Carcinoma of the uterine cervix. II. Lack of impact of prolongation of overall treatment time on morbidity of radiation therapy

PURPOSE: Several reports document a negative impact of prolongation of overall treatment time in a course of irradiation on tumor control and survival. A correlation has been documented of incidence of significant treatment sequelae with increasing doses of irradiation, volume of the specific organ, and dose per fraction. However, no data were found on the potential correlation of overall irradiation treatment time with significant sequelae. METHODS AND MATERIALS: Records were reviewed of 1,269 patients with carcinoma of the cervix (Stage IB to HI) treated with definitive irradiation (combination of external beam and two intracavitary insertions). Follow-up was obtained in 97% of patients (median, 12 years; minimum, 3 years; maximum, 28 years). The relationships between overall treatment time and time of brachytherapy and incidence of treatment sequelae were analyzed for each stage. RESULTS: Overall incidence of Grades 2 (moderate) sequelae was 7% and of Grade 3 (severe) sequelae, 11%. There was no significant correlation of various incidences of Grade 2 and 3 sequelae with overall treatment times (8% in patients treated in less than 7 weeks, 9% in 7.1 to 9 weeks, and 12% when treatment time was longer than 9 weeks) (p = 0.08). In patients with Stage IB and IIA tumors, incidence of rectal toxicity (mostly proctitis) was comparable in patients treated in less than 7 or 7.1 to 9 weeks (4.1 and 6%, respectively) and slightly higher in those treated in longer periods (11.5%) (p = 0.24). In patients with Stage IIB and III, the incidence of Grade 2 and 3 small bowel morbidity was 2% in those treated in less than 7 weeks, 6% for 7.1 to 9 weeks, and 4.9% for longer times (p < or = 0.01). This increased morbidity was also correlated with total dose of irradiation to the lateral pelvic wall: 5 of 257 (2%) for less than 60 Gy and 21 of 438 (4.8%) for higher doses (p < or = 0.01). There was no significant correlation between the timing of brachytherapy (usually two low dose rate intracavitary insertions performed within 4.5 to 6.5 weeks of initiation of external beam therapy) and significant treatment sequelae. CONCLUSIONS: We observed a varied average incidence of Grade 2 and 3 morbidity in the bladder, rectum, and small intestine with different overall treatment times, without a definite pattern to suggest an impact of prolongation of treatment time on morbidity. Likewise, there was no significant correlation with the timing of intracavitary insertions and morbidity of therapy. Because prolongation of the overall treatment time has a well-documented detrimental effect on pelvic tumor control and survival in carcinoma of the cervix with no significant impact on morbidity, it is imperative to deliver radiation therapy in the shortest possible time and without schedule interruptions.     

The significance ofheregulin in breast cancer tumor progression and drug resistance

Summary TheerbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship betweenerbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) oferbB-2 overexpression remains elusive. The discovery ofheregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through theerbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studiesin vitro have shown thatheregulin induces a biphasic growth effect on cells witherbB-2 overexpression. Interestingly, we observed that expression ofheregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated thatheregulin is involved in breast cancer tumor progression. We have shown thatheregulin inducesin vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, aheregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively expressheregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifenin vitro andin vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lostbcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, theheregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of theerbB-2/4 andheregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study ofheregulin and its co-expression witherbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance ofheregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

Blood conservation techniques for cardiac surgery: a survey of French centres

A survey resulting from a partnership between CECEC (Centre d'Etudes en Circulation Extra-Corporelle) and Laboratoires Hoechst, France was carried out amongst all French adult cardiac surgery centres. The aim of this study was to investigate the various strategies used to decrease blood loss during open-heart surgery. Due to an exceptionally high response rate, we are able to report the current practice of French cardiac centres which account for 75% of open-heart adult surgery. The three most interesting strategies for blood conservation appear to be haemodilution, blood salvage from the extracorporeal circuit and previously deposited autologous blood transfusion, yet the three methods which are predominantly used are haemodilution (92.7%), aprotinin therapy (87.8%) and blood salvage from the extracorporeal circuit (82.9%).     

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     

Comprehensive mutational scanning of the p53 coding region by two- dimensional gene scanning

A comprehensive mutational scanning test for the p53 coding region based on multiplex PCR and two-dimensional DNA electrophoresis was designed and evaluated. In a 2-step multiplex PCR, the p53 coding region (exons 2-11) was amplified as a single 8646-bp fragment by long- distance PCR in step one. This fragment served as a template for the subsequent co-amplification of the individual exons in two multiplex groups in step two. The multiplex products were then separated, first on the basis of size in non-denaturant polyacrylamide gels and then on the basis of sequence by denaturing gradient gel electrophoresis (DGGE). Primers for optimal PCR, melting behavior and 2-D gel distribution were designed using a recently developed computer program. The resulting two-dimensional gene scanning (TDGS) test was evaluated by screening, in a blinded fashion, 29 coded DNA samples from Li- Fraumeni syndrome patients with previously identified germline mutations. All mutations were correctly detected. This assay provides an accurate, cost-effective and non-radioactive method for simultaneous mutational scanning of all p53 coding exons.      

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.