Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older.

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

Nutritional status and anxious and depressive symptoms in anorexia nervosa: a prospective study.

The interweaving of malnutrition and symptoms of anxiety and depression in anorexia Nervosa (AN) is mentioned without any consensus regarding the course of anxious-depressive symptoms in relation to nutritional status in the course of treatment of patients with AN. The objectives of the current study in a large sample of AN inpatients were to assess the relationships between anxiety and depression symptoms and nutritional status both over the course of inpatient treatment and at discharge. 222 consecutive inpatients with AN (DSM-IV TR) were assessed (entrance and discharge) for duration of illness, psychiatric treatments, sociodemographic data and with psychometric scales for different psychopathological symptoms [depressive (BDI), anxiety and depressive (HAD scale), obsessive-compulsive (MOCI) and social phobia (LSAS fear score)]. Nutritional status was assessed with Body Mass Index (BMI) and body composition by bioelectrical impedance. The Fat free mass index [FFMI = FFM (kg)/height (m2)] was considered for the analysis. Two models were developed where the dependent variables were each psychopathological score at discharge (BDI, HAD anxiety, MOCI, and LSAS fear) in the cross-sectional model, and their variation in the longitudinal model (where a positive score reflected symptom decrease at discharge). A fixed set of predictors, defined on presumed clinical and statistical relevance (FFMI in the cross-sectional model and Variation of FFMI in the longitudinal model), were considered in each model, without any model selection procedure. This is the first study to confirm a positive relationship between the course of eating disorder symptoms and that of anxious-depressive symptoms during inpatient treatment of AN even after adjustment on a vast array of possibly confounding factors.

Clinical results of peroneal tendon repair in a retrospective series of 30 patients.

INTRODUCTION: Peroneal tendinopathy is an under-diagnosed pathology, mainly triggered by ankle sprain. Failure of medical treatment often leads to surgery, with modalities adapted to the lesion type. The present study aimed to assess clinical and functional results of tendon repair and to analyze the influence of hindfoot alignment on quality of outcome. The study hypothesis was that hindfoot varus impairs medium-term results. MATERIALS AND METHODS: A retrospective series of 30 patients undergoing peroneal tendon repair or tenodesis was analyzed at a mean 20 months' follow-up. All patients had preoperative ultrasound scan or NMRI. Clinical assessment was based on AOFAS and FAAM scores. Hindfoot alignment was assessed on Méary view; 2 groups were distinguished: valgus (n=11) and varus (n=17). RESULTS: Mean AOFAS score improved, from 74.5±11.2 preoperatively to 86.7±9.4 at follow-up. There was a significant intergroup difference (p=0.0003) in AOFAS at follow-up: valgus, 93/100; varus, 82/100. There was no significant intergroup difference in FAAM score. Time to surgery, lesion type and surgical technique did not influence clinical results. DISCUSSION/CONCLUSION: Clinical results for surgical repair of peroneal tendons were satisfactory and in line with literature reports. However, hindfoot varus was associated with poorer results, raising the possibility of correction by opening wedge calcaneal osteotomy. LEVEL OF EVIDENCE: IV, retrospective case series.

Results and limitations of humeral head resurfacing: 105 cases at a mean follow-up of 5 years.

BACKGROUND: The objective of this study was to assess clinical and computed-tomography (CT) outcomes at least 2 years after humeral head resurfacing to treat concentric gleno-humeral osteoarthritis. HYPOTHESIS: Humeral head resurfacing provides similar outcomes to those achieved with stemmed humeral head implants. MATERIALS AND METHODS: This single-centre retrospective study included 40 Copeland™ and 65 Aequalis™ humeral resurfacing heads implanted between 2004 and 2012. Mean patient age at diagnosis was 64 years. The diagnoses were osteoarthritis with an intact (68%) or torn (21%) rotator cuff, avascular necrosis (5%), osteoarthritis complicating chronic instability (3%), post-traumatic osteoarthritis (2%), and chronic inflammatory joint disease (1%). Validated clinical scores, radiographs, and CT before surgery and at last follow-up were compared. RESULTS: During the mean follow-up of 56 months, complications occurred in 24 implants. Revision surgery with reverse shoulder replacement was required in 18 cases, after a mean of 43.6 months, to treat glenoid wear or a rotator cuff tear. At last follow-up, for the implants that did not require revision surgery, the mean Constant score was 64/100. The implants had a mean varus of 5° and mean retroversion of -13.3°. The mean increase in glenoid cavity depth was 2.4mm. Mean increases in medial and lateral humeral offset were 1.9mm and 2.7mm, respectively. Pre-operative factors significantly associated with failure were rotator cuff tear (P=0.017) and glenoid erosion (P=0.001). DISCUSSION: We found a high failure rate related to glenoid wear or progressive rotator-cuff impairment, although CT showed no evidence of implant malposition or overstuffing. Previous studies of stemmed humeral head implants showed better outcomes. Given the low medium-term prosthesis survival rate, we now reserve humeral head resurfacing for concentric osteoarthritis without glenoid erosions or rotator cuff damage. LEVEL OF EVIDENCE: IV, retrospective study.

Increase of progesterone receptor by tamoxifen as a hormonal challenge test in breast cancer.

In 25 cases of postmenopausal breast cancer, estradiol receptor (ER) and progesterone receptor (PR) were measured in cutaneous metastatic nodules before and after administration of 30 mg of tamoxifen per day for 1 week. No response was recorded in ER-poor cases. However, in tumors containing greater than 10 fmol ER per mg cytosol protein, 6 of 14 cases showed an increase in PR of greater than 30 fmol/mg cytosol protein. The presence or absence of PR before administration of tamoxifen did not discriminate systematically between hormone-responsive and nonresponsive tumors. These findings demonstrate in vivo that biochemical changes brought about by an agent binding to ER can be observed only in ER-positive cases. In addition they suggest that, in these ER-positive cases responding to tamoxifen by increase of PR, the simultaneous or sequential administration of both antiestrogen (rescuing PR) and progestagen (decreasing PR) may allow better hormonal control of the disease.

Establishment, characterization, chemosensitivity, and radiosensitivity of two different cell lines derived from a human breast cancer biopsy.

In vitro culture of a human breast cancer biopsy fragment gave rise to two permanent cell lines, CAL 18 A and CAL 18 B, which were differentiated by both morphological and ultrastructural analysis. The karyotypic and growth properties of these two cell lines also differed, providing further evidence of cell heterogeneity within a given tumor. Both cell lines lost their hormone receptors in vitro. CAL 18 A cells grew in agar and were tumorigenic after inoculation into nude mice; neither of these properties was observed in CAL 18 B cells. The chemosensitivity of 12 antineoplastic drugs was assessed by a short-term assay, using inhibition of tritiated thymidine incorporation by the cells after contact with the drugs as the end point. Only a few drugs were active at moderate concentrations. The overall responses of both cell lines were similar. The cell survival curves, established by the colony method following a single dose of radiation, were also very similar, despite the greater heterogeneity of CAL 18 B cells. The two cell lines appear to be interrelated, since CAL 18 B cells were occasionally observed to emerge from CAL 18 A clones, suggesting that malignant cell redifferentiation may occur spontaneously in vitro.

Prospective observational study of midtarsal joint sprain: Epidemiological and ultrasonographic analysis.

INTRODUCTION: Foot and ankle injuries (FAI) are very common, with about 6000 cases per day in France. Unlike lateral ankle sprain (LAS), the diagnosis of midtarsal joint sprain (MJS, also known as Chopart's joint sprain) is not widely known. This prospective study aims to detail the epidemiology of MJS and compare it to LAS. PATIENTS AND METHOD: The study was conducted within our institution over a period of 16 months. Patients with clinical signs predictive of MJS without radiographic bone lesion underwent ultrasound assessment. MJS was diagnosed in case of at least 1 lesion of the dorsal midtarsal joint ligaments. RESULTS: A total of 2412 patients consulted for FAI; 188 had clinical and radiographic criteria for ultrasound examination. Eighty-two cases of MJS were diagnosed (3.4% of FAIs). Sports injuries were more frequent in MJS (P=0.04), and mechanisms more varied than in LAS, with inversion injury in 75% of cases and plantar hyperflexion in 22%. Sprain was severe in 70% of cases, with complete ligament tear. Clinical and ultrasound analyses correlated in only 40% of cases of MJS, versus 98% for LAS. CONCLUSION: MJS is frequent, difficult to diagnose clinically, and often severe. Clinical presentation and injury mechanisms differ from ankle sprain. Ultrasound seems to be an indispensable tool in diagnosis.

Type 1 and type 2 autoimmune hepatitis in adults share the same clinical phenotype.

BACKGROUND: Autoimmune hepatitis (AIH) is historically classified into type 1 and type 2 on the basis of the autoantibody profile, anti-nuclear and/or anti-smooth muscle antibodies being the serological markers of type 1 AIH, whereas anti-liver/kidney microsomal antibody type 1 and/or anti-liver cytosol antibody type 1 characterise type 2 AIH. AIM: To evaluate whether such a distinction is justified on the basis of different expression of the disease in adults. METHODS: Twenty-six adult patients with type 2 AIH and 52 age- and sex-matched patients with type 1 AIH, representative of the entire cohort of adults with type 1 AIH, were compared at onset and during follow-up. RESULTS: At diagnosis, median age was 26 years (range 17-53), female sex 86%, acute presentation 43%, severe liver histology 54%, cirrhosis 14%, complete response to treatment 52%, progression of the disease 17%, and median disease duration 72 months (range 12-280). HLA-DRB1*0301 was present in 26%, HLA-DRB1*0401 in 23% and HLA-DRB1*0701 in 25%. Clinical presentation, biochemical parameters, severe liver histology, genetic profile, response rate and progression of the disease were identical between type 1 and type 2 AIH. CONCLUSION: There is not enough clinical, biochemical, histological or genetic reason to subdivide adults with autoimmune hepatitis into type 1 and type 2 on the basis of the autoantibody profile, and the term 'autoimmune hepatitis' without qualification should be preferred.

Conservative treatment of breast cancer: a report on 108 patients.

Between 1975 and 1980, 108 breast cancers (T1 and small T2) were treated at the Centre Antoine-Lacassagne (Nice, France) by a combination of conservative surgery and irradiation. Ninety-two of these patients underwent axillary node dissection; 17% of them presented with nodal involvement. All irradiation was given by telecobalt: 45 Gy to the entire breast, 60 Gy to the site of the tumor. All cosmetic results were acceptable. Intramammary recurrences were rare (6%) and independent of the tumor site or size or of any nodal involvement. Solitary metastases (not associated with a local recurrence) were extremely rare (4%) and were observed in patients who had had no nodal involvement. The actuarial survival rate at 5 years is 90%.

Development and use of a computer system in a radiotherapy department: SISGRAD.

SISGRAD, the interactive computer system of the Antoine-Lacassagne Cancer Center Radiotherapy Department, has been operational since January 1982. It completes the computerized dosimetry system installed several years earlier and is fully integrated with the institution's central network. SISGRAD is in charge of surveillance of the radiotherapy treatments given by the Center's three radiotherapy units (1400 patients per year); it is also used for administrative purposes in the Department and physically connects all of the Department's operating stations. SISGRAD consists of a series of microcomputers connected to a common mass memory; each microcomputer is used as an intelligent console. SISGRAD was developed to guarantee that the treatments comply with prescriptions, to supply extemporaneous dosimetric data, to improve administrative work, and to supply banks with data for statistical analysis and research. SISGRAD actively intervenes to guarantee treatment quality and helps to improve therapy-related security factors. The present text describes the results of clinical use over a 4-year period. The consequences of integration of the system within the Department are analyzed, with special emphasis being placed on SISGRAD's role in the prevention and detection of errors in treatment prescription and delivery.

CT measurement of lung density: the role of patient position and value for total body irradiation.

To obtain more precise data on pulmonary doses in preparation for total body irradiation, the lung density of patients was systematically analyzed in treatment positions using data obtained by computed tomography (CT). With the patient supine, the lung density was not significantly different for the right and left lungs. In contrast, considerable differences were noted between the two lungs in lateral decubitus positions owing to variations in ventilation and perfusion. The relative electron density of lung was also found to decrease with age, dropping to pe = 0.160 at 71 years.

Contractions of rat uterine smooth muscle induced by acetylcholine and angiotensin II in Ca2+-free medium.

The effects of acetylcholine (ACh, 10(-4)M) and angiotensin II (Ang II, 10(-6) M) have been studied on the mechanical and electrical activities of rat myometrial strips perfused in Ca2+-free EGTA-containing solutions. Both ACh and Ang II produced transient contractions, the amplitude of which can be taken as a measurement of the amount of Ca2+ present in a drug-sensitive Ca2+ store. The degree of filling of this store depended on the external Ca2+ concentration, and on the presence of contractile responses during the Ca2+ loading period. The existence of two pathways (either direct or transcytoplasmic) is suggested for Ca2+ uptake into the internal Ca2+ store. The rate of filling of the Ca2+ store in 2.1 mM-Ca2+-containing solution was faster (time to half-maximal response, t 1/2 = 29 +/- 2.2 s, n = 4) than the rate of depletion in Ca2+-free solution (t 1/2 = 3 +/- 0.3 min, n = 3). The gradual depletion of this store was much slower at 18 degrees C than at 35 degrees C, and in the presence of vanadate which is known to inhibit Ca2+-ATPases. Methoxyverapamil (D600, 10(-6)-10(-5) M) had no appreciable effect on the direct Ca2+ uptake or on the release of Ca2+ from the store by ACh and Ang II. Mn2+ (10(-3) M) completely inhibited the direct pathway to the internal Ca2+ store and also reduced the release of Ca2+. ACh and Ang II induced repetitive depolarizations close to zero potential which did not parallel the transient contractions as a function of the time of perfusion in Ca2+-free solution. Applications of 2 mM EGTA, 135 mM K+ or Ca2+ antagonists which suppressed or reduced the drug-induced depolarizations did not affect appreciably the drug-induced contractions. These results suggest that myometrial cells have an intracellular Ca2+ store sensitive to different stimulus substances. This store is not affected by depolarization of the plasma membrane and is certainly different from that described in voltage-clamp experiments.

Plasma levels of 7-hydroxymethotrexate after high-dose methotrexate treatment.

Thirteen patients with cancer being treated with high-dose methotrexate (MTX) chemotherapy (350-5,000 mg/6 h IV were entered in this study. Plasma levels of MTX and 7-OHMTX, its main circulating metabolite, were measured by an HPLC technique. 7-OHMTX appears rapidly in the blood, reaching a maximum 6-12 h after the beginning of treatment. The elimination of 7-OHMTX is slower than that of MTX, but the elimination half-lives (24-48 h) are not significantly different: 25.2 h for 7-OHMTX versus 20.3 h for MTX. In all cases, 24 h after starting infusion plasma levels of 7-OHMTX exceeded those of MTX. There was a positive and significant correlation between the dose administered and peak plasma 7-OHMTX. Finally, 7-OHMTX formation was shown to be relatively stable throughout the treatment.

Comparison of pinaverium bromide, manganese chloride and D600 effects on electrical and mechanical activities in rat uterine smooth muscle.

The effects of pinaverium bromide, were compared with those of D600 and manganese chloride (Mn), on membrane potentials, ionic currents and isometric contractions in uterine smooth muscle strips from pregnant rats. Pinaverium bromide (10(-7) - 10(-6) M) depressed twitch contractions and K-contractures within 15-20 min while D600 (2 X 10(-6) M) and Mn (10(-3) M) abolished both contractions. D600 and pinaverium bromide were more potent inhibitors in K-depolarized preparations than in polarized tissues. At a supramaximal dose (10(-5) M), pinaverium bromide decreased the rate of rise, amplitude, and rate of repolarization of the action potential, and prolonged the potential duration. The inward Ca current was depressed and the reduction in Cai was responsible for the decrease in K current. Pinaverium bromide (10(-5) M) depressed the myometrial contractions induced in Ca-free solution by acetylcholine (10(-4) M) and by prolonged membrane depolarizations. Mn (2.5 X 10(-3) M) only reduced the Ach-induced contraction and D600 (10(-5) M) had no effect on intracellular Ca stores. The results indicate that pinaverium bromide has Ca channel blocking properties similar to those of currently used Ca antagonists; it may also exert an effect to depress contractions supported by intracellular Ca release.

Fenoverine: a novel synchronizer of smooth muscle motility by interference with cellular calcium flow.

Several in vivo and in vitro test models were used to study the mechanism of action of fenoverine, a novel synchronizer of smooth muscle motility. In vivo, the effects of fenoverine were tested in the rabbit proximal colon, recording its ability to modify the electromyographic activity, either spontaneous or electrically elicited, in the presence or absence of atropine. Fenoverine did not influence the spontaneous motility nor did it modify the effects of atropine, but it significantly reduced the contractions elicited by electrical stimulation. In vitro, isolated rabbit and rat colon and isolated rat myometrium were used. In rabbit colon, fenoverine failed to influence the spontaneous motility as well as the effects of atropine, while significantly inhibiting the electrically elicited excitatory junction potential. Fenoverine also significantly inhibited the isometric contractions induced in rat myometrium and colon by electrical stimulation, by depolarization with hyperpotassic solution, as well as those induced by acetylcholine in calcium-free/EGTA medium, with ID50 ranging from 8.10(-7) to 3.1.10(-6) M except in the isolated colon following K+ depolarization (5.10(-5) M), all actions compatible with a calcium-modulating mechanism. Based on the reported data, it is concluded that fenoverine does not act as a muscarinic or opiate-receptor antagonist, but that its main mechanism of action is due to modulation of the calcium gradient across the muscular cell membrane by regulating the influx of the extracellular calcium and/or the release of the intracellular pool.

Comparative study of gamma glutamyl transferase, alkaline phosphatase and its alpha 1 isoenzyme as biological indicators of liver metastases.

Biological detection of liver metastases represents an important factor in the surveillance of the course of cancerous affections. The authors present a report on a potential new indicator, the isoenzyme of alkaline phosphatase migrating to the alpha 1 region (alpha 1 ALP). In comparison to those tests considered the most sensitive at present-gamma glutamyl transferase and total alkaline phosphatase-this alpha 1 isoenzyme appears more sensitive and more specific, capable of detecting 97% of liver metastases with a specificity of 90%.

In vitro study of the cell populations in two cases of Kaposi's sarcoma.

Despite numerous studies, the histogenesis of Kaposi's sarcoma remains unclear. In connection with the culture of two Kaposi's sarcomas, the morphological, ultrastructural, and immunological properties of the various cell types observed are discussed. Cloning in agar, loss of contact inhibition, and karyotyping were used to determine which cells had undergone malignant transformation. Findings for both cases revealed that endothelial cells had undergone neoplastic transformation. Fibroblastic cell lines were isolated from both sarcoma fragments; although their growth characteristics distinguished them from normal fibroblasts (increased growth and possibility of culture in soft agar), cytogenetic investigations on both lines confirmed that they were genetically normal, and occurred along with malignant cells as a accessory compartment within lesions. Endothelial cells appear to be the sole origin of Kaposi's sarcoma, and may release factors which alter fibroblastic growth.

The MEDICYC programme.

The major goal of MEDICYC, the medical cyclotron programme of the Antoine-Lacassagne Cancer Center (Nice, France) is radiotherapy based on protons and fast neutrons. This cyclotron has also been designed to meet the medical requirements for the Center's Nuclear Medicine Department. Technical specifications and anticipated applications are discussed. The construction of the machine is nearly finished and a first axially injected beam is scheduled for early 1987.

Prospects for the application of fast neutrons in cancer therapy. Radiobiological bases and survey of the clinical data.

The rationale for introducing fast neutrons in therapy initially was a reduction in the Oxygen Enhancement Ratio (OER). The recent radiobiological developments indicate that, more generally, fast neutrons tend to reduce the difference in radiosensitivity between cell lines, or related to the degree of oxygenation (Oxygen Gain Factor), the position of the cells in the mitotic cycle (Kinetics Gain Factor), etc. The reduction of the differences in radiosensitivity brings a benefit for certain types of tumours (normally resistant to photons), but a disadvantage for other types of tumours (those which can currently be controlled by photon treatment). A review of the available clinical data is presented. The tumour types or sites for which a benefit has been observed are discussed: locally advanced tumours of the salivary glands, paranasal sinuses, some tumours of the head and neck area with metastatic lymph nodes, slowly growing, well differentiated soft tissue sarcomas, inoperable/recurrent melanomas, locally extended (C, D1) prostatic adenocarcinomas. Selection of the patients suitable for neutron therapy remains the main problem. Collaboration between neutron therapy centres is essential to accelerate the acquisition of sufficient clinical data needed in order to improve patient selection, as well as the optimum modality of application of fast neutrons.