Efficacy and safety of intravenous bevacizumab on severe bleeding associated with hemorrhagic hereditary telangiectasia: A national, randomized multicenter trial.

BACKGROUND: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted. METHODS: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment. RESULTS: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. CONCLUSION: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.

Avelumab in patients with gestational trophoblastic tumors with resistance to polychemotherapy: Cohort B of the TROPHIMMUN phase 2 trial.

PURPOSE: There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here. METHODS: In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design). RESULTS: Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3). CONCLUSIONS: Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed.

PREDICTORS OF ONE-YEAR VISUAL OUTCOMES AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To determine predictors of best-corrected visual acuity (BCVA) outcomes 1 year after ranibizumab or bevacizumab treatment for neovascular age-related macular degeneration, within the French Study Group Avastin versus Lucentis for neovascular age-related macular degeneration (GEFAL). METHODS: Patients aged ≥50 years presenting subfoveal neovascular age-related macular degeneration were randomized to receive ranibizumab or bevacizumab (3 monthly intravitreal injections followed by an as-needed regimen). The main outcome measures were BCVA and its change from baseline at 1 year. Variables with a P value <0.20 in the univariate model and/or which were clinically relevant were included in the multivariate analysis. RESULTS: The following baseline factors were associated with a lower BCVA score at 1 year and with less improvement in BCVA (multivariate analysis): intraretinal fluid, thickness of central subfield macular ≤277 µm, predominantly classic choroidal neovascularization, and total area of choroidal neovascularization (all P ≤ 0.01). Pigment epithelium detachment and high baseline BCVA were associated with less improvement in BCVA (P = 0.03, P = 0.05, respectively). Patients who met retreatment criteria but did not receive the corresponding injection had significantly poorer outcomes (only tested in the univariate analysis). CONCLUSION: This study confirms the predictors of BCVA score at 1 year posttreatment; the presence of intraretinal fluid was associated with a poor prognosis.

High-Resolution Manometry Improves the Diagnosis of Esophageal Motility Disorders in Patients With Dysphagia: A Randomized Multicenter Study.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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).

Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial.

BACKGROUND: Epistaxis is the most frequent and disabling manifestation of hereditary hemorrhagic telangiectasia (HHT). The efficacy of intravenous bevacizumab (an anti-vascular endothelial growth factor monoclonal antibody) for epistaxis has been shown. However, the efficacy of intranasal bevacizumab has yet to be evaluated. OBJECTIVE: To evaluate the efficacy of 3 different doses of bevacizumab administered as a nasal spray in a repeated manner for the duration of nosebleeds in patients with HHT. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, phase 2/3 clinical trial with dose selection at an intermediate analysis and prespecified stopping rules (nonbinding stopping for futility). Patients aged 18 years or older with a diagnosis of HHT were recruited from 5 French centers from April 2014 to January 2015 with a 6-month follow-up after the end of treatment. Participants had a history of self-reported nosebleeds with a monthly duration of more than 20 minutes in at least the 3 months prior to inclusion corroborated by epistaxis grids completed during the same preinclusion period. INTERVENTIONS: Eighty consecutive HHT patients were randomized and treated in the phase 2 study, with 4 parallel groups in a 1:1:1:1 ratio. One group received placebo (n = 21); the other 3 received bevacizumab nasal spray. Each bevacizumab group received a different dose of the drug (25 mg [n = 20], 50 mg [n = 20], or 75 mg [n = 19] per treatment) in 3 doses 14 days apart for a total treatment duration of 4 weeks, resulting in a total dose of 75 mg, 150 mg, and 225 mg in each treatment group. MAIN OUTCOMES AND MEASURES: Mean monthly epistaxis duration for 3 consecutive months immediately after the end of the treatment. RESULTS: Of the 80 patients who were randomized (mean age, 60.47 [SD, 10.61] years; 37 women [46.25%]), 75 completed the study. Mean monthly epistaxis duration measured at 3 months was not significantly different in the 59 patients receiving bevacizumab in comparison with the placebo group (P = .57) or between the bevacizumab groups. The mean monthly epistaxis duration was 259.2 minutes (95% CI, 82.1-436.3 minutes) in the 25-mg group, 244.0 minutes (95% CI, 81.8-406.2 minutes) in the 50-mg group, 215.0 minutes (95% CI, 102.8-327.2 minutes) in the 75-mg group, and 200.4 minutes (95% CI, 109.3-291.5 minutes) in the placebo group. Toxicity was low and no severe adverse events were reported. This study was terminated prior to phase 3 for treatment futility after interim analysis on the recommendations of an independent data monitoring committee. CONCLUSIONS AND RELEVANCE: In patients with HHT, a bevacizumab nasal spray treatment of 3 administrations at 14-day intervals with doses of 25 mg, 50 mg, or 75 mg per spray, compared with a placebo, did not reduce monthly epistaxis duration in the 3 consecutive months immediately after the end of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02106520.

Congenital bile duct cyst (BDC) is a more indolent disease in children compared to adults, except for Todani type IV-A BDC: results of the European multicenter study of the French Surgical Association.

AIM: To compare clinical presentation, operative management and short- and long-term outcomes of congenital bile duct cysts (BDC) in adults with children. METHODS: Retrospective multi-institutional Association Francaise de Chirurgie study of Todani types I+IVB and IVA BDC. RESULTS: During the 37-year period to 2011, 33 centers included 314 patients (98 children; 216 adults). The adult population included more high-risk patients, with more active, more frequent prior treatment (47.7% vs 11.2%; p < 0.0001), more complicated presentation (50.5% vs 35.7%; p = 0.015), more synchronous biliary cancer (11.6% vs 0%; p = 0.0118) and more major surgery (23.6% vs 2%; p < 0.0001), but this latter feature was only true for type I+IVB BDC. Compared to children, the postoperative morbidity (48.1% vs 20.4%; p < 0.0001), the need for repeat procedures and the status at follow-up were worse in adults (27% vs 8.8%; p = 0.0009). However, severe postoperative morbidity and fair or poor status at follow-up were not statistically different for type IVA BDC, irrespective of patients' age. Synchronous cancer, prior HBP surgery and Todani type IVA BDC were independent predictive factors of poor or fair long-term outcome. CONCLUSION: BDC is a more indolent disease in children compared to adults, except for Todani type IV-A BDC.

Sirolimus and secondary skin-cancer prevention in kidney transplantation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Local recurrence after radical nephrectomy for kidney cancer: management and prediction of outcomes. a multi-institutional study.

BACKGROUND: Local recurrence (LR) after radical nephrectomy (RN) for kidney cancer is uncommon. Our objectives were to analyse characteristics and therapeutic options of LR after RN and to identify survival prognostic factors. MATERIALS AND METHODS: From a multi-institutional retrospective database, we identified 72 patients who experienced LR after RN. RESULTS: Mean time to LR was 26.5 ± 3.3 months. The location of the recurrence was renal fossa, regional lymph node, homolateral adrenal and both renal fossa and regional lymph node for 43 (59.7%), 27 (37.5%), 9 (12.5%) and 7 (9.7%) patients, respectively. Patients were treated by surgery, systemic therapies, combination of therapies and palliative treatment in 24 (33.3%), 18 (25%), 24 (33.3%) and 6 (8.4%) cases, respectively. Within a mean follow-up of 26.4 ± 3.3 months from the date of local recurrence, 12 (16.6%) patients were alive without disease, 30 (41.7%) patients were alive with disease, 30 patients (41.6%) died including 28 (38.8%) from the disease. In multivariate analysis, time to recurrence <1 year (P < 0.001; HR: 4.81) and surgical treatment (P = 0.027; HR: 0.33) were predictive factors. CONCLUSIONS: Local recurrence after radical nephrectomy is associated with poor prognosis. The time to recurrence and the completeness of the surgical treatment are major prognostic factors.

Surgical management of congenital intrahepatic bile duct dilatation, Caroli's disease and syndrome: long-term results of the French Association of Surgery Multicenter Study.

OBJECTIVE: To assess clinical presentation and long-term results of surgical management of congenital intrahepatic bile duct dilatation (IHBDD) (Caroli disease and syndrome) in a multicenter setting. BACKGROUND: Congenital IHBDD predisposes to biliary stasis, resulting in intrahepatic lithiasis, septic complications, and cholangiocarcinoma. Although liver resection (LR) is considered to be the treatment of choice for unilobar disease extent into the liver, the management of bilobar disease and/or associated congenital hepatic fibrosis remains challenging. METHODS: From 1978 to 2011, a total of 155 patients (median age: 55.7 years) were enrolled from 26 centers. Bilobar disease, Caroli syndrome, liver atrophy, and intrahepatic stones were encountered in 31.0%, 19.4%, 27.7%, and 48.4% of patients, respectively. A complete resection of congenital intrahepatic bile ducts was achieved in 90.5% of the 148 patients who underwent surgery. RESULTS: Postoperative mortality was nil after anatomical LR (n = 111) and 10.7% after liver transplantation (LT) (n = 28). Grade 3 or higher postoperative morbidity occurred in 15.3% of patients after LR and 39.3% after LT. After a median follow-up of 35 months, the 5-year overall survival rate was 88.5% (88.7% after LT), and the Mayo Clinic score was considered as excellent or good in 86.0% of patients. The 1-year survival rate was 33.3% for the 8 patients (5.2%) who presented with coexistent cholangiocarcinoma. CONCLUSIONS: LR for unilobar and LT for diffuse bilobar congenital IHBDD complicated with cholangitis and/or portal hypertension achieved excellent long-term patient outcomes and survival. Because of the bad prognosis of cholangiocarcinoma and the sizeable morbidity-mortality after LT, timely indication for surgical treatment is of major importance.

Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.

CONTEXT: 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. OBJECTIVES: 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. DESIGN, SETTING, AND PATIENTS: 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. INTERVENTION: 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. MAIN OUTCOME MEASURE: Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00843440.

Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy: Cohort A of the TROPHIMMUN Phase II Trial.

PURPOSE: 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. METHODS: 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). RESULTS: 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%). CONCLUSION: 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.

Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

Adding methylphenidate to prism-adaptation improves outcome in neglect patients. A randomized clinical trial.

Spatial neglect is one of the main predictors of poor functional recovery after stroke. Many therapeutic interventions have been developed to alleviate this condition, but to date the evidence of their effectiveness is still scarce. OBJECTIVE: The purpose of this study was to test whether combining prism adaptation (PA) and methylphenidate (MP) could enhance the recovery of neglect patients at a functional level. METHODS: RITAPRISM is a multicentre, randomized, double-blind, placebo-controlled study comparing PA plus placebo (control) versus PA plus MP. 24 patients were prospectively enrolled (10 in the placebo group and 14 in the MP group). RESULTS: The main result is a long-term functional improvement (on the functional independence measure (FIM) and on Bergego's scale) induced by MP combined with PA. No serious adverse event occurred. CONCLUSIONS: The long-term benefit on activities of daily living (ADL) obtained in this randomized controlled trial set this intervention apart from previous attempts and supports with a high level of evidence the value of combining PA and MP in order to improve the autonomy of neglect patients. Further studies will be needed to clarify the mechanism of this improvement. Although not specifically assessed at this stage, a part of the improvement in ADL might be related to the collateral effect of MP on mood, executive functions or fatigue, and/or the combined effect of PA and MP on motor intentional bias of neglect patients. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that adding MP to PA improves the functional outcome of neglect patients. WHO TRIAL REGISTRATION ID: EUCTR2008-000325-20-FR.

Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer's Disease Patients and Their Caregivers?

BACKGROUND: It has been suggested that age-related hearing loss (ARHL) and Alzheimer's disease (AD) are commonly associated. OBJECTIVE: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL). METHODS: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer's disease related quality of life, and simplified Duke scales. RESULTS: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores. CONCLUSION: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.

Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer's Disease and Hearing Loss: A Multicenter Controlled Randomized Trial.

BACKGROUND/OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

Establishment of reference values of α-tocopherol in plasma, red blood cells and adipose tissue in healthy children to improve the management of chylomicron retention disease, a rare genetic hypocholesterolemia.

BACKGROUND: Chylomicron retention disease (CMRD), a rare genetic hypocholesterolemia, results in neuro-ophtalmologic damages, which can be prevented by high doses of vitamin E during infancy. In these patients, plasma vitamin E concentration is significantly reduced due to defects of chylomicron secretion. Vitamin E in adipose tissue (AT) and red blood cells (RBC) have been proposed as potential relevant biomarkers of vitamin E status but no reference values in children are available. The objectives were (i) to establish age-reference intervals in healthy children for α-tocopherol in plasma, red blood cells (RBC) and adipose tissue (AT) and (ii) to determine the variations of α-tocopherol in patients with CMRD after oral treatment with vitamin E. METHODS: This prospective study included 166 healthy children (1 month - 18 years) and 4 patients with CMRD. Blood and AT were collected in healthy children during a scheduled surgery and in patients before and after a 4-month treatment with α-tocopherol acetate. RESULTS: The reference ranges for α-tocopherol were 11.9 - 30 µmol/L in plasma, 2.0 - 7.8 µmol/L packed cells in RBC and 60 - 573 nmol/g in AT. α-tocopherol levels in plasma correlated with those of RBC (r = 0.31; p < 0.01). In patients with CMRD after 4 months treatment, α-tocopherol concentrations remained less than 70 % of the control values in plasma, increased by 180 % to reach normal values in RBC, and remained stable in the normal range in AT. CONCLUSION: This study establishes pediatric reference intervals for α-tocopherol in plasma, RBC and AT. These values will be beneficial in assessing accurate α-tocopherol status in children and to optimize the monitoring of rare diseases such as CMRD. Our data suggest that RBC α-tocopherol, appears as a relevant biomarker to appreciate the effectiveness of treatment with α-tocopherol in patients with a rare primary hypocholesterolemia. The biopsy of AT could be used at diagnosis to assess the severity of the vitamin E deficiency and periodically after a long duration of vitamin E therapy to assess whether the treatment is effective, based on reference intervals defined in this study.

Impact of previous cyst-enterostomy on patients' outcome following resection of bile duct cysts.

AIM: To analyze the impact of previous cyst-enterostomy of patients underwent congenital bile duct cysts (BDC) resection. METHODS: A multicenter European retrospective study between 1974 and 2011 were conducted by the French Surgical Association. Only Todani subtypes I and IVb were included. Diagnostic imaging studies and operative and pathology reports underwent central revision. Patients with and without a previous history of cyst-enterostomy (CE) were compared. RESULTS: Among 243 patients with Todani types I and IVb BDC, 16 had undergone previous CE (6.5%). Patients with a prior history of CE experienced a greater incidence of preoperative cholangitis (75% vs 22.9%, P < 0.0001), had more complicated presentations (75% vs 40.5%, P = 0.007), and were more likely to have synchronous biliary cancer (31.3% vs 6.2%, P = 0.004) than patients without a prior CE. Overall morbidity (75% vs 33.5%; P < 0.0008), severe complications (43.8% vs 11.9%; P = 0.0026) and reoperation rates (37.5% vs 8.8%; P = 0.0032) were also significantly greater in patients with previous CE, and their Mayo Risk Score, during a median follow-up of 37.5 mo (range: 4-372 mo) indicated significantly more patients with fair and poor results (46.1% vs 15.6%; P = 0.0136). CONCLUSION: This is the large series to show that previous CE is associated with poorer short- and long-term results after Todani types I and IVb BDC resection.

Histopathologic features predictive of aggressiveness of post-transplant cutaneous squamous-cell carcinomas.

BACKGROUND: Squamous cell carcinomas (SCC), the commonest malignancies developing in organ-transplant recipients (OTR), may behave aggressively. We searched for pathological features of post-transplant SCC that could predict an aggressive outcome early. MATERIALS AND METHODS: We pathologically examined 34 SCC developed in OTR that developed later recurrences/metastases, and compared them with 25 non-aggressive SCC excised from the same OTRs over the same period of time for features believed to predict an aggressive outcome (tumour size and thickness, ulceration, deep tissue invasion, mitotic rate, differentiation, peritumoural infiltrate density, acantholysis, perineural and lymphovascular invasion). RESULTS: A statistically significant difference was found for the level of tumour invasion (Clark), as 58% (18/34) of aggressive SCCs (vs 24% (6/25) of non-aggressive SCCs) were of levels IV or V. CONCLUSION: Post-transplant SCCs with a Clark level of IV or V are associated with a higher risk for recurrence and metastasis and call for a close patient follow-up.

Dose - response relationship of bevacizumab in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder associated with epistaxis and hepatic shunts, is responsible for high-output cardiac failure in rare cases. Bevacizumab, which targets vascular endothelial growth factor, was shown to decrease both cardiac index (CI) and epistaxis duration in HHT patients with severe liver involvement. The relationship between its serum concentration and change in both CI and epistaxis duration was investigated to design the bevacizumab maintenance dosing regimen of future therapeutic studies. Twenty-five HHT patients with dyspnea and high CI were included in a prospective non-comparative study. They received bevacizumab at a dose of 5 mg/kg per infusion every 14 days for a total of 6 injections. The relationships between bevacizumab serum concentration and both CI and epistaxis duration were described using transit compartments and direct inhibition pharmacokinetic-pharmacodynamic models. The performances of different maintenance regimens were evaluated using simulation. Infusions every 3, 2 and one months were predicted to maintain 41%, 45% and 50% of patients with CI <4 L/min/m(2) at 24 months, respectively. The fraction of patients with <20 min epistaxis per month was predicted to be 34%, 43% and 60%, with infusion every 3, 2 or one months, respectively. Simulations of the effects of different maintenance dosing regimens predict that monthly 5 mg/kg infusions of bevacizumab should allow sustained control of both cardiac index and epistaxis.

Skin cancers after liver transplantation: retrospective single-center study on 371 recipients.

BACKGROUND: The increased risk of skin cancer is well known in heart and kidney transplant recipients, but fewer data exist on liver-transplant recipients (LTRs). The aim of this study was to analyze the prevalence, clinical features and risk factors of skin cancers in LTR treated mainly with tacrolimus. METHODS: We selected LTR grafted in our hospital between January 1996 and December 2008, aged 20 years or more at the time of the study. Data were collected from the patients' medical files and with a questionnaire. RESULTS: Three hundred seventy-one LTR were included. The median follow-up period was 8.2 years. The overall prevalence of skin cancers was 13.5%. The prevalence of melanoma was 1.3%. The squamous cell carcinoma to basal cell carcinoma ratio was 1:3. Both the overall cumulative patient risk of de novo skin malignancies and the squamous cell carcinoma-to-basal cell carcinoma ratio increased with time postgraft. The duration of immunosuppression was a risk factor, in addition to those common in the general population. No association was found between the primary liver disease and the development of skin cancer. CONCLUSION: Contrasting with previous data of the literature, our findings suggest that, for a similar follow-up time, the risk of skin cancer in LTR is comparable to that of kidney transplant recipients.