Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies. METHODS: We retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018-2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was

Impact of multidisciplinary team meetings on the management of venous thromboembolism. A clinical study of 142 cases.

OBJECTIVE: Numerous guidelines have been published on the management of venous thromboembolism (VTE). However, therapeutic decision-making may prove challenging in routine clinical practice. With this in mind, multidisciplinary team (MDT) meetings have been set up in Rennes University Hospital, France. This study sought to describe the situations discussed during MDT meetings and to assess whether the meetings bring about changes in the management of these patients. MATERIALS AND METHODS: A retrospective single-center study conducted at the Rennes University Hospital included cases presented from the beginning of the MDT meetings (February 2015) up to May 2017. RESULTS: In total, 142 cases were presented in 15 MDT meetings, corresponding to a mean of 10±4 cases per meeting. Of these, 129 related to VTE patients: 33 provoked VTEs, 22 unprovoked VTEs, 49 cancer-related VTEs, and 25 unspecified VTEs. MDT meetings led to significant changes in the anticoagulation type (therapeutic, prophylactic, or discontinuation) and duration, but not in the anticoagulant choice (direct oral anticoagulants, vitamin K antagonists, heparins, etc.). CONCLUSION: Requests for MDT meetings are made for all VTE types, and these meetings have an impact on VTE management.

Clinical validation of a prognostic tool in a population of outpatients treated for incurable cancer undergoing anticancer therapy: PRONOPALL study.

BACKGROUND: In 2008, a study of the characteristics of hospitalised patients led to the development of a prognostic tool that distinguished three populations with significantly different 2-month survival rates. The goal of our study aimed at validating prospectively this prognostic tool in outpatients treated for cancer in terminal stage, based on four factors: performance status (ECOG) (PS), number of metastatic sites, serum albumin and lactate dehydrogenase. PATIENTS AND METHODS: PRONOPALL is a multicentre study of current care. About 302 adult patients who met one or more of the following criteria: life expectancy under 6 months, performance status ≥ 2 and disease progression during the previous chemotherapy regimen were included across 16 institutions between October 2009 and October 2010. Afterwards, in order to validate the prognostic tool, the score was ciphered and correlated to patient survival. RESULTS: Totally 262 patients (87%) were evaluable (27 patients excluded and 13 unknown score). Median age was 66 years [37-88], and women accounted for 59%. ECOG PS 0-1 (46%), PS 2 (37%) and PS 3-4 (17%). The primary tumours were: breast (29%), colorectal (28%), lung (13%), pancreas (12%), ovary (11%) and other (8%). About 32% of patients presented one metastatic site, 35% had two and 31% had more than two. The median lactate dehydrogenase level was 398 IU/l [118-4314]; median serum albumin was 35 g/l [13-54]. According to the PRONOPALL prognostic tool, the 2-month survival rate was 92% and the median survival rate was 301 days [209-348] for the 130 patients in population C, 66% and 79 days [71-114] for the 111 patients in population B, and 24% and 35 days for [14-56] the 21 patients in population A. These three populations survival were statistically different (P <0.0001). CONCLUSION: PRONOPALL study confirms the three prognostic profiles defined by the combination of four factors. This PRONOPALL score is a useful decision-making tool in daily practice.

Intraoperative study of polarization and evoked response signals in different endocardial electrode designs.

Some new generation pacemakers use an algorithm based on evoked response (ER) detection to verify beat-to-beat capture and to enable automatic adjustment of output. This is a prospective acute study of polarization signal (PS) and ER in nine currently available electrodes. Intraoperative testing of ventricular bipolar electrodes used the Autocapture (AC) algorithm. The intrinsic R wave, PS, ER, acceptance of AC function, and stimulation thresholds (STs) were obtained. Ventricular electrodes were categorized as follows: titanium nitride (TiN)-coated passive and active fixation, high impedance (HI), passive fixation (VP), iridium oxide-coated titanium (IROX) (VI), and platinum helix (PH) active fixation. Acute testing was performed in 217 patients with an average age of 74.26 years, 59.6% were men with primary pacing indication-SSS (46.3%). There were no significant differences found with respect to R wave and threshold between the various electrodes. PH active-fixation electrodes had significantly higher ER and PS than other groups including the TiN-coated active-fixation electrodes. TiN-coated electrodes (active and passive fixation) had significantly lower PS than other electrodes. As a result, TiN electrodes had a significantly higher functional rate of AC (91.7%), whereas PH had the lowest rate (0%). In conclusion, (1) polarization characteristics are significantly different for commercially available ventricular electrodes, (2) certain physical features at the tissue to electrode interface like TiN coating appears to be more important in determining PS than electrode tip size and fixation method, and (3) the current algorithm for AC requires electrodes that provide low polarization for satisfactory performance.

[Aromatase inhibitors: a review of clinical trials]. / Antiaromatases: revue des résultats cliniques.

To increase the therapeutic index of second line hormonal treatment of breast cancer, new aromatase inhibitors have been synthetized; they belong to two groups: type I (formestane and exemestane) are steroidal irreversible and specific inhibitors, type II (anastrozole, letrozole and vorozole) are non steroidal reversible inhibitors, interfering with the aromatase heme. Several phase II and III trials demonstrated that these drugs are, at least, as active as aminoglutethimid or progestins in second line treatment, and are less toxic. Recently, an identical activity have been observed for anastrozole and tamoxifen in first line. In metastatic and adjuvant settings, large trials are ongoing to clarify the exact value of these drugs.

Biopharmaceutics and pharmacokinetics of 5-phenyl-1, 2-dithiole-3-thione complexed with sulfobutyl ether-7-beta-cyclodextrin in rabbits.

The biopharmaceutics and pharmacokinetics of 5-phenyl-1, 2-dithiole-3-thione (5PDTT) were investigated in rabbits, after administration as a complex with sulfobutyl-ether-7-beta-cyclodextrin (SBE7-beta-CD) by intravenous and oral routes and as a micronized powder by oral route. 5PDTT had a rapid and large red blood cell partitioning that was not dependent on drug concentration either in vitro or ex vivo. The blood clearance was very high (354 +/- 131 mL/min) suggesting extrahepatic metabolism and/or nonrenal elimination and a significant volume of distribution (67 +/- 76 L). The renal clearance was 0.17% of total clearance. 5-phenyl-1,2-dithiol-3-one (5PDTO) was identified as a metabolite in blood and urine. The bioavailability of 5PDTT following administration of 5PDTT/SBE7-beta-CD complex was estimated to 41% while it was close to zero when 5PDTT was given as a micronized powder.

[Stewart-Treves syndrome arising in post-traumatic lymphedema]. / Syndrome de Stewart-Treves sur lymphoedème chronique post-traumatique.

The authors report a case-history of lymphangiosarcoma or Stewart-Treves syndrome which occurred in a patient with posttraumatic lymphedema of the arm. He presented two recurrences after surgery which led to the decision of amputation. He is now disease free nine years after this treatment. Initially defined as "lymphangiosarcoma arising in chronic lymphedematous extremities after mastectomy for breast cancer", Stewart-Treves syndrome complicates rarely traumatic, postsurgical, postradiation, idiopathic, congenital or filarial lymphedema. Clinical diagnosis is based on nodular, purple and frequently multiple skin lesions on chronic lymphedema of the limb. A proliferating malignant endothelium with affinity for anti-factor-VIII is found on histological slides. The tumor aggressivity explains the short survival if no treatment is given. Stewart-Treves syndrome prognosis is poor, with the occurrence of multiple local recurrences and pulmonary metastasis. On account of its rarity, there is no therapeutic consensus. In localized stage, radical surgery is usually performed. Conservative treatment with complete tumour removal and postoperative radiotherapy has not been yet evaluated. In metastatic or locally advanced tumours, it is necessary to study the benefit of cytotoxic drugs like anthacyclins and ifosfamide known to be effective on soft tissue sarcomas.

[Epidemiology of hepatitis C virus infection in 1,304 HCV positive patients: variations according to the origin of transmission and year of diagnosis]. / Epidémiologie de l'infection virale C chez 1,304 sujets VHC positif. Variations en fonction du mode de contamination et de l'année du diagnostic.

UNLABELLED: The evolution of epidemiological data on hepatitis C virus infection is poorly documented and thus the impact of screening is difficult to evaluate. AIM: To study epidemiological variations based on the origin of transmission and the year of diagnosis of hepatitis C virus infection. METHODS: The files of all 1304 patients seen in the hepatology unit of the Rennes University Hospital were analyzed (retrospectively before and prospectively after October 1995) in relation to epidemiological features. RESULTS: Despite widespread screening which is the source of 60% of the diagnoses, the total number of new cases of hepatitis C infection per year has not increased. Compared to patients diagnosed in the first years following the discovery of the virus, patients recently identified were younger (42 +/- 14 years) and frequently drug addicts (40%). Aminotransaminases were normal in 20% of cases. The frequency of cirrhosis has declined (17%). There has been a decrease in the proportion of patients who undergo liver biopsy (50%) and treatment with interferon (one third of patients). CONCLUSIONS: The impact of screening on the number of newly treated patients seems to be lower than previously predicted.

Iatrogenic risks of endometrial carcinoma after treatment for breast cancer in a large French case-control study. Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC).

Since tamoxifen is widely used in breast cancer treatment and has been proposed for the prevention of breast cancer, its endometrial iatrogenic effects must be carefully examined. We have investigated the association between endometrial cancer and tamoxifen use or other treatments in women treated for breast cancer in a case-control study. Cases of endometrial cancer diagnosed after breast cancer (n = 135) and 467 controls matched for age, year of diagnosis of breast cancer and hospital and survival time with an intact uterus were included. Women who had received tamoxifen were significantly more likely to have endometrial cancer diagnosed than those who had not (crude relative risk = 4.9, p = 0.0001). Univariate and adjusted analyses showed that the risk increased with the length of treatment (p = 0.0001) or the cumulative dose of tamoxifen received (p = 0.0001), irrespective of the daily dose. Women who had undergone pelvic radiotherapy also had a higher risk (crude relative risk = 7.8, p = 0.0001). After adjusting for confounding factors, the risk was higher for tamoxifen users (p = 0.0012), treatment for more than 3 years (all p < 0.03) and pelvic radiotherapy (p = 0.012). Women who had endometrial cancer and had received tamoxifen had more advanced disease and poorer prognosis than those with endometrial cancer who had not received this treatment. Our results suggest a causal role of tamoxifen in endometrial cancer, particularly when used as currently proposed for breast cancer prevention. Pelvic radiotherapy may be an additional iatrogenic factor for women with breast cancer. Endometrial cancers diagnosed in women treated with tamoxifen have poorer prognosis. Women who receive tamoxifen for breast cancer should be offered gynaecological surveillance during and after treatment. A long-term evaluation of the risk-benefit ratio of tamoxifen as a preventive treatment for breast cancer is clearly warranted.