TNF-alpha and melphalan modulate a specific group of early expressed genes in a murine melanoma model.

BACKGROUND: Cutaneous melanoma displays high morbidity and mortality rates. Isolated limb perfusion with melphalan (Mel) is used for the treatment of non-resectable, locally advanced extremity melanomas. When combined with tumor necrosis factor alpha (TNF-alpha) treatment, the complete response varies between 70% and 90%. The mechanisms underlying the effects of Mel and TNF-alpha are not completely understood. We evaluated the impact of systemic Mel and TNF-alpha administration on tumor growth, analyzed the morphological changes promoted by each treatment, and identified early expressed genes in response to Mel and TNF-alpha treatment, either alone or in combination, in a murine melanoma model. METHODS: Six- to eight-week-old male mice were subcutaneously inoculated with B16F10 melanoma cells and then intravenously injected with TNF-alpha, melphalan or a combination of both drugs when the tumors reached 1.0 cm(2). Tumor growth was monitored every other day, and histological analysis was performed when the tumors reached 3.0 cm(2). Total RNA was extracted from the resected tumors and submitted to amplification, labeling and hybridization on an oligonucleotide microarray (Fox Chase Cancer Center). Tumor growth and histological parameters were compared using ANOVA. Survival curves were calculated using the Kaplan-Meier method. Two-way ANOVA was used to identify differentially expressed genes among the various treatments, and Dunn's test was used for pair-wise comparisons. RESULTS: Systemic administration of Mel impaired tumor growth (p<0.001), improved animal survival (p<0.001), and decreased mitotic rate (p=0.049). Treatment with TNF-alpha alone had no impact, neither on tumor growth, nor on survival, but it increased necrosis (p<0.024) and decreased mitotic rates (p=0.001) in the tumors. Combined treatment with Mel and TNF-alpha had similar effects in tumor growth, survival, necrosis and mitotic rate as observed with individual treatments. Moreover, 118 genes were found differentially expressed by microarray analysis and 10% of them were validated by RT- real time PCR. In our model we found that the treatments regulate genes that play important roles in tumorigenesis such as cell adhesion (Pard3, Pecam1, Ilk, and Dlg5), proliferation (Tcfe3 and Polr1e), cell motility (Kifap3, Palld, and Arhgef6), apoptosis (Bcl2l11), and angiogenesis (Flt1 and Ptprj). CONCLUSIONS: Our data reproduces, in mice, some of the features observed in melanoma patients treated with the combination of Mel and TNF-alpha. The identification of genes with altered expression by these drugs both individually and in combination might help in the understanding of their mechanism of action and, as a consequence, improved strategies that could impact their clinical application.

Prognostic factors for incomplete response in thyroid microcarcinoma: an analysis of initial response to therapy in 517 patients.

OBJECTIVE: Although thyroid microcarcinoma (TMC) usually has a favorable prognosis, some patients present a higher risk of disease recurrence or persistence. Thus, we aimed at identifying possible risk factors associated with an incomplete response to therapy in TMC. METHODS: This was a retrospective study of 517 patients with TMC treated with total thyroidectomy, with or without radioactive iodine (RAI) therapy, reclassified after 1.1 ± 0.4 years according to the response to treatment into "favourable" (excellent/indeterminate) or "unfavorable" (biochemical/structural incomplete) responses. We evaluated participants' age, sex, tumor size, histological variants, multifocality, presence of vascular/lymphatic/perineural invasion, extrathyroidal extension, metastatic lymph nodes (LN), and distant metastasis. The effect of RAI therapy on the response range was analyzed in a given subgroup. RESULTS: The mean age observed was 46.4 ± 12.0 years, and 89.7% were female. We noted 97.5% with papillary carcinoma, 27.8% with multifocality and 11.2% with LN metastasis. Although the majority of patients had a low risk of recurrence/persistence (78%), 75% were submitted to RAI therapy. Incomplete response (20.7%) was associated with multifocality (p=0.041; OR=1.619) and metastatic LN (p=0.041; OR=1.868). These variables were strongly correlated (p=0.000; OR=3.283). No cut-off of tumor size was identified as a predictor of incomplete response by the receiver operating curve analysis. RAI treatment did not influence the response of patients with multifocality or LN metastasis. CONCLUSION: Multifocality and LN metastasis are independent risk factors for incomplete response in TMC patients and are strongly correlated. Additional RAI therapy was not associated with a more favorable response in these subgroups.

APACHE II, POSSUM, and ASA scores and the risk of perioperative complications in patients with oral or oropharyngeal cancer.

BACKGROUND: The indications for surgical treatment of patients with head and neck cancer can be limited by the risk of perioperative complications. Prediction of outcome is important in disease stratification and the subsequent decision-making process. OBJECTIVE: To assess the value of the APACHE II (Acute Physiology and Chronic Health Evaluation II) score, POSSUM (Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity), and ASA (American Society of Anesthesiologists) classification in the prediction of complications in patients with oral or oropharyngeal cancer. METHODS: Five hundred thirty patients with oral or oropharyngeal carcinomas who underwent surgical treatment were evaluated using ASA, POSSUM, and APACHE II scores. The outcome measure was morbidity within 30 days. Logistic regression and receiver operating characteristic curve analyses were used to estimate the predictive ability of the scoring systems. RESULTS: The overall complication rate was 58.9%. Most of the patients had local complications. The mortality was 2.6%. The results showed that APACHE II (relative risk, 1.09; P =.001) and POSSUM (relative risk, 1.09; P<.001) equally predicted perioperative complications and were superior to the ASA system (relative risk, 0.98; P =.89) (area under the curve, 0.65 for APACHE II, 0.68 for POSSUM, and 0.56 for ASA). CONCLUSIONS: The POSSUM and APACHE II scores were useful in predicting perioperative morbidity for patients with oral or oropharyngeal cancer, serving as objective methods to assist the surgeon in classifying patients into risk groups with different probabilities of perioperative complications. The poorer results achieved with the ASA classification are possibly because this system is primarily based on subjective clinical judgments.

Perioperative complications, comorbidities, and survival in oral or oropharyngeal cancer.

OBJECTIVES: To establish the value of clinical factors in the prediction of perioperative complications and death in patients with oral and oropharyngeal carcinomas and to develop a new extended clinical severity staging system that combines patient and tumor factors. PATIENTS AND METHODS: A total of 530 patients with oral or oropharyngeal carcinomas submitted to surgical treatment were studied. Logistic regression was used to identify risk factors for perioperative complications, and the Cox proportional hazards regression model was used to establish independent prognostic factors. RESULTS: Daily alcohol consumption, smoking, sex, neck lump, earache, pain, dysphagia, weight loss, oral bleeding, odynophagia, body mass index, National Cancer Institute comorbidity index score, American Society of Anesthesiologists surgical risk, hematocrit level, and total lymphocyte count had an impact on prognosis in univariate analysis. Survival according to extended clinical severity stage was 76.7% for stage 1, 64.4% for stage 2, 44.8% for stage 3, and 25.5% for stage 4 (chi( 2) = 64.16; P<.001). In multivariate analysis, only APACHE II score, neck dissection, POSSUM index score, and type of reconstruction were independent risk factors for perioperative complications. The final prognostic model included development of local plus systemic complications, extended clinical severity stage, type of reconstruction, and APACHE II score. CONCLUSIONS: Clinical variables have a predictive effect on morbidity and mortality of patients with oral and oropharyngeal cancer treated surgically. Local plus systemic perioperative complications can adversely affect the prognosis. The uniformity of results confirms that survival estimates can be enhanced by the addition of clinical characteristics to the TNM classification, creating a more accurate system for the estimation of prognosis.

Trends in childhood renal cancer mortality in Brazil, 1980-2000.

Mortality from childhood cancers has shown substantial declines in developed countries since 1960, with smaller favourable trends in South America. This study describes mortality trends in renal childhood cancer mortality in São Paulo state, Brazil, from 1980 to 2000. The age-standardised mortality rates among the boys decreased from 0.36 per 100,000 inhabitants in 1984 to 0.09 in 1992, whereas the observed corresponding decline among girls was from 0.43 per 100,000 inhabitants in 1981 to 0.07 in 1990. Statistically significant declining trends in mortality rates were observed for boys (adjusted r(2) = 0.51, P < 0.001) and also for girls (adjusted r(2) = 0.40, P = 0.002), achieving in this group a significant reduction in age-standardised mortality rates in the period (annual percentage change = -4.21). Consistent decrease in mortality rates from childhood renal cancer was noted at São Paulo state. In the absence of changes in incidence rates, this decline could be attributed to the improvement in treatment protocols and supportive measures.

Prognostic score in gastric cancer: the importance of a conjoint analysis of clinical, pathologic, and therapeutic factors.

BACKGROUND: This study was designed to establish a prognostic score for gastric cancer that takes into account factors related to the tumor, the patient, and the treatment. METHODS: Two hundred thirty patients with gastric adenocarcinoma admitted t o the Department of Abdominal Surgery at Hospital do Câncer A. C. Camargo (São Paulo) and treated by gastrectomy from January 1992 until December 1996 were included in this retrospective cohort. The prognostic score was created according to the variables identified in the multivariate analysis and by using the regression coefficients generated by the Cox regression. RESULTS: The 5-year overall survival rate was 44.5%. The final multivariate model identified six variables with a significant and independent effect on survival: sex, weight loss, lymphocyte count, tumor-node-metastasis staging, lymphadenectomy, and lymph node ratio. Patients were divided into four groups according to their scores, as follows: group 1, 0 to 3.0; group 2, 3.5 to 5.5; group 3, 6.0 to 8.5; and group 4, 9.0 to 14.0. The 5-year survival rates were 91.5%, 49.3%, 20.3%, and .0% for the score groups 1, 2, 3, and 4, respectively (P<.001). The score was superior in the assessment of prognosis when compared with tumor-node-metastasis staging alone. CONCLUSIONS: It is possible to create a prognostic score that simultaneously includes factors related to the tumor, patient, and treatment, thus generating a more effective system in predicting the prognosis than the morphology-based staging systems.

Extraocular retinoblastoma: a 13-year experience.

BACKGROUND: The current study was performed to evaluate two regimens of treatment and to describe clinical and epidemiologic characteristics in patients with extraocular retinoblastoma. METHODS: Eighty-three patients with extraocular retinoblastoma according to Childrens Cancer Group (CCG) classification were admitted to the Pediatric Department of the A. C. Camargo between 1987-2000. The age, gender, race, lag time, first clinical presentation, staging, laterality, and treatment regimen were analyzed. Treatment was comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide during the first treatment period (1987-1991) or cisplatin and teniposide with alternating courses of ifosfamide and etoposide during the second treatment period (1992-2000). RESULTS: The mean age of the patients was 32.9 months (range, 2-145 months). The mean lag time was 10.5 months. Forty-three patients were treated in the first period and 40 patients were treated in the second period. Locally advanced tumors (Class I-III) were present in 83.1% of the patients. There was a positive correlation between lag time and age for unilateral tumors (correlation coefficient [r] = 0.35; P = 0.006), whereas the correlation was negative for bilateral tumors (r = -0.12; P = 0.63). The 5-year overall survival was 55.1% in the first treatment period and 59.4% in the second treatment period (P = 0.69). No significant differences with regard to survival rates were noted for unilateral tumors between the two treatment periods (44.6 noted for unilateral tumors vs. 59.1 noted for unilateral tumors). CONCLUSIONS: In the current study, the addition of ifosfamide and etoposide to a treatment regimen comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide did not appear to improve the survival of patients with extraocular retinoblastoma. Patients with dissemination to the central nervous system or metastatic disease remain incurable and die of progressive disease, despite the aggressive treatment. A multicenter trial should be considered to evaluate the best strategy for these situations.