Summary
The long‐term consequences of pre‐eclampsia (PrE) for renal function have never been determined in patients with sickle cell disease (SCD). Between 2008 and 2015, we screened 306 pregnancies ...in women with SCD and identified 40 with PrE (13%). The control group consisted of 65 pregnant SCD patients without PrE. In multivariable analysis, PrE events were associated with an increase of 1 log of lactate dehydrogenase level (adjusted odds ratio, aOR = 3·83, P = 0·05), a decrease of 10 g/l of haemoglobin levels (aOR = 2·48, P = 0·006) and one or more vaso‐occlusive crisis during pregnancy (aOR = 16·68, P = 0·002). Estimated glomerular filtration rate (eGFR) was similar in the two groups at steady state but was significantly lower in the PrE group after one year of follow‐up and at last follow‐up (130 vs 148 ml/min/1·73 m2, P < 0·001 and 120 vs 130 ml/min/1·73 m2, P < 0·001, respectively). In multivariable analysis, eGFR had returned to steady‐state levels one year after pregnancy in patients without PrE but continued to decrease in patients with PrE (β = −18·15 ml/min/1·73 m2, P < 0·001). This decline was more marked at the end of follow‐up (β = −31·15 ml/min, P < 0·001). In conclusion, PrE episodes are associated with a significant risk of subsequent renal function decline in SCD patients.
Herein, we develop a novel and straightforward access to cyclic conjugated enynes catalyzed by silver carbonate/DBU from readily available substrates with good yields. The reaction is easy to set up, ...broad in scope, and can also be conducted in a one-pot fashion from easily accessible substrates through a sequence Michael addition reaction/cyclization. Based on our previous works, the mechanism proposed would involve an allenyl silver intermediate and decarboxylation reaction.
Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide ...therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.
At the sites of Monruz and Champréveyres highly diverse allochtonous siliceous raw materials were introduced sometimes from very distant regions (up to 200 km). Analysis of the composition of the ...lithic assemblages enables us to identify the form in which these materials arrived and to observe that some cores and tools were exported from the site. Other materials, such as jet, fossil shells and amber, are geolocatable and also demonstrate circulations over very long distances (over 200 km). While the flints suggest regions that were directly frequented by Magdalenian people and/or exchanges between human groups, the other materials were most likely obtained through exchanges of objects and/or persons. They attest to contacts beyond the territory directly occupied by the groups living at Monruz and Champréveyres.
Gene inactivation of the orphan G protein‐coupled receptor LGR4, a paralogue of the epithelial‐stem‐cell marker LGR5, results in a 50% decrease in epithelial cell proliferation and an 80% reduction ...in terminal differentiation of Paneth cells in postnatal mouse intestinal crypts. When cultured ex vivo, LGR4‐deficient crypts or progenitors, but not LGR5‐deficient progenitors, die rapidly with marked downregulation of stem‐cell markers and Wnt target genes, including Lgr5. Partial rescue of this phenotype is achieved by addition of LiCl to the culture medium, but not Wnt agonists. Our results identify LGR4 as a permissive factor in the Wnt pathway in the intestine and, as such, as a potential target for intestinal cancer therapy.
Lgr4, a paralogue of Lgr5, is also expressed in intestinal crypts. Crypts from Lgr4 hypomorphic mice display signs of defective Wnt signalling: reduced cell proliferation and defective terminal differentiation of Paneth cells in vivo. When cultured ex vivo, the crypts show downregulation of stem cell markers, including Lgr5, and die rapidly.
Anti-synthetase syndrome (anti-SS) is frequently associated with myositis and interstitial lung disease (ILD). We evaluated prospectively, in a multicenter, open-label, phase II study, the efficacy ...of rituximab on muscle and lung outcomes.
Patients were enrolled if they were refractory to conventional treatments (prednisone and at least 2 immunosuppressants). They received 1 g of rituximab at D0, D15, and M6. The primary endpoint was muscular improvement based on manual muscular testing (MMT10, Kendall score in 10 muscles) at M12. Secondary endpoints were normalization of creatine kinase (CK) level, ILD improvement based on forced vital capacity and/or diffuse capacity for carbon monoxide, and number and/or doses of associated immunosuppressants.
Twelve patients were enrolled, and 10 completed the study. Only 2 patients presented an improvement of at least 4 points on at least two muscle groups (primary end-point). Overall, seven patients had an increase of at least 4 points on MMT10. CK level decreased from 399 IU/L (range, 48-11,718) to 74.5 IU/L (range, 40-47,857). Corticosteroid doses decreased from 52.5 mg/d (range, 10-70) to 9 mg/d (range, 7-65) and six patients had a decrease in the burden of their associated immunosuppressants. At baseline, all 10 patients presented with ILD. At M12, improvement of ILD was observed in 5 out of the 10 patients, stabilization in 4, and worsening in 1.
This pilot study of rituximab treatment in patients with refractory anti-SS provided data on evolution of muscular and pulmonary parameters. Rituximab should now be evaluated in a larger, controlled study for this homogenous group of patients.
Clinicaltrials.gov NCT00774462.
BACKGROUND
Blood donation deferral for men who have sex with men (MSM) in France was reduced from permanent to 12 months in July 2016. To inform a further reduction of the deferral period, an HIV ...risk assessment was conducted with two scenarios: S1, 4‐month deferral; S2, 4‐month deferral only in the case of more than one sexual partner (i.e., similar to other blood donors).
METHODS
Baseline HIV residual risk (RR) was calculated from July 2016 to December 2017, using the Incidence Rate–Window Period method. The impact of both scenarios on RR was assessed using data from surveys on MSM and blood donors, to estimate 1) the number of additional MSM expected to donate in each scenario and 2) HIV incidence among these donors.
RESULTS
Baseline HIV RR was estimated at 1 in 6,380,000 donations. For S1, an additional 733 MSM donors, and an additional 0.09 HIV‐positive donations were estimated, yielding an unchanged RR of 1 in 6,300,000. For S2, these numbers were estimated at 3102 and 3.92, respectively, yielding an RR of 1 in 4,300,000. Sensitivity analyses showed that, under worst‐case assumptions, the RR would equal 1 in 6,225,000 donations for S1 and 1 in 3,000,000 for S2.
CONCLUSION
For both scenarios, the HIV RR remains very low. For S1, the risk is identical to the baseline RR. For S2, it is 1.5 times higher, and sensitivity analysis shows that this estimate is less robust than for S1. The French Minister of Health announced that S1 will be implemented in April 2020.
See editorial on page 437–440, in this issue
Decisions on market authorization (MA) and reimbursement have different durations across countries because of health technology assessment (HTA) procedures and negotiations between manufacturers and ...national authorities. To overcome this delay, France has implemented a Temporary Authorization for Use (ATU) program that allows early access to drugs before MA, in order to treat patients with unmet medical needs. The objectives of our study were to establish the added therapeutic benefit (ATB) of ATUs for solid tumors and to investigate the correlations between three tools evaluating ATB and survival outcomes and drug costs. Data on ATUs granted from January 2009 to December 2019 to treat solid tumors were analyzed. An assessment of their ATB was conducted using the American Society of Clinical Oncology‐Value Framework (ASCO‐VF), the European Society for Medical Oncology‐Magnitude Clinical Benefit Scale (ESMO‐MCBS) and the French HTA criterion, clinical added value (CAV). The latter score determines reimbursement and national market access. Thirty‐five drugs in 39 indications were granted ATUs. All of them obtained MA and derived a clinical benefit to be reimbursed by the Social Security. Twenty‐eight (71.8%) had CAV compared to preexisting therapies. 24/38 (63.2%) had a 4‐5 ESMO‐MCBS score and 19/33 (57.6%) had an ASCO‐VF score over 45. No correlations were found between cost, PFS, OS, CAV and ASCO‐VF score, while high ESMO‐MCBS scores were correlated to OS. In conclusion, many patients were treated with innovations before MA thanks to ATU, although there are discrepancies between ATB scales, hence the importance of international collaboration in the evaluation of innovative therapies.
What's new?
In 1994, France implemented a Temporary Authorization for Use (ATU) program for early drug access before marketing authorization. Since its inception, the program has enabled thousands of cancer patients to be treated with innovative therapies. In our study, ATUs granted for the treatment of solid tumors over the period 2009‐2019 were assessed for added therapeutic benefit (ATB). Of the 39 indications granted ATUs, all obtained marketing authorization and reimbursement. The majority had significant ATB. Analyses further indicate that ATB evaluation tools differ markedly. Thus, while the ATU program is successful, challenges remain for international harmonization of measurements in clinical benefit.
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