trajectory in chronic disease: Example of end-stage renal disease.

Stat Methods Med Res 2019 06 9;28(6):1731-1740. Epub 2018 May 9.

1 Univ Rennes, EHESP, REPERES (Recherche en Pharmaco-épidémiologie et Recours aux Soins) - EA 7449, Rennes, France.

Background: Patients with chronic diseases, like patients with end-stage renal disease (ESRD), have long history of care driven by multiple determinants (medical, social, economic, etc.). Although in most epidemiological studies, analyses of health care determinants are computed on single health care events using classical multivariate statistical regression methods. Only few studies have integrated the concept of treatment trajectories as a whole and studied their determinants.

Methods: All 18- to 80-year-old incident ESRD patients who started dialysis in Ile-de-France or Bretagne between 2006 and 2009 and could be followed for a period of 48 months after initiation of a renal replacement therapy were included ( = 5568). Their care trajectories were defined as categorical state sequences. Associations between patients' characteristics and care trajectories were assessed using a regression tree model together with a discrepancy analysis.

Results: On average, each patient experienced 1.56 different renal replacement therapies (min = 1; max = 5) during the 48 months of follow-up. About 55% of patients never changed treatment and only 1% tried three or more renal replacement therapy modalities. Twelve homogeneous care trajectory groups were identified. Covariates explained 12% of the discrepancy between groups, particularly age, regions and initiation of hemodialysis with a catheter.

Conclusions: Regression tree analysis of categorical state sequence highlighted geographical disparities in the care trajectory of French patients with ESRD that cannot be observed when focusing on a single outcome, such as survival. This method is an original tool to visualize and characterize care trajectories, notably in the context of chronic condition like ESRD.
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http://dx.doi.org/10.1177/0962280218774811DOI Listing
June 2019

Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials.

J Clin Oncol 2018 06 19;36(16):1603-1610. Epub 2018 Apr 19.

Matthew J. Maurer, Thomas M. Habermann, Carrie A. Thompson, Cristine Allmer, Patrick B. Johnston, Ivana N. Micallef, David J. Inwards, William R. Macon, Andrew L. Feldman, Susan L. Slager, Stephen M. Ansell, James R. Cerhan, Thomas E. Witzig, and Grzegorz S. Nowakowski, Mayo Clinic, Rochester, MN; Hervé Ghesquières and Gilles A. Salles, Université Claude Bernard, Lyon; Jean-Philippe Jais, Richard Delarue, Thierry J. Molina, Hopital Necker, Paris; Corinne Haioun, Groupe Hospitalier Mondor, Créteil; Frederic Peyrade, Centre Antoine Lacassagne, Nice; Olivier Fitoussi, Polyclinique Bordeaux Nord-Aquitaine, Bordeaux; Hervé Tilly, Centre de lutte Contre le Cancer Henri Becquerel, Rouen, France; Brian K. Link, Umar Farooq, Sergei Syrbu, and George J. Weiner, University of Iowa, Iowa City, IA; and Nicolas Ketterer, Clinique Bois-Cerf, Lausanne, Switzerland.

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.
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http://dx.doi.org/10.1200/JCO.2017.76.5198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978469PMC
June 2018

Total metabolic tumor volume, circulating tumor cells, cell-free DNA: distinct prognostic value in follicular lymphoma.

Blood Adv 2018 04;2(7):807-816

Paris-Est Créteil University, Créteil, France.

Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline F-fluorodeoxyglucose-positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs ( < .0001) and cfDNA ( < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm ( = .0004), CTCs >0.0018 PB cells ( = .03), or cfDNA >2550 equivalent-genome/mL ( = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.
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http://dx.doi.org/10.1182/bloodadvances.2017015164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894260PMC
April 2018

Interim PET Response-adapted Strategy in Untreated Advanced Stage Hodgkin Lymphoma: Results of GOELAMS LH 2007 Phase 2 Multicentric Trial.

Clin Lymphoma Myeloma Leuk 2018 03 31;18(3):191-198. Epub 2018 Jan 31.

Hematology Department, Grenoble University Hospital, Grenoble, France.

Background: Patients with advanced stage Hodgkin lymphoma still present unsatisfactory outcomes.

Patients And Methods: The Groupe d'étude des Leucémies Aigues et des Maladies du Sang (GOELAMS) group conducted a prospective multicentric trial (NCT00920153) for advanced stage Hodgkin lymphoma to evaluate a positron emission tomography (PET)-adapted strategy. Patients received an intensive regimen (VABEM [vindesine, doxorubicin, carmustine, etoposide, and methylprednisolone]) in front-line and interim FDG-PET evaluation after 2 courses (PET-2). Patients with negative PET-2 findings received 1 additional course. Patients with positive PET-2 findings underwent early salvage therapy followed by high-dose therapy/autologous stem cell transplantation.

Results: Fifty-one patients were included. The final complete remission rate was 88%. With a median follow up of 5.3 years, 5-year event-free survival and overall survival rates were 75.3% and 85.3%, respectively, for the whole cohort. Patients who were PET-2-negative had 5-year event-free survival and overall survival rates of, respectively, 77.8% and 88.2% versus 85.1% and 91.7% for patients who were PET-2-positive.

Conclusion: A PET-guided strategy with early salvage therapy and high-dose therapy/autologous stem cell transplantation for patients with interim PET-2-positive findings is safe and feasible and provide similar outcome as patients with a negative PET-2.
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http://dx.doi.org/10.1016/j.clml.2018.01.003DOI Listing
March 2018

Authors' Reply.

J Mol Diagn 2018 03;20(2):266

INSERM U1245 Team 03, Centre Henri Becquerel, Rouen; Department of Biological Hematology, Rouen University Hospital, Rouen.

Authors' Reply to the Letter to the Editor by Y. Lynn Wang (MYD88 mutations and sensitivity to ibrutinib therapy).
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http://dx.doi.org/10.1016/j.jmoldx.2017.12.001DOI Listing
March 2018

A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts.

Lancet Oncol 2018 04 20;19(4):549-561. Epub 2018 Feb 20.

Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Lyon, France; Service d'Hématologie Clinique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France. Electronic address:

Background: Patients with follicular lymphoma have heterogeneous outcomes. Predictor models to distinguish, at diagnosis, between patients at high and low risk of progression are needed. The objective of this study was to use gene-expression profiling data to build and validate a predictive model of outcome for patients treated in the rituximab era.

Methods: A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0-7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab-tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts.

Findings: In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0·0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3·68, 95% CI 2·19-6·17 [p<0·0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2·57 [95% CI 1·65-4·01] in cohort 1; 2·12 [1·32-3·39] in cohort 2; and 2·11 [1·01-4·41] in cohort 3). In the combined validation cohort, the median progression-free survival was 3·1 years (95% CI 2·4-4·8) in the high-risk group and 10·8 years (10·1-not reached) in the low-risk group (p<0·0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15-24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2·30, 95% CI 1·72-3·07).

Interpretation: We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category.

Funding: Roche, SIRIC Lyric, LYSARC, National Institutes of Health, the Henry J Predolin Foundation, and the Spanish Plan Nacional de Investigacion.
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http://dx.doi.org/10.1016/S1470-2045(18)30102-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882539PMC
April 2018

Cardiac function and exercise adaptation in 8 children with LPIN1 mutations.

Mol Genet Metab 2018 03 5;123(3):375-381. Epub 2018 Jan 5.

Reference Centre of Inherited Metabolic Diseases, Hospital Necker Enfants Malades, APHP, Institute Imagine, University Paris Descartes, Paris, France.

Introduction: Lipin-1 deficiency is a major cause of rhabdomyolysis that are precipitated by febrile illness. The prognosis is poor, with one-third of patients dying from cardiac arrest during a crisis episode. Apart from acute rhabdomyolysis, most patients are healthy, showing normal clinical and cardiac ultrasound parameters.

Patients And Methods: We report cardiac and exercise examinations of 8 children carrying two LPIN1 mutations. The examinations were performed outside of a myolysis episode, but one patient presented with fever during one examination.

Results: All but one patient displayed normal resting cardiac function, as determined by echocardiography. One patient exhibited slight left ventricular dysfunction at rest and a lack of increased stroke volume during cycle ramp exercise. During exercise, peripheral muscle adaptation was impaired in 2 patients compared to healthy controls: they presented an abnormal increase in cardiac output relative to oxygen uptake: dQ/dVO=8.2 and 9.5 (>2DS of controls population). One patient underwent 2 exercise tests; during one test, the patient was febrile, leading to acute rhabdomyolysis in the following hours. He exhibited changes in recovery muscle reoxygenation parameters and an increased dQ/dVO during exercise compared with that under normothermia (7.9 vs 6), which did not lead to acute rhabdomyolysis. The four patients assessed by cardiac H-magnetic resonance spectroscopy exhibited signs of intracardiac steatosis.

Conclusion: We observed abnormal haemodynamic profiles during exercise in 3/8 patients with lipin-1 deficiency, suggesting impaired muscle oxidative phosphorylation during exercise. Fever appeared to be an aggravating factor. One patient exhibited moderate cardiac dysfunction, which was possibly related to intracardiac stored lipid toxicity.
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http://dx.doi.org/10.1016/j.ymgme.2017.12.429DOI Listing
March 2018
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