Role of immunoexpression of nitric oxide synthases by Hodgkin and Reed-Sternberg cells on apoptosis deregulation and on clinical outcome of classical Hodgkin lymphoma.

Hodgkin and Reed-Sternberg (H-RS) cells of classical Hodgkin lymphoma (cHL) present an impaired expression of immunoglobulin genes, but escape apoptotic death. We investigated whether nitric oxide synthases (NOS) are expressed by H-RS cells, studied their association with EBV status and the expression of apoptotic proteins, and investigated their relationship to the clinical outcome of 171 patients. NOS1 and NOS2 were expressed in a large number of cases, whereas NOS3 expression was not detected. Positive associations were found between NOS1 and p53, bax and NOS2, bcl-2 and NOS2, bax and p53, and between bax and fasL. Inverse correlations were established between EBV and NOS2 and between EBV and bcl-2. A shorter overall survival (OS) was associated with strong expression of NOS2. In conclusion, NOS are expressed by H-RS cells of cHL.

Improvement in the outcome of children with germ cell tumors.

PURPOSE: To describe the clinical characteristics and estimate the survival of children and adolescents with germ cell tumors treated with cisplatin-based combination chemotherapy according to three different protocols in Brazil. METHODS: From 1983 to 1997, 106 patients were treated at the Hospital do Cancer, Sao Paulo for a diagnosis of germ cell tumor. We performed a retrospective review of the clinical and histopathological data to identify prognostic factors and evaluate their outcome. RESULTS: Patients were treated with only surgery (n = 32), surgery and radiotherapy (n = 1) and chemotherapy (n = 73). From 1983 to 1986 (period I), there were 30 patients and 21 received chemotherapy according to the modified VAB-6 protocol. Twenty-two of 35 patients registered between 1987 and 1991 (period II) were treated with EPO/VAC combination chemotherapy. From 1991 to 1997 (period III), there were 41 patients and 31 received chemotherapy according to the Brazilian TCG-91 protocol. Important prognostic factors included stage (P < 0.001), metastatic status (P < 0.001) and surgical procedure at diagnosis (P < 0.001). An incremental improvement in outcomes was noted across the periods of treatment (P = 0.070). Five-year OS was respectively 42.9 +/- 10.8%, 53.9 +/- 11.4% and 80.6 +/- 7.1% for periods I, II, and III for the patients who received chemotherapy. CONCLUSION: An improvement in the survival of children with germ cell tumors was achieved in the most recent trial (TCG-91) with a risk adapted approach incorporating only cisplatin and etoposide. These results indicate that in selected patients complex three-agent regimens may not be necessary to achieve long term survival.

Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins.

The physiological functions of the cellular prion protein, PrP(C), as a cell surface pleiotropic receptor are under debate. We report that PrP(C) interacts with vitronectin but not with fibronectin or collagen. The binding sites mediating this PrP(C)-vitronectin interaction were mapped to residues 105-119 of PrP(C) and the residues 307-320 of vitronectin. The two proteins were co-localized in embryonic dorsal root ganglia from wild-type mice. Vitronectin addition to cultured dorsal root ganglia induced axonal growth, which could be mimicked by vitronectin peptide 307-320 and abrogated by anti-PrP(C) antibodies. Full-length vitronectin, but not the vitronectin peptide 307-320, induced axonal growth of dorsal root neurons from two strains of PrP(C)-null mice. Functional assays demonstrated that relative to wild-type cells, PrP(C)-null dorsal root neurons were more responsive to the Arg-Gly-Asp peptide (an integrin-binding site), and exhibited greater alphavbeta3 activity. Our findings indicate that PrP(C) plays an important role in axonal growth, and this function may be rescued in PrP(C)-knockout animals by integrin compensatory mechanisms.

Comorbidity measurement in patients with laryngeal squamous cell carcinoma.

INTRODUCTION: The evaluation of a cancer patient can be affected by many factors. Cancer patients often have other diseases or medical conditions in addition to their cancer. These conditions are referred to as comorbidities. They can influence the treatment option, the rate of complications, the outcome, and can confound the survival analysis. OBJECTIVE: It was the aim of this study to measure comorbidities in patients with laryngeal squamous cell carcinoma. PATIENTS AND METHODS: Ninety adult patients treated for newly diagnosed laryngeal squamous cell carcinoma were studied. We measured comorbid illness applying the following validated scales: the Cumulative Illness Rating Scale (CIRS), the Kaplan-Feinstein Classification (KFC), the Charlson index, the Index of Coexistent Disease (ICED), the Adult Comorbidity Evaluation-27 (ACE-27), the Alcohol-Tobacco-Related Comorbidities Index (ATC), and the Washington University Head and Neck Comorbidity Index (WUHNCI). Survival analysis was performed using the Kaplan-Meier method (with the log-rank test value being used to compare groups). The Cox proportional hazards model was chosen to identify independent prognostic factors. RESULTS: The mean age was 62.3 years. The majority of patients (36.7%) had early tumors. Forty patients were treated by surgery only, while the remaining 49 patients also received postoperative radiation therapy. Only 5 patients (5.6%) were lost to follow-up. Median follow-up time was 42.5 months. The 4-year overall survival was 63%. There was a statistically significant difference between survival rates according to clinical stage (CS I 87.3%, CS II 48.9%, CS III 74.7%, CS IV 23.9%; p < 0.001). Patients treated by surgery only presented a better survival rate (79.6%) than those receiving postoperative radiation therapy (48.9%; p = 0.001). A statistically significant difference in survival rates was also noted when patients were analyzed according to the type of surgical procedure. In a univariate analysis, comorbidity had impact on prognosis, no matter which scale was utilized: CIRS (p = 0.008), ACE-27 (p = 0.010), ATC (p = 0.004), WUHNCI (p = 0.003), Charlson index (p = 0.020), KFC (p = 0.001), and ICED (p = 0.010). However, in the multivariate analysis, only CIRS and TNM staging were identified as independent prognostic factors. CONCLUSION: The comorbidity is an independent prognostic factor in patients with surgically treated laryngeal cancer. In the univariate analysis, all indexes were able to stratify patients. However, in the multiple analysis, only the CIRS was predictive of death. Comorbidities are an important factor in the analysis of overall survival.

Treatment of retinoblastoma patients with chemoreduction plus local therapy: experience of the AC Camargo Hospital, Brazil.

To evaluate the efficacy of conservative management of intraocular retinoblastoma with chemoreduction combined with local therapy with or without plaque radiation in the preservation of the eye, and avoidance of external beam radiation therapy (EBRT) (success rate). From 1995 to 2000, 84 newly diagnosed patients with intraocular retinoblastoma were admitted to the Pediatric Department of the Hospital do Cancer A.C. Camargo, São Paulo, Brazil. All children were treated with 2 to 6 cycles of chemotherapy (carboplatin, vincristine, and etoposide) plus local therapy (cryotherapy, laser photocoagulation, and thermotherapy), or plaque radiation therapy during and/or after the chemotherapy. The Mann-Whitney test was used to compare means of quantitative variables. The chi test or the Fisher exact test were employed to verify the association between the outcome and the independent variables. For all tests alpha=5% was adopted. Success rate was higher for patients with bilateral tumors (54%) than for children with unilateral tumors (19%) (P=0.003). For patients with Reese-Ellsworth stages I, II, and III, no statistically significant differences in the success rates were noted in the group of unilateral (50%) and bilateral tumors (79.1%) (P=0.179). Among children with Reese-Ellsworth stages IV and V, the success rate was significantly higher for patients with bilateral tumors (40.7%) than for those with unilateral (0%) (P=0.012). Chemoreduction combined with local therapy, with or without plaque radiotherapy, is efficacious in avoiding enucleation and the use of external beam radiation therapy for children with intraocular retinoblastoma.

Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways.

Understanding the physiological function of the cellular prion (PrPc) depends on the investigation of PrPc-interacting proteins. Stress-inducible protein 1 (STI1) is a specific PrPc ligand that promotes neuroprotection of retinal neurons through cAMP-dependent protein kinase A (PKA). Here, we examined the signaling pathways and functional consequences of the PrPc interaction with STI1 in hippocampal neurons. Both PrPc and STI1 are abundantly expressed and highly colocalized in the hippocampus in situ, indicating that they can interact in vivo. Recombinant STI1 (His6-STI1) added to hippocampal cultures interacts with PrPc at the neuronal surface and elicits neuritogenesis in wild-type neurons but not in PrPc-null cells. This effect was abolished by antibodies against either PrPc or STI1 and was dependent on the STI1 domain that binds PrPc. Binding of these proteins induced the phosphorylation/activation of the mitogen-activated protein kinase, which was essential for STI1-promoted neuritogenesis. His6-STI1, but not its counterpart lacking the PrPc binding site, prevented cell death via PKA activation. These results demonstrate that two parallel effects of the PrPc-STI1 interaction, neuritogenesis and neuroprotection, are mediated by distinct signaling pathways.

Implantaçäo do registro hospitalar de câncer e a qualidade das informaçöes hospitalares - A. C. Camargo Säo Paulo / The imptementution of a hospital-based c&ncer registry and the qualitY of information

O presente artigo tem como objetivo descrever as diferentes fases do processo de implantação do registro de base hospitalar num centro de referência em oncologia, com os respectivos procedimentos para se assegurar a qualidade das informações. As análises preliminares foram realizadas com os primeiros 2.300 pacientes incluídos, com diagnóstico confirmado de neoplasia maligna, admitidos durante o ano de 1994. A confiabilidade das codificações foi avaliada através da recodificação de 15(por cento) dos casos de estudo piloto selecionados aleatoriamente. Nesta análise de concordância todos os ítens da ficha foram incluídos, porém com maior ênfase na topografia do tumor, no tipo histológico e no estadiamento. O estadiamento clínico, que se baseia na classificação TNM, teve uma concordância média de 82(por cento) entre a primeira e a segunda codificação, feita por diferentes codificadores. Os tumores de próstata, retina e cérebro foram as topografias que apresentaram codificações discordantes. A manutenção da qualidade das informações ocupou uma posição de destaque dentre os desafios enfrentados pelo RHCHACC durante a sua fase de implantação. Os seguintes aspectos mereceram cuidados maiores no decorrer deste processo: o estadiamento dos tumores pediátricos, a codificação dos linfomas devido à grande variedade de tipos histológicos, o estadiamento de tumores em que o TNM não pode ser aplicado, o treinamento e a supervisão de codificadores e a qualidade do prontuário médico