Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer ...has not been assessed.
In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus.
Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups.
Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).
The
Module Learning With Errors
(
M-LWE
) problem is a core computational assumption of lattice-based cryptography which offers an interesting trade-off between guaranteed security and concrete ...efficiency. The problem is parameterized by a
secret
distribution as well as an
error
distribution. There is a gap between the choices of those distributions for theoretical hardness results (standard formulation of
M-LWE
, i.e., uniform secret modulo
q
and Gaussian error) and practical schemes (small bounded secret and error). In this work, we make progress toward narrowing this gap. More precisely, we prove that
M-LWE
with uniform
η
-bounded secret for any
1
≤
η
≪
q
and Gaussian error, in both its search and decision variants, is at least as hard as the standard formulation of
M-LWE
, provided that the module rank
d
is at least logarithmic in the ring degree
n
. We also prove that the search version of
M-LWE
with large uniform secret and uniform
η
-bounded error is at least as hard as the standard
M-LWE
problem, if the number of samples
m
is close to the module rank
d
and with further restrictions on
η
. The latter result can be extended to provide the hardness of search
M-LWE
with uniform
η
-bounded secret
and
error under specific parameter conditions. Overall, the results apply to all cyclotomic fields, but most of the intermediate results are proven in more general number fields.
The Rényi divergence is a measure of closeness of two probability distributions. We show that it can often be used as an alternative to the statistical distance in security proofs for lattice-based ...cryptography. Using the Rényi divergence is particularly suited for security proofs of primitives in which the attacker is required to solve a search problem (e.g., forging a signature). We show that it may also be used in the case of distinguishing problems (e.g., semantic security of encryption schemes), when they enjoy a public sampleability property. The techniques lead to security proofs for schemes with smaller parameters, and sometimes to simpler security proofs than the existing ones.
Summary Background Open-heart surgery can result in adhesions, which can complicate resternotomy. Aims To document the occurrence of adhesions after the use of a new collagen membrane; to evaluate ...its tolerability; and to compare surgical parameters with control patients. Methods Paediatric patients who underwent cardiac surgery with the collagen membrane (Cova™ CARD; Biom’up, Saint Priest, France) were analysed retrospectively for levels of adhesion and tolerability. The times of dissection and intervention and the transfusion of packed red blood cells and haemostatic products were compared to a historic cohort who did not receive an anti-adhesion device. Results From January 2010 to December 2011, 36 patients received a collagen membrane. Nineteen re-interventions were performed, after a mean of 169 days. No grade 3 adhesions were observed and no tolerability problems were reported. During re-interventions after more than 30 days, the propensity score-adjusted durations of dissection and the total process for patients with and without a collagen membrane were 32 vs 41 minutes and 151 vs 182 minutes, respectively (not significant). The mean quantities of red blood cells and biological glue administered in the two groups were 98 vs 139 mL and 1.2 vs 0.5 mL, respectively (not significant). Conclusions This feasibility study shows the potential use of the new membrane in paediatric patients, both in terms of prevention from severe adherence and tolerability. This is the first study of this membrane in humans. A prospective, controlled study is necessary to provide strong evidence of its efficiency.
High-resolution manometry (HRM) might be superior to conventional manometry (CM) to diagnose esophageal motility disorders. We aimed to compare the diagnosis performed with HRM and CM and confirmed ...at 6 months in a multicenter randomized trial.
Patients with unexplained dysphagia were randomized to undergo either CM or HRM. Motility disorders were diagnosed using the Castell and Spechler classification for CM and the Chicago classification for HRM. Diagnosis confirmation was based on clinical outcome and response to treatment after 6-month follow-up. The initial diagnosis and percentage of confirmed diagnoses were compared between the two arms (CM and HRM).
In total, 247 patients were randomized and 245 analyzed: 122 in the CM arm and 123 in the HRM arm. A manometric diagnosis was more frequently initially achieved with HRM than with CM (97% vs. 84%; P<0.01). Achalasia was more frequent in the HRM arm (26% vs. 12% in the CM arm; P<0.01) while normal examinations were more frequent in the CM arm (52% vs. 28% in the HRM arm; P<0.05). After follow-up, the initial diagnosis was confirmed in 89% of patients in the HRM arm vs. 81% in the CM arm (P=0.07). Finally, overall procedure tolerance was better with CM than with HRM (P<0.01).
This randomized trial demonstrated an improved diagnostic yield for achalasia with HRM compared with CM. Diagnoses tended to be more frequently confirmed in patients who underwent HRM, suggesting that esophageal motility disorders could be identified earlier with HRM than with CM (ClinicalTrial.gov, NCT01284894).
Women with gestational trophoblastic tumors (GTT) resistant to single-agent chemotherapy receive alternative chemotherapy regimens, which, although effective, cause considerable toxicity. All GTT ...subtypes express programmed death-ligand 1 (PD-L1), and natural killer (NK) cells are involved in trophoblast immunosurveillance. Avelumab (anti-PD-L1) induces NK cell-mediated cytotoxicity. The TROPHIMMUN trial assessed avelumab in women with chemotherapy-resistant GTT.
In this phase II multicenter trial (ClinicalTrials.gov identifier: NCT03135769), women with GTT who experienced disease progression after single-agent chemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. Rate of hCG normalization was the primary endpoint (2-step Simon design).
Between December 2016 and September 2018, 15 patients were treated. Median age was 34 years; disease stage was I or III in 53.3% and 46.7% of women, respectively; and International Federation of Gynecology and Obstetrics (FIGO) score was 0-4 in 33.3%, 5-6 in 46.7%, and ≥ 7 in 20% of patients. Prior treatment included methotrexate (100%) and actinomycin D (7%). Median follow-up was 25 months, and median number of avelumab cycles was 8 (range, 2-11). Grade 1-2 treatment-related adverse events occurred in 93% of patients, most commonly (≥ 25%) fatigue (33.3%), nausea/vomiting (33.3%), and infusion-related reaction (26.7%). One patient had grade 3 uterine bleeding (treatment unrelated). Eight patients (53.3%) had hCG normalization after a median of 9 avelumab cycles; none subsequently relapsed. Probability of normalization was not associated with disease stage, FIGO score, or baseline hCG. One patient subsequently had a healthy pregnancy. In avelumab-resistant patients (46.7%), hCG was normalized with actinomycin D (42.3%) or combination chemotherapy/surgery (57.1%).
In patients with single-agent chemotherapy-resistant GTT, avelumab had a favorable safety profile and cured approximately 50% of patients. Avelumab could be a new therapeutic option, particularly in patients who would otherwise receive combination chemotherapy.
Abstract
The Fiat-Shamir with Aborts paradigm of Lyubashevsky has given rise to efficient lattice-based signature schemes. One popular implementation is Dilithium, which has been selected for ...standardization by the US National Institute of Standards and Technology (NIST). Informally, it can be seen as a lattice analog of the well-known discrete-logarithm-based Schnorr signature. An interesting research question is whether it is possible to combine several unrelated signatures, issued from different signing parties on different messages, into one single aggregated signature. Of course, its size should be significantly smaller than the trivial concatenation of all signatures. Ideally, the aggregation can be done offline by a third party, called public aggregation. Previous works have shown that it is possible to half-aggregate Schnorr signatures, but it was left open if the underlying techniques can be adapted to the lattice setting. In this work, we show that, indeed, we can use similar strategies to obtain a signature scheme allowing for public aggregation whose hardness is proven assuming the intractability of well-studied problems on module lattices. Unfortunately, our scheme produces aggregated signatures that are larger than the trivial solution of concatenating. This is due to peculiarities that seem inherent to lattice-based cryptography. Its motivation is thus mainly pedagogical.
The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth ...factor treatments such as bevacizumab may be an effective treatment.
To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life.
Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT.
Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment.
Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography.
A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response CR) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated.
In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis.
clinicaltrials.gov Identifier: NCT00843440.
This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization.
A multicenter ...double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success.
Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed.
No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.
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