Conservative treatment with transurethral resection, neoadjuvant chemotherapy followed by radiochemotherapy in stage T2-3 transitional bladder cancer.

PURPOSE: Organ preservation has been investigated in patients (p) with infiltrating transitional cell carcinoma (TCC) of the bladder over the past decade as an alternative to radical cystectomy. This is a trimodal schedule study, including transurethral resection of bladder tumor (TURB), neoadjuvant chemotherapy and concomitant radiochemotherapy (RTC). PATIENTS AND METHODS: From April 1996 until August 2005, 29 evaluable patients (p) with T2-T3NXM0 bladder cancer were enrolled. After a transurethral resection of bladder tumor (TURB), we administered 2 cycles of induction chemotherapy with CMV (15 p) or Gemcitabine-Cisplatin (14 p) followed by radiotherapy 45 Gy 1.8 Gy/fraction and two cycles of concomitant cisplatin 70 mg/m(2). 2-3 weeks later, a cystoscopy with tumor-site biopsy was performed. If complete histological response, p were treated with consolidation radiotherapy until 64.8 Gy. For p with residual or recurrent tumor, cystectomy was performed. RESULTS: We included 28 men and 1 women (median age 63, range 39-72 years) with PS (ECOG) 0-1. The stage was: 21 p T2; 6 p T3a; and 2 p T3b. Toxicity was higher in CMV compared with Gem- Cis: grade (3/4) neutropenia 4/15 (26%) vs 1/14 (7%); febrile neutropenia 3/15 (20%) vs 1/14 (7%); grade (3/4) trombocytopenia 2/15 (13%) vs 1/14 (7%). Toxicities with concomitant RCT were low-moderate: urocystitis (26%) and enteritis (18%). RESPONSE: microscopically complete TURB was obtained in 20 p (69%), but not in 9 p (31%) (7 microscopic, and 2 macroscopic residual tumor). We found a complete histologic response after induction RCT in 25 p (86%). After a median follow-up of 69.4 months (m) (range: 8-97.7), there were 8 deaths, with a overall survival of 72%. Furthermore 14 of 29 p (48%) were alive with intact bladder, and median survival time with intact bladder was 63.6 m (50.1-77.2); were predictive of best outcome T2 stage vs T3 (p < 0.0001), and complete histologic resection in initial TURB vs residual tumor (p = 0.0004). CONCLUSIONS: Combined treatment provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients with TCC. Patients with T2 stage and complete histologic resection in initial TURB had the best outcome.

1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency.

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.

Bicyclic N-hydroxyurea inhibitors of 5-lipoxygenase: pharmacodynamic, pharmacokinetic, and in vitro metabolic studies characterizing N-hydroxy-N-(2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl)urea.

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.

Effect of staurosporine on transcription factor NF-kappaB in human keratinocytes.

Activation of the transcription factor NF-kappaB is known to be important in the regulated expression of a large number of pro-inflammatory genes including interleukin-8 (IL-8). Previously, we showed that the protein kinase inhibitor staurosporine potentiates IL-1-stimulated IL-8 production in human keratinocytes. Moreover, recent studies by other investigators demonstrated that staurosporine treatment alone results in a concentration-dependent increase in IL-8 mRNA and protein production. Therefore, in order to understand the mechanism underlying this observation, the effect of staurosporine on the activation of NF-kappaB was investigated. Electrophoretic mobility shift assays using an oligonucleotide containing the NF-kappaB consensus motif demonstrated that staurosporine treatment resulted in the activation of NF-kappaB by 15 min post-treatment. The ability of staurosporine to activate NF-kappaB was investigated further, using luciferase reporters under the control of the HIV-LTR or IL-8 core promoter transfected into human U937 cells. Stimulation with staurosporine resulted in a concentration-dependent induction of luciferase activity. In contrast, the very selective protein kinase C inhibitor 3-[8-[(dimethylamino)methyl]-6,7,8,9-tetrahydropyrido-[1,2-a]indol -10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride (Ro32-0432) did not stimulate the activation of NF-kappaB, as measured in the luciferase reporter assay. The mechanism underlying NF-kappaB activation does not appear to involve the classical activation pathways in that staurosporine does not induce the disappearance of IkappaB family members. In conclusion, staurosporine appears to stimulate the activation of NF-kappaB in at least two cell types, and this effect appears to be independent of protein kinase C.

Tegafur and uracil plus leucovorin in advanced colorectal cancer: a phase II trial.

The objective of this study was to evaluate the activity and toxicity of tegafur and uracil (UFT; 1:4 molar ratio) plus leucovorin (LV) in patients with advanced colorectal cancer. One hundred forty-one patients were entered into the study. The treatment schedule consisted of UFT 300 mg/m2/day (in three divided doses) plus oral LV 150 mg/day (50 mg t.i.d.) over 28 days. The treatment cycle was repeated every 5 weeks until progression or unacceptable toxicity was observed. The treatment was interrupted if grade 3/4 toxicity appeared and was resumed at the same dosage on recovery. One hundred thirty-six patients were evaluable for response and 141 were evaluable for toxicity. The response rate was 19.9% (95% confidence interval: 12%-28%). The total number of patients without progression (objective response + stable disease) was 76 (55.9%). The median time to progression was 5.6 months, and the overall survival was 11.6 months. The toxicity profile was low, with 11% of patients experiencing grade 3/4 nausea and vomiting, while 17% had grade 3/4 diarrhea. Oral administration of UFT modulated with LV is a comfortable regimen of chemotherapy for patients with advanced colorectal cancer.

In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with anti-inflammatory activity.

Leukotriene B4 (LTB4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SB 201993, (E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB4, was evaluated as an antagonist of LTB4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SB 201993 competitively antagonized [3-H]-LTB4 binding to intact human neutrophils (Ki = 7.6 nM) and to membranes of RBL 2H3 cells expressing the LTB4 receptor (RBL 2H3-LTB4R; IC50 = 154 nM). This compound demonstrated competitive antagonism of LTB4- and 12-(R)-HETE-induced Ca2+ mobilization responses in human neutrophils (IC50s of 131 nM and 105 nM, respectively) and inhibited LTB4-induced Ca2+ mobilization in human cultured keratinocytes (IC50 = 61 nM), RBL 2H3-LTB4R cells (IC50 = 255 nM) and mouse neutrophils (IC50 = 410 nM). SB 201993 showed weak LTD4-receptor binding affinity (Ki = 1.9 microM) and inhibited 5-lipoxygenase (IC50 of 3.6 microM), both in vitro and ex vivo. In vivo, SB 201993 inhibited LTB4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED50 of 580 microg/ear and 390 microg/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED50 of 770 and 730 microg/ear, respectively, against the fluid and cellular phases). These results indicate that SB 201993 blocks the actions of LTB4 and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.

Industrial disaster and mental health of children and their parents.

OBJECTIVE: We report the findings of research conducted a year after an industrial disaster (PCB fire), which occurred on Montreal's South Shore in 1988. A total of 1,663 families were evacuated for a period of 18 days. The study evaluated 174 children between the ages of three and eleven years: 87 in the exposed group and 87 in the control sample. METHOD: Structured questionnaires were administered to the children and their mothers and fathers during home visits. RESULTS: Based on the responses of the children and the mothers, children aged 6 to 11 years displayed more overall internalized and post-traumatic stress disorder (PTSD) symptoms than did those in the control group. CONCLUSIONS: The study demonstrates that the mental health of fathers as well as mothers correlates with children's symptoms and that parents are able to accurately observe their child's reaction to a disaster.

Do children aged 9 through 11 years understand the DISC Version 2.25 questions?

OBJECTIVE: To assess the understanding of Diagnostic Interview Schedule for Children-Version 2.25 (DISC-2.25) questions by children aged 9 through 11 years. METHOD: Two hundred forty children were recruited from four public schools. The cognitive appraisal of 280 questions from the most prevalent DSM-III-R diagnoses was evaluated. The collaboration of four children was necessary to cover one DISC. Sixty DISCs, evenly distributed according to age and sex, were completed. Two child psychiatrists evaluated the children's answers. Nonparametric tests were used to assess understanding of questions as a whole, of time concepts (overall, categories, number), and of questions based on the number of words. RESULTS: Children aged 9, 10, and 11 years understood 38%, 38%, and 42% of the questions as a whole, respectively, and 26%, 24%, and 30% of the overall time concepts, respectively. The understanding rates of questions as a whole were significantly higher than those of overall time concepts. Durations were significantly better understood than periods and frequencies, and questions having one time component were significantly better grasped than those with two or more. Shorter questions were significantly better understood than longer ones. CONCLUSION: Although the DISC has been greatly improved since the initial version, the results suggest that additional revision is needed before clinicians or researchers use the DISC with younger children.

Diagnostic Interview Schedule for Children (DISC-2.25) in Quebec: reliability findings in light of the MECA study.

OBJECTIVE: To examine the reliability of the French Diagnostic Interview Schedule for Children (DISC-2.25) in Quebec in light of other DISC-2 studies conducted in the National Institute of Mental Health's Methods for the Epidemiology of Child and Adolescent Mental Disorders Study. METHOD: Reliability was assessed for DSM-III-R disorders in a community sample comprising 260 parents of youths aged 6 to 14 years and 145 adolescents aged 12 to 14 years. The DISC was completed at home. The mean test-retest interval was 13.8 days for parents and 12.8 days for adolescents. RESULTS: Parents' reports: Internal consistency was acceptable for a majority of disorders. The kappa coefficients were in the fair or good ranges except for depressive disorders and were higher for children than for adolescents, and intraclass correlations were higher than kappa coefficients. Adolescents' reports: Internal consistency was acceptable or nearly acceptable for a majority of disorders. The kappa coefficients were in the fair range, and intraclass correlations were higher than kappa coefficients. The kappa coefficients were significantly higher for the test-retest interval of 7 to 14 days than for 14 to 21 days for adolescents' reports of anxious disorders and internalizing disorders. CONCLUSION: The French DISC-2.25 shows acceptable internal consistency and fair to good test-retest reliability. Across DISC-2 studies, test-retest reliability of the parents' reports improved for anxiety and depressive disorders. Among sources of variation, studies on attributes of questions would be meaningful.

Estrogen and progesterone receptors, c-erbB-2, p53, and Bcl-2 in thirty-three invasive micropapillary breast carcinomas.

Tests for estrogen (ER) and progesterone (PR) receptors, c-erbB-2, p53 and Bcl-2 were made on paraffin sections of thirty-three cases of invasive micropapillary carcinoma (MPCa) of the breast. The relations between these proteins and general parameters and the patients' evolution, were analyzed and their statistical significance determined by Fisher's exact test. Follow up was available on twenty one patients of whom thirteen were alive after a mean of sixty months. Tumor size, metastatic nodes, c-erbB-2 and Bcl-2 all showed higher values in the dead patient group, but only nuclear grade and extensive lymphatic vessel invasion (LVI) were statistically significant prognostic factors. Hormone receptors and oncogenes were positive in quite similar figures to those of common breast cancers (NOSCa) and offered supplementary information about differentiation and cell atypia of individual cancers. Accordingly, ER (72.7%), PR (45.4%) and Bcl-2 (69.6%) were directly interrelated and inversely related with nuclear grade, mitotic grade, c-erbB-2 (36.3%) and p53 (12.1%). In conclusion, MPCa is a lymphotropic cancer phenotype whose prognosis can be influenced by known prognostic factors, including molecular. The lack of discriminative power between MPCa and NOSCa of ER, PR, c-erbB-2, p53, and Bcl-2 reinforces the importance of recognizing this particular type of cancer.

Correlates of mental disorders in the Quebec general population of 6 to 14-year olds.

Previous epidemiological studies of correlates of child and adolescent mental disorders in the general population have focused more on child/adolescent and socioeconomic/sociodemographic characteristics than on family characteristics. Moreover, there are no generally accepted methods to analyze and interpret correlates. The purpose of the Quebec Child Mental Health Survey in this regard was twofold: (1) to identify correlates of DSM-III-R internalizing and externalizing disorders according to informant (youth, parent, teacher), for three age groups (6-8, 9-11, and 12-14 years), including relevant family characteristics not considered in previous studies; and (2) to interpret the relative importance of risk indicators by ranking correlates according to strength and consistency of association across age groups. Logistic regression models suggest the inconsistency of correlates across informants. The ranking of correlates reveals that individual and family characteristics make a more important contribution than do socioeconomic characteristics, thereby supporting the relevance of proximal variables in the development of psychopathology.

Differentiation in vivo of classical non-steroidal antiinflammatory drugs from cytokine suppressive antiinflammatory drugs and other pharmacological classes using mouse tumour necrosis factor alpha production.

The stimulation of tumour necrosis factor alpha (TNF alpha) production by lipopolysaccharide (LPS) has been widely used, both in vitro and in vivo, to examine the biochemistry and pharmacology of inflammatory cytokine production. It appears that classical nonsteroidal antiinflammatory drugs (NSAIDs) (prostaglandin H synthase 1 (PGHS-1) inhibitors) do not inhibit but instead stimulate cytokine production. In the current study, the authors utilized LPS-induced TNF alpha production in the Balb/c mouse to evaluate the activity of a classical NSAID, a mixed inhibitor, and SmithKline Beecham cytokine suppressive antiinflammatory drugs (CSAID). The results corroborated the stimulation of TNF alpha production by NSAIDs (indomethacin, naproxen, ibuprofen) and indicated that the stimulation rank-ordered with the potency of inhibition of PGHS-1. Neither acetaminophen nor nabumetone was found to stimulate TNF alpha production significantly. Tenidap, a compound reported to inhibit 5-lipoxygenase, cyclooxygenase and cytokine production, also stimulated TNF alpha production while the 5-lipoxygenase inhibitor, phenidone, was inactive. The CSAID (exemplified by SK&F 86002, SK&F 105809 and SK&F 104351), strongly inhibited TNF alpha production in this model system (ED50s of 32, 48, and 34 mg/kg p.o., respectively). These results clearly differentiate CSAID from the other compounds tested and suggest that CSAID are relatively weak inhibitors of PGHS 1 while being potent inhibitors of inflammatory cytokine production.

Weekly first-line chemotherapy of metastatic breast cancer with cyclophosphamide and epirubicin.

Forty-six patients with metastatic breast cancer who had not received previous chemotherapy for advanced disease entered a phase II trial of weekly chemotherapy with cyclophosphamide (250 mg/m2) + epirubicin (25 mg/m2) for 16 weeks. The overall response rate was 61% (95% confidence limits, 47-75%), with 10 complete and 17 partial responses. Toxicity was mild and confined to nausea and vomiting and asymptomatic neutropenia (except in 2 cases). Sixty-three per cent of patients had no side effects. Weekly cyclophosphamide + epirubicin is an active and nontoxic regimen for patients with metastatic breast cancer who have had no prior anthracycline-containing adjuvant chemotherapy.

[Neoadjuvant treatment with cisplatin, 5-FU and folinic acid in advanced head and neck cancer]. / Tratamiento neoadyuvante en el cáncer avanzado de cabeza y cuello con cisplatino, 5-fluorouracilo y ácido folínico.

From May to February 1992, 32 patients diagnosed as advanced cancer of the head and neck were included in a program of neoadjuvant treatment with cisplatin, 5-FU, and folinic acid, followed by radiotherapy (45 at 70 Gy) and/or surgery. Twenty patients were considered fully evaluable; their global response rate was 75% (7 complete responses and 8 partial responses). Five patients had no appreciable response or progression. Radiotherapy after chemotherapy enhanced the response, yielding complete responses in 4 patients and partial response in 1. Toxicity was moderate, except for mucositis (9 cases grade 3-4), despite high doses of drugs and radiotherapy. Given the clinical results, this combination may be promising as a first-line treatment against advanced cancer of the head and neck.

Complementary development of prevention and mental health promotion programs for Canadian children based on contemporary scientific paradigms.

Confusion regarding definitions and standards of prevention and promotion programs is pervasive, as revealed by a review of such programs in Canada. This paper examines how a discussion of scientific paradigms can help clarify models of prevention and mental health promotion and proposes the complementary development of prevention and promotion programs. A paradigm shift in science contributed to the emergence of the transactional model, advocating multiple causes and dynamic transactions between the individual and the environment. Consequently, the view of prevention applying over a linear continuum and of single stressful events causing mental disorders may no longer be appropriate. It is the author's belief that the new science of chaos theory, which addresses processes involved in the development of systems, can be applied to child development and thus to the heart of prevention and promotion programs. Critical moments followed by transitions or near-chaotic behaviours lead to stable states better adapted to the environment. Prevention programs would focus on the critical moments and target groups at risk to reduce risk factors. Promotion programs would focus on stable states and target the general population to develop age-appropriate life skills. The concept of sensitive dependence on initial conditions and certain empirical studies suggest that the programs would have the greatest impact at the beginning of life. It is hoped that this effort to organize knowledge about conceptual models of prevention and mental health promotion programs will foster the development of these programs to meet the urgent needs of Canadian children.

[Pediatric psychiatry and dermatology: presentation of a case of atopic dermatitis]. / Pédopsychiatrie et dérmatologie: présentation d'un cas de dermite atopique.

As consultants in child psychiatry to the Dermatological service of a large pediatric hospital, the authors, like other clinicians, think that psychological factors have an effect upon the course of atopic dermatitis. They present the case of a child showing the existence of three important psychological factors. These are a closed parents-child relationship, conflict around aggressiveness and the meaning of somatic regressions. Finally, while referring to the literature, they discuss the way these factors might operate in the course of the disease.

Pilot study for the Quebec Child Mental Health survey: Part I. Measurement of prevalence estimates among six to 14 year olds.

A pilot study for a Quebec Child Mental Health Survey was completed in 1990 with 139 children aged six to 14 years from the general population. Six month prevalence estimates for seven disorders were established using DSM-III-R criteria alone and in combination with an impairment index related to the diagnoses. Prevalence estimates were studied separately for parents and children. Each age group (six to 11, 12 to 14) was also studied separately. The impairment index, working as a severity scale, lowered prevalence estimates and allowed identification of impairing and non impairing diagnoses. Little overlap was found between informants.