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Viral infections can promote cytokine storm and multiorgan failure in individuals with an underlying immunosuppression or specific genetic background. Hyperinflammatory states, including critical forms of COVID-19, are characterized by a remodeling of the lipid profile including a dramatic decrease of the serum levels of apolipoprotein-A-I (ApoA-I), a protein known for its capacity to reduce systemic and lung inflammation, modulate innate and adaptive immunity, and prevent endothelial dysfunction and blood coagulation. In this study, four immunocompromised patients with severe COVID-19 cytokine storm that progressed despite standard-of-care therapy [Omicron ( n = 3) and Delta ( n = 1) variants] received 2- 4 infusions (10 mg/kg) of CER-001, an ApoA-I-containing HDL mimetic. Injections were well-tolerated with no serious adverse events. Three patients treated while not on mechanical ventilation had early clinical and biological improvement (oxygen withdrawal and correction of hematological and inflammatory parameters, including serum levels of interleukin-8) and were discharged from the hospital 3-4 days after CER-001 infusions. In the fourth patient who received CER-001 after orotracheal intubation for acute respiratory distress syndrome, infusions were followed by transient respiratory improvement before secondary worsening related to ventilation-associated pneumonia. This pilot uncontrolled exploratory compassionate study provides initial safety and proof-of-concept data from patients with a COVID-19 cytokine storm receiving ApoA-I. Further randomized controlled trial evaluation is now required to ascertain whether ApoA-I has any beneficial effects on patients with a COVID-19 cytokine storm., Competing Interests: SF has received personal consulting fees from Abionyx Pharma for the development of CER-001 in LCAT deficiency related-glomerulopathy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Faguer, Del Bello, Danet, Renaudineau, Izopet and Kamar.)

Background: Preventive strategies for invasive aspergillosis (IA) have still not been determined in heart transplant recipients whereas IA leads to a high mortality rate at 12 months posttransplantation. The use of voriconazole or echinocandins was proposed but can favor emergence of Aspergillus or Candida sp. resistant strains or promote neurological and liver disorders in some patients., Objectives: To assess whether universal prophylaxis with weekly high-dose of liposomal amphotericin-B (L-AmB) can safely prevent IA in heart transplant recipients., Patients/methods: Retrospective before/after study that included 142 patients who received heart transplantation between 2010 and 2019 at the University Hospital of Toulouse (France). Weekly high dose of L-AmB (7.5 mg/kg/week) was used as universal prophylaxis from 2016 because of high environmental exposure to Aspergillus sp. and high incidence of IA., Results: Cumulative 1-year incidence of IA decreased from 23% to 5% after introduction of L-Amb prophylaxis. Multivariate analysis (Cox model) identified L-AmB prophylaxis as a protective factor against IA (hazard ratio [HR] 0.21 [95% confidence interval 0; 0.92], p = .04), whereas postoperative renal replacement therapy was associated with IA (HR 3.6 [95% confidence interval 1.38; 9.3], p = .001), after correction for confounding effects (induction regimen, methylprednisolone pulses and history of hematological malignancy). The incidence of acute kidney injury requiring renal replacement therapy was similar in the two groups, suggesting a low risk of kidney toxicity when L-AmB is used weekly. No patient developed severe kidney electrolyte loss nor L-AmB-related anaphylaxis., Conclusions: Once-weekly high-dose L-AmB is safe and may prevent the development of IA after heart transplantation., (© 2021 Wiley Periodicals LLC.)

Oncogenesis is considered to result from chromosomal instability, in addition to oncogene and tumor-suppressor alterations. Intermediate to aneuploidy and chromosomal instability, genome doubling is a frequent event in tumor development but the mechanisms driving tetraploidization and its impact remain unexplored. Cell fusion, one of the pathways to tetraploidy, is a physiological process involved in mesenchymal cell differentiation. Besides simple genome doubling, cell fusion results in the merging of two different genomes that can be destabilized upon proliferation. By testing whether cell fusion is involved in mesenchymal oncogenesis, we provide evidence that it induces genomic instability and mediates tumor initiation. After a latency period, the tumor emerges with the cells most suited for its development. Furthermore, hybrid tumor genomes were stabilized after this selection process and were very close to those of human pleomorphic mesenchymal tumors. Thus genome restructuring triggered by cell fusion may account for the chromosomal instability involved in oncogenesis.

Purpose: There is little data on the effects of cancer chemotherapy in pregnant women. The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database., Methods: We performed a descriptive, prospective study of the pregnancies of women exposed to cancer chemotherapy recorded in Terappel between June 1984 and December 2016. Terappel is a French database that has recorded questions of health professionals and/or individuals at the Regional Pharmacovigilance Centres about drugs and pregnancy. For each question, pregnancies are monitored and the outcome is recorded in the database., Results: In total, 75 questions about "anti-cancer drugs and pregnancy" received by 16 Regional Pharmacovigilance Centres between 1997 and 2016 were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%) (two cases of twins), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). We found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies., Conclusion: Pregnancy of women taking anti-cancer drugs resulted in birth in 73% of cases. Nevertheless, pregnant women exposed to cancer chemotherapy remains at risk of malformations and neonatal conditions related to prematurity and drugs., (© 2018 John Wiley & Sons, Ltd.)

Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%-80% of patients. However, some important challenges remain in diagnosing high-risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four-gene signature: hydroxysteroid 17-beta dehydrogenase 6, integrin alpha 6, topoisomerase 2-alpha, and vimentin, with topoisomerase 2-alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT-PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway-associated double-strand DNA repair, and significantly impedes HB growth in vivo., Conclusion: The highly proliferating C2A subtype is characterized by topoisomerase 2-alpha gene up-regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89-102)., (© 2017 by the American Association for the Study of Liver Diseases.)

Aim: To evaluate the relationship between the state of transplanted liver graft and the recipient quality of life (QOL) of histologically proven lesions in a 10-year post liver transplantation (LT) cohort of patients., Methods: Seventy-two recipients with a functional first graft at 10 years post-LT underwent liver biopsy and completed a QOL questionnaire. Logistic regression analysis was used to explore associations between histological, clinical and QOL criteria., Results: Ten years after LT, fibrosis was detected in 53% of patients, and affected the general health perception, while ductopenia, present in 36%, affected the well-being ( P = 0.05). Hepatic steatosis (HS) was present in 33% of patients and was associated with the worst QOL score on multiple domains. When compared to patients without HS, patients with HS had significantly higher incidence of fibrosis ( P = 0.03), hepatitis C virus (HCV) infection ( P = 0.007), and more patients had retired from their job ( P = 0.03). Recurrent or de novo HCV-associated fibrosis and patient retirement as objective variables, and abdominal pain or discomfort and joint aches or pains as subjective variables, emerged as independent determinants of HS., Conclusion: Long-term liver graft lesions, mainly HS presumably as a surrogate marker of HCV infection, may have a substantial impact on QOL 10 years after LT., Competing Interests: Conflict-of-interest statement: The authors who have taken part in this study declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

In the case of a liver transplant, the patient undergoes a particular space-time experience. From the announcement of the diagnosis and the prospect of death in the absence of a transplant, until the moment of the procedure, the nurse-coordinator supports the patient who will experience successive times of waiting, hope, fear and survival.

Objectives: To assess acceptance and acceptable estimated mortality levels for right lobe adult-to-adult living related liver transplantation for the medical and allied professions., Methods: A paper questionnaire was sent to the physicians practicing with the French Graft Agency (Etablissement Français des Greffes) and to all nurses and ancillary staff of the Paul Brousse Hospital Hepatobiliary Center. Responses were received from surgeons: 38/73; internists specialized in hepatology: 44/120; nurses: 98/100; health care assistants: 45/86; others: 17/20., Results: Acceptance of living donor transplantation is above average for all professional categories and indications may be extended including patients with cancer. Acceptable mortality for the donor was 4%, except among internists (0.7%). Currently, the real risk of mortality for the donor (1%) is lower. Acceptable mortality for the recipient was between 15 and 20%., Conclusions: Acceptance of adult living donor liver transplantation among health care professionals is clearly above average. Thus the psychological involvement of transplantation teams, which is very strong in such situations, should not hamper the development of this type of transplantation.

Background: The yearly increasing survival rates testify to the success of transplantation, but questions remain relating to the quality of life (QOL) associated with long-term survival., Methods: A sample of 126 liver recipients (Liver-R), 229 kidney recipients (Kidney-R), and 113 heart recipients (Heart-R) with more than 10 years posttransplant follow-up were included in the study with a response rate of 86%. Respondents were matched with healthy subjects recruited from general population (GP). The three groups of recipients and GP subjects completed a French version of the questionnaire used by the National Institute of Diabetes and Digestive and Kidney Disease, Pittsburgh, PA, and were compared for each score, with adjustments for age and sex., Results: Personal function and measures of disease by the transplant recipients were significantly worse than in the GP (P<0.0001), with the worst score in Kidney-R. No difference, either between organs or between organs and GP, was found regarding the perceived social and role function. However, for psychologic status and general health perception, Kidney-R had the least favorable performance when compared with GP (P<0.01) and also when compared with Liver-R (P<0.05). With the exception of Kidney-R, the well-being index of Liver-R and Heart-R was significantly better than the GP (P<0.001 and P<0.05, respectively)., Conclusions: The QOL beyond 10 years after liver, heart, and kidney transplantation is quite similar to the GP, with Kidney-R starting out as the worst, Heart-R as intermediate, and Liver-R the best.

We assessed the impact of liver transplantation (LT) on the quality of life (QOL) of French recipients 1 year after surgery. A French version of the questionnaire used by the National Institute of Diabetes and Digestive and Kidney Disease-Pittsburg, USA (NIDDK), was validated by the back-translation method. Five QOL domains were evaluated: measures of disease, psychological distress, personal function, social function, and general health perception. Patients enrolled onto the waiting list completed the questionnaire before and 1 year after LT. Respondents were age- and gender-matched with healthy subjects recruited from the general population (GP). One year after LT, the analysis of data from 67 consecutive patients showed dramatic improvement in the five domains. Compared with baseline, patients noted fewer disease-related symptoms (P <.0001) and lower level of distress overall (P <.001). However, levels of distress caused by excess appetite (P <.01), trembling (P <.05), and headaches (P =.06) were more likely to increase than decrease. Twenty-five percent of patients prevented by their disease from going to work before LT were no longer so limited at 1-year follow-up. General health perception improved remarkably, with seven times as many recipients reporting improved health as reporting worse health. A correlation was found between the pretransplantation severity of cirrhosis and the social and role function after LT (P <.05). In summary, the French version of the NIDDK questionnaire seems to be reliable. The results of transplant recipients were generally close to those of the general population. Although it is not a true return to normal status, it approaches it.