Treatment of small cell lung cancer with a combination of VP16-213 and cyclophosphamide with cisplatin or radiotherapy

Summary Fifty five patients with small cell lung cancer were treated with a VP16-213 combination chemotherapy regimen in two consectutive series. The first series included 24 patients; 10 with limited and 14 with extensive disease were treated with VP16-213, 120 mg/m² p.o. daily for 5 consecutive days, Cyclophosphamide 600 mg/m² i.v. and Cisplatin 80 mg/m² i.v. with hydratation and manitol induced diuresis. The cycle was repeated every 3 weeks. The second series included 31 similar patients, 16 limited, and 15 extensive disease, treated with VP16-213 at the same dose and Cyclophosphamide at 1,200 mg/m² i.v. also repeated every 3 weeks; after three cycles the patients were treated with radiotherapy to the primary tumor and regional lymph nodes with 4,000 rads in a split course of three weeks interval, followed by the same combination chemotherapy. Response rate was 75% for the first series with 6 of 24 (25%) of complete responses in four limited and two extensive disease and a median survival time of 24 weeks. In the second series of patients there were 26 of 31 (83.8%) responses with 10 of 31 (32%) complete responses in nine limited and one extensive disease and a median survival time of 33 weeks for responders. Duration of response for complete responders was 36.8 weeks for the first series and 51 weeks for the second. Toxicity was mild and includes nausea and vomiting, myelosupression, alopecia in both series, with one toxic death in the second series.Both regimens are active with a low complete response rate, which was increased in the second series by the addition of radiotherapy, which did not increase overall survival. Send offprint requests to H. Cortés Funes, Section Oncologia Medica, Servicio de Radioterapia y Oncologia     

Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment

Objective: During the last decade, much attention has been given to the role of signal transduction pathways in affective disorders. This review describes the possible role of the cAMP signaling in such disorders.

Methods: Among the components of cAMP signaling, this review focuses on the cAMP-dependent phosphorylation system. We analyzed the basic components of the cAMP-dependent phosphorylation system and the preclinical evidence supporting their involvement in the biochemical action of antidepressants and mood stabilizers. The clinical data available until now, concerning the possible link between the cAMP-dependent phosphorylation system and the pathophysiology of affective disorders, are also reviewed.

Results: The studies herein presented demonstrated that the levels and the activity of cAMP-dependent protein kinase are altered by antidepressants and mood stabilizers. Furthermore, these medications are able to modify the phosphorylation state, as well as the levels of some of the cAMP-dependent protein kinase substrates. More recently, clinical studies have reported abnormalities in the cAMP-dependent phosphorylation system in both peripheral cells and the postmortem brain of patients with affective disorders.

Conclusions: Overall, these studies support an involvement of cAMP signaling in affective disorders. The precise knowledge of the findings has the potential to improve the understanding of pharmacotherapy and to provide directions for the development of novel biochemical and genetic research strategies on the pathogenesis of affective disorders.     

Clinical experience with intraurethral alprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated urethral system for erection

OBJECTIVE: The Food and Drug Administration (USA) approved the transurethral administration of prostaglandin (alprostadil in January 1997), which had an efficacy of approximately 50% in clinical trials. We studied its effectiveness in clinical practice. METHODS: Patient and partner education was followed by an initial office trial of a medicated urethral system for erection (MUSE) after other medical risk factors were corrected during a 2- to 4-month period. The initial titration dose of alprostadil was usually 125 or 250 microg. Further titration, if needed, was instituted by the patient at home. Success was determined as the satisfactory completion of sexual intercourse in more than 66% of attempts, with a minimum of two being required. RESULTS: Two hundred and seventy patients entered the trials, and follow-up information was available in 229 (85%). The overall success rate was 56%. The dose required was 500 microg in 49.2% and 1,000 microg in 42.2%. Of the 44% in whom treatment failed, 61.4% did so because of lack of efficacy and 38.6% because of side effects (genital pain or urethral bleeding). Minor urogenital symptoms, which did not interfere with treatment, occurred in an additional 40% of patients. CONCLUSIONS: The efficacy of transurethral administration of alprostadil (56%) is higher than the initial published clinical trial data and higher than recent reported clinical experiences, although higher doses were required in our study. Men over 50 years of age, having an organic cause for erectile dysfunction, had better responses. Patient and partner education is important for successful treatment, and the in-office initial titration is an integral part of this success. Prior correction of medical risk factors may enhance the success rate.     

Plasmodium vivax CS peptides display conformational preferences for folded forms in solution

Abstract: Spectroscopic techniques have been used to study the conformations of several synthetic peptides with sequences corresponding to the repeat regions of the circumsporozoite proteins of Plasmodium vivax, variants vk‐210 and vk‐247. As has previously been shown for P. falciparum, turn‐like folded conformations are observed, in rapid dynamic equilibrium with extended‐chain forms. These results are consistent with the known similarity of the structural, biosynthetic and immunological properties of the circumsporozoite proteins of different plasmodial species. Additionally, the observation of folded conformers provides a rationale for the effectiveness of these peptides as immunogens and potential vaccines.     

Venous graft repair following brachial artery thrombosis in a neonate

A case of venous graft repair to recover blood flow of a newborn's upper extremity, is described. Eventhough this complication remains uncommon, we emphasize on to avoid brachial artery for vascular monitorization and to perform microsurgical revision as elective procedure if conservative therapy is unsuccessful. Accepted: 4 February 1997     

Promoting and sustaining health through increased vegetable and fruit consumption among European schoolchildren: The Pro Children Project

Aim The Pro Children consortium consists of the following partners: Knut-Inge Klepp (Coordinator), Department of Nutrition, University of Oslo, Norway; Carmen Perez Rodrigo, Unidad de Nutricion Comunitaria, Bilbao, Spain; Inga Thorsdottir, Unit for Nutrition Research, Landspitali University Hospital, Reykjavik, Iceland; Pernille Due, Department of Social Medicine, University of Copenhagen, Denmark; Maria Daniel Vaz de Almeida, Faculdade de Ciências da Nutrição e Alimentação da Universidade do Porto, Portugal; Ibrahim Elmadfa and Alexandra Wolf, Institute of Nutrition, University of Vienna, Austria; Jóhanna Haraldsdóttir, Research Department of Human Nutrition, Royal Veterinary and Agricultural University, Copenhagen, Denmark; Johannes Brug, Erasmus Medical Center Rotterdam, Department of Public Health, The Netherlands; Michael Sjöström and Agneta Yngve, Unit for Preventive Nutrition, Karolinska Institutet, Stockholm, Sweden; Ilse De Bourdeaudhuij, Department of Movement and Sport Sciences, Ghent University, Belgium.The Pro Children study is designed to assess vegetable and fruit consumption and determinants of the consumption patterns among European school children and their parents. A second objective is to develop and test strategies for promoting increased consumption of vegetables and fruits among school children and their parents.Subjects and methods Surveys of national, representative samples of 11-year-old school children and their parents were conducted in nine countries during October–November 2003, i.e. in Austria, Belgium, Denmark, Iceland, The Netherlands, Norway, Portugal, Spain and Sweden. Comprehensive school-based educational programmes were developed and tested in three settings, i.e. in the Bilbao region, Spain, in Rotterdam, The Netherlands, and in Buskerud county of Norway. A 24-h recall format and frequency items assessing regular intake were used to assess vegetable and fruit consumption. Determinants were assessed employing the theoretical framework of the ASE model (Attitudes, Social Influences and Self-Efficacy), including cognitive factors, normative influences, skills and environmental barriers related to vegetable and fruit consumption. The intervention programmes were tested employing a group-randomized trial design where schools were randomly allocated to an intervention arm and a delayed intervention arm. Surveys among all participating children and their parents were conducted prior to the initiation of the intervention (September 2003; month 0), immediately after the end of the intervention (at month 8) and at the end of the subsequent school year (month 20).Results Preliminary data from the project indicate that girls eat vegetables and fruit significantly more often than do boys across all participating countries. There are no sex differences, however, with respect to perceived availability of vegetables and fruit at home and outside the home setting. In all countries, perceived availability appears to be significantly associated with reported frequency of both vegetable and fruit consumption.Conclusion Experience so far indicates that the Pro Children Project will succeed in producing valid and reliable research instruments for assessing vegetable and fruit consumption among school children and their parents and that comparable, comprehensive intervention programmes can be implemented across geographic and cultural settings within Europe.     

Clinical significance of abdominal scintigraphy using 99mTc-HMPAO-labelled leucocytes in patients with seronegative spondyloarthropathies

Abdominal scintigraphy shows silent gut inflammation in patients with spondyloarthropathies (Sp) without clinical evidence of gut inflammation. Abdominal scintigraphy images are different than those obtained in patients with ulcerative colitis or Crohn's disease and are not related to the anti-inflammatory drugs administered. The aim of this study was to examine the clinical associations of findings on abdominal scintigraphy in patients with Sp. A total of 204 Sp patients (European Spondylarthropathy Study Group 1991 criteria) and 54 non-Sp controls receiving non-steroidal anti-inflammatory drugs were studied. Abdominal scintigraphy images were obtained at 30 and 120 min after injection of technetium-99m hexamethylpropylene amine oxime (^99mTc-HMPAO)-labelled leucocytes. ^99mTc-HMPAO-labelled leucocyte scans were positive in 104 Sp patients (50.9%) and in six non-Sp controls (2.9%) (P<0.001; OR=8.32; 95% CI=3.23-22.67). Silent gut inflammation was not associated with any of the following: age of onset, duration of evolution, sex, family history of Sp or psoriasis, articular manifestations, extra-articular manifestations, radiological findings or HLA-B27 positivity. Positive abdominal scintigraphy was associated with active disease (P<0.0001; OR=52.7; 95% CI=19-145.6) and an increase in the C-reactive protein (P<0.005; OR=3.4; 95% CI=1.5-7.4). It is concluded that (a) abdominal scintigraphy using ^99mTc-HMPAO-labelled leucocytes is of value in detecting the silent gut inflammation in Sp patients, and (b) silent gut inflammation is related to the clinical activity, but is not associated with any particular type of illness or with HLA-B27.     

Caloric and rotatory chair test results in patients with Ménière's disease.

OBJECTIVES: To determine whether an association exists between the parameters of the caloric and rotatory chair tests in patients with unilateral Ménière's disease. METHODS: Patients with unilateral Ménière's disease (n = 100) were subjected to the caloric and the rotatory chair test (sinusoidal harmonic acceleration and impulsive tests) on the same day. Canal paresis and directional preponderance were assessed in the caloric test, and different variables were measured in the rotatory chair test based on the existence of abnormal parameters in the vestibulo-ocular reflex at two or three consecutive frequencies of those tested and on the time constant of the vestibulo-ocular reflex. STUDY DESIGN AND SETTING: A prospective study was conducted at a University hospital. RESULTS: An abnormal result in the caloric test was obtained from 73% of the patients. In the rotatory chair test, the most frequent abnormal findings involved increases in the normal phase lead at 2 consecutive frequencies tested (23%). There was a stronger association between an abnormal result in phase, gain, and/or symmetry at three adjacent frequencies and a pathological result in the caloric test. CONCLUSION: Very few of the criteria used to define the caloric and rotatory chair tests seem to be associated. This confirms previous knowledge that both tests examine vestibulo-ocular reflex by different ways. Only when vestibular dysfunction is severe enough (manifested by the finding of an abnormal result in at least three consecutive frequencies in the rotatory chair test), the caloric test is also found to be abnormal.     

Expression of BAG-1 and BcL-2 Proteins Before and After Neoadjuvant Chemotherapy of Locally Advanced Breast Cancer

It has been suggested that expression of anti-apoptotic proteins such as Bcl-2 or BAG-1 may confer cellular resistance to chemotherapy. A corollary of this hypothesis is that expression of these proteins may predict clinical response to treatment and that Bcl-2- or BAG-1-positive cells may selectively be enriched in postchemotherapy tissue specimens. The goal of this exploratory pilot study was to assess these two predictions by using immunohistochemistry in 29 paired pre- and postchemotherapy breast tissue specimens obtained from patients who underwent preoperative doxorubicin-based chemotherapy. All breast cancers expressed BAG-1 protein, and, in individual tumors, 40-100% of neoplastic cells stained positive for this protein. Homogenous cytoplasmic staining was typically observed, though neoplastic cells also showed nuclear staining in many specimens. We found no correlation between prechemotherapy expression of BAG-1 and subsequent pathological response to cytotoxic therapy. Paired pre- and posttreatment specimens showed similar levels of BAG-1 expression when residual tumor could be assessed. Bcl-2 was expressed in 55% of cancers and was localized to the cytoplasm. Absence of Bcl-2 expression in prechemotherapy specimens was associated with more frequent complete pathological response (58% vs. 20%; p = 0.04). However, similar to BAG-1, no difference between pre- and posttherapy expression of Bcl-2 was observed in neoplastic cells in paired tissue specimens. These observations suggest that BAG-1 contributes an important cellular function to breast epithelial cells, which is reflected by its ubiquitous expression in these tissues. However, it does not appear to determine response to doxorubicin-based chemotherapy. In contrast, lack of Bcl-2 expression was associated with a higher probability of complete pathological response to doxorubicin-based chemotherapy.     

Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.