Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel,Cabazitaxel, and Androgen Receptor–Targeted Agents

Background

Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

The Cardiovascular Toxicity of Abiraterone and Enzalutamide in Prostate Cancer

Introduction

The cardiovascular toxicity related to abiraterone and enzalutamide has been previously studied by our group. In this analysis, we aim to update our previous findings related to abiraterone and enzalutamide, including the new available evidence, both in castration-resistant and hormone-sensitive prostate cancer.

Radiotherapy of meningioma: a treatment in need of radiobiological research

Purpose: Meningiomas account for one third of primary intracranial tumors; nevertheless information on meningioma cell lines and in vivo models is scant. Although radiotherapy is one of the most relevant therapeutic options for the treatment of patients with meningioma, radiobiological research to understand tumor response to this treatment is far from being thoroughly figured out. The aim of this report is to provide a comprehensive picture of the current literature on this field, so as to foster research in this regard.

Methods: We carried out a review of meningioma radiobiology based on a peer-reviewed PubMed search.

Results: Our findings confirm that the main limitation of radiobiological research into meningioma is the paucity of robust in vitro and in vivo models. Alternative approaches to overcome the already identified problems, and to allow better understanding of the entire histopathological spectrum of meningiomas have been explored.

Conclusions: A radiobiological perspective of meningioma may help to improve clinical results both in terms of tumor control and healthy tissue sparing. Although we are far from drawing any conclusions, this review can lead researchers to identify some clues for future areas of study.     

Phosphorylation of the Third Intracellular Loop of the Mouse α1b-Adrenergic Receptor by cAMP-dependent Protein Kinase

The third intracellular loop of adrenergic receptors has been implicated in their interaction with guanine nucleotide-binding proteins (G proteins). One of the mechanisms involved in the modulation of receptor function is the phosphorylation of specific residues by intracellular kinases.

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-Adrenergic receptor is phosphorylated in vitro by cAMP-dependent protein kinase (PKA), although its physiological effect remains to be determined. We have produced fusion proteins formed by glutathione S-transferase and sequences of the third intracellular loop of mouse

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-,

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-, and

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-adrenergic receptor subtypes, and used them as substrates for PKA. Only the fusion protein containing the

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sequence was phosphorylated in vitro by this kinase. Site-directed mutagenesis of a serine (homologue to serine 278 of the rat sequence, RSS) to an alanine residue precluded phosphorylation by PKA.     

Prevalence of Hearing Loss Among Children 6 to 19 Years of Age: The Third National Health and Nutrition Examination Survey

Context.— Hearing loss in children influences the development of communication and behavioral skills, but few studies in the United States have used pure-tone audiometry to derive hearing loss prevalence estimates for children. Objective.— To describe the prevalence of hearing loss among US children by sociodemographic characteristics, reported hearing loss, and audiometric screening factors. Design.— National population-based cross-sectional survey with an in-person interview and audiometric testing at 0.5 to 8 kHz. Setting/Participants.— A total of 6166 children aged 6 to 19 years completed audiometry in the mobile examination center of the Third National Health and Nutrition Examination Survey conducted between 1988 and 1994. Main Outcome Measure.— Hearing loss, defined as audiometric threshold values of at least 16-dB hearing level based on a low or high pure-tone average. Results.— A total of 14.9% of children had low-frequency or high-frequency hearing loss of at least 16-dB hearing level, 7.1% had low-frequency hearing loss of at least 16-dB hearing level, and 12.7% had high-frequency hearing loss of at least 16-dB hearing level. Most hearing loss was unilateral and slight in severity (16- to 25-dB hearing level). Of those with measured hearing loss, 10.8% were reported to have current hearing loss during the interview. Conclusions.— This analysis indicates that 14.9% of US children have low-frequency or high-frequency hearing loss of at least 16-dB hearing level in 1 or both ears. Among children in elementary, middle, and high school, audiometric screening should include low-frequency and high-frequency testing to detect hearing loss.      

Serum levels of eosinophil cationic protein in allergic diseases and natural allergen exposure

BACKGROUND: Eosinophil cationic protein (ECP) is a cytotoxic preformed mediator stored in eosinophil granules and released under various in vitro and in vivo conditions. OBJECTIVE: This study was carried out to evaluate the clinical value of ECP as a marker of allergic inflammation. METHODS: ECP was measured by a competitive radioimmunoassay in serum samples from 265 patients and 45 matched control subjects and related to the type of allergic disease (asthma, rhinitis, conjunctivitis) and to the type of allergic sensitization. RESULTS: All the patient groups studied showed significantly higher levels of serum ECP than control groups (p < 0.001). The type of sensitization was shown to be the only variable influencing ECP serum levels. In fact, subjects sensitized to perennial allergens had significantly higher ECP values than subjects with seasonal allergy (p < 0.001), whereas in patients with seasonal allergy ECP levels were significantly increased only during the pollen season. Differences in ECP values between various allergic diseases or age groups were only due to a nonhomogeneous distribution of the type of sensitization or to time of sera collection. CONCLUSIONS: Results obtained indicate that persistent natural exposure to a sensitizing allergen is responsible for a measurable increase in serum ECP levels in patients with allergy. (J ALLERGY CLIN IMMUNOL 1996;97:1350-5.)     

Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: a randomized pilot study

The main goal of this study was to assess the role of mycophenolate mofetil (MMF) during interruption of highly active antiretroviral therapy (HAART). Seventeen patients with early-stage chronic HIV type 1 infection were treated with HAART for 12 months. They were then randomized (day 0) to receive MMF (HAART-MMF group, n = 9) or to continue the regimen (HAART group, n = 6) for 120 additional days. At day 120 in the HAART-MMF group, HAART was discontinued, and MMF administration was continued. The primary end point of the study was the number of individuals maintaining a plasma viral load (VL) set point of <200 copies/mL after at least 6 months off HAART. At day 120, all patients in both groups had undetectable plasma VLs. After 6 months off HAART, 5 of 9 patients in the HAART-MMF group versus 1 of 6 patients in the HAART group maintained a plasma VL of <200 copies/mL (P = 0.28). According to the ability of their plasma to inhibit cellular proliferation, patients were reclassified and divided into an inhibition group (n = 6) and a no inhibition group (n = 9). The doubling time of VL rebound was significantly higher in the inhibition group (mean +/- SE, 10.22 +/- 1.3) than in the no inhibition group (mean +/- SE, 4.6 +/- 1.6; P = 0.03). Moreover, 5 of 6 patients in the inhibition group maintained a plasma VL of <200 copies/mL versus 1 of 9 patients in the no inhibition group (P = 0.005) after 6 months off HAART. We found that combining MMF and HAART delayed VL rebound and improved control of viral replication without HAART but only when inhibition of lymphocyte proliferation was achieved.     

Isolation of a polypeptide from the venom of Bungarus multicinctus that binds to ganglia and blocks the ganglionic transmission in mammals

A 15,000 dalton polypeptide purified from Bungarus multicinctus venom (which normally copurifies with alpha-bungarotoxin) was characterized biochemically and its biological effects were studied. This polypeptide, P15, had an aminoacid composition and molecular weight different from those of both alpha- and beta-bungarotoxin. It inhibited the ganglionic transmission in the guinea-pig hypogastric nerve-vas deferens preparation and did not block, even at very high concentrations, the neuromuscular transmission in the rat phrenic nerve-diaphragm preparation. In the same preparations alpha-bungarotoxin was unable to block the response at the ganglionic synapse while it was fully active in blocking the neuromuscular transmission. However, a pretreatment of the vas deferens preparation with alpha-bungarotoxin prevented the inhibitory effect of P15. 125I-Labeled P15 showed a specific and saturable binding to rat superior cervical ganglia homogenate and to a Torpedo postsynaptic membrane fraction. The binding of P15 to ganglia was inhibited by curare. The binding was Ca2+ dependent. The density of binding sites was of 300 fmol/mg of protein in the ganglion and 500 fmol/mg of protein in Torpedo membranes. The amount of P15-binding sites in ganglia was not modified by denervation, indicating that P15 binds to postsynaptic receptors. The binding of 125I-labeled P15, both in ganglia and Torpedo membranes, was inhibited by alpha-bungarotoxin. P15 had a Ca2+-dependent phospholipase A2 activity. Lowering Ca2+ concentration in incubation media affected the phospholipase A2 activity more than binding properties and inhibition of phospholipase activity with p-bromophenacyl bromide did not affect the activity of P15 on vas deferens preparation, suggesting that the phospholipase activity is not necessary for the activity of P15 on nicotinic receptors. Our results suggest that P15 toxin may be a specific and valuable probe for studying the ganglionic nicotinic receptor.     

Prophylaxis of Hepatitis C with Intramuscular Immunoglobulin

Hepatitis C virus (HCV) affects millions of individuals worldwide. In most cases, HCV infection progresses to chronic liver disease and, subsequently, to liver cirrhosis and hepatocellular carcinoma. HCV is transmitted by the parenteral route, for example by transfusion of blood or blood products, injection during drug abuse, etc., and by the inapparent parenteral route (penetration of the virus through difficult-to-identify microlesions present on the skin or mucosae), for example, sexual exposure or household exposure to infected contacts, etc. The cost of chronic hepatitis C and its sequelae is high in both financial and human terms. At present, only anti-HCV screening of blood/organ/tissue donors and universal precautions for the prevention of blood-borne infections are recommended for HCV prevention. Before the discovery of the main aetiological agent of non-A, non-B hepatitis (HCV), several randomised controlled clinical trials demonstrated that standard intramuscular immunoglobulin exerted a preventive effect on post-transfusional and sexual and /or horizontal transmission of non-A, non-B hepatitis. When serological tests for HCV infection became available, bimonthly inoculation of standard unscreened intramuscular immunoglobulin (prepared from plasma pools containing about 2% of anti-HCV-positive units) was demonstrated to significantly prevent sexually transmitted HCV infection. The immunoglobulin used contained high titres of anti-HCV neutralising antibodies (anti-E2 neutralisation of binding assay), whereas currently available commercial screened immunoglobulin (prepared from anti-HCV-negative blood units) did not. This finding suggested that anti-HCV neutralising antibodies are concentrated only in anti-HCV-positive units (which are currently discarded). Thus, anti-HCV hyperimmune globulin (HCIg) can be produced only from anti-HCV-positive units. The neutralising titre can be increased by the exclusive use of units with higher titres of neutralising antibodies. Unlike other hyperimmune globulins, which are produced from a limited number of selected donors, HCIg should be produced from a large number of units so as to contain neutralising antibodies to the different HCV strains. HCIg will have a number of advantages: (i) it is easy to produce and inexpensive; (ii) it has a long half-life, allowing infrequent administration; (iii) new additional viral inactivation procedures have been introduced to eradicate transmission of infection, and (iv) it may be possible to neutralise all the emerging HCV strains. HCIg could be used in all individuals at risk of HCV infection (sexual partners, haemodialysis patients, etc), in preventing reinfection of transplanted livers, and perhaps also in the treatment of chronic hepatitis C, alone or associated with other drugs.