Evaluación del tratamiento de linfoma de Hodgkin con esquema ABVD en Chile / Treatment of Hodgkin lymphoma: analysis of 915 patients

Background: Hodgkin lymphoma has a high rate of curability, even in advanced stages. Aim: To assess the results of Hodgkin lymphoma treatment using the ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy regimen. Material and Methods: Analysis of a database held by the Chilean Ministry of Health, including all patients treated at accredited cancer treatment centers. Results: Data for 915 patients, median age 35 years (range 15-86 years) and followed for a median of 97 months (range 1-347 months) were analyzed. Forty-one percent had localized disease. Overall survival at five years for localized and advanced stages was 92% and 74%, respectively. The figures for progression free survival were 87% and 64%, respectively. Patients with relapse who received autologous stem cell transplantation (ASCT) had a five year overall survival of 92%, compared to 64% among those who did not undergo this procedure (p < 0.01). The Guarantees in Health Program set up by the Ministry of Health, was associated with earlier stage disease at diagnosis. Conclusions: The ABVD regimen achieves high rates of cure in localized stages of the disease but the results in advanced stages are not optimal. ASCT significantly improves survival in patients with relapse. The Guarantees in Health Program is associated with earlier diagnosis of the disease.

Terapia-alvo versus dacarbazina no tratamento de primeira linha do melanoma avançado não cirúrgico e metastático: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde, 2018-2020 / Terapia dirigida versus dacarbazina en el tratamiento de primera línea del melanoma avanzado no quirúrgico y metastásico: análisis de impacto presupuestario en la perspectiva del Sistema Nacional de Salud de Brasil, 2018-2020 / Target therapy versus dacarbazine in first-line treatment of advanced non-surgical and metastatic melanoma: budget impact analysis from the perspective of the Brazilian National Health System, 2018-2020

Objetivo: estimar o impacto orçamentário incremental da terapia-alvo para tratamento de primeira linha do melanoma avançado não cirúrgico e metastático, em comparação à dacarbazina. Métodos: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde (SUS) do Brasil; a partir de dados demográficos e estimativas da incidência, foi delimitada a população no horizonte temporal de três anos (2018-2020) e estimados os custos diretos médicos; foi considerado cenário de referência o tratamento com dacarbazina, e como cenários alternativos a terapia-alvo com vemurafenibe, dabrafenibe, vemurafenibe + cobimetinibe e dabrafenibe + trametinibe; a avaliação das incertezas foi conduzida mediante análise por cenários. Resultados: o impacto orçamentário incremental variou de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% dos gastos anuais totais com medicamentos ambulatoriais no SUS; no melhor e no pior cenário, os resultados variaram de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusão: a terapia-alvo, comparada à dacarbazina, implica impacto excessivo no orçamento, desfavorecendo eventual incorporação.

Objetivo: estimar el impacto presupuestario incremental de la terapia dirigida para tratamiento de primera línea del melanoma avanzado no quirúrgico y metastásico comparado con la dacarbazina. Métodos: análisis de impacto presupuestario, en la perspectiva del Sistema Único de Salud (SUS) de Brasil; a partir de datos demográficos y estimaciones de incidencia se delimitó la población en un horizonte temporal de tres años (2018-2020) y se estimaron los costos directos médicos. El escenario de referencia fue el tratamiento con dacarbazina y los escenarios alternativos la terapia dirigida con vemurafenib, dabrafenib, vemurafenib + cobimetinib y dabrafenib + trametinib; la evaluación de incertidumbre se llevó a cabo mediante análisis por escenarios. Resultados: el impacto presupuestario incremental varió de R$ 451.867.881,00 a R$ 768.860.968,00, representando 0,70 a 1,53% de gastos anuales totales con medicamentos de ambulatorios en el SUS; en el mejor y el peor escenario los resultados variaron de R$ 289.160.835,00 a R$ 1.107.081.926,00. Conclusión: el uso de terapia dirigida comparado a la dacarbazina implica en impacto excesivo en el presupuesto, desfavoreciendo una eventual incorporación.

Objective: to estimate the incremental budget impact of target therapy for first-line treatment of advanced non-surgical and metastatic melanoma compared to dacarbazine treatment. Methods: budget impact analysis, from the Brazilian National Health System (SUS) perspective; based on demographic data and incidence estimates, the population over a three-year time horizon (2018-2020) was delimited and the direct medical costs were estimated; the reference scenario was treatment with dacarbazine, and the alternative scenarios were target therapy with vemurafenib, dabrafenib, vemurafenib + cobimetinib and dabrafenib + trametinib; uncertainty assessment was conducted through scenario analysis. Results: the incremental budget impact ranged from R$ 451,867,881.00 to R$ 768,860,968.00, representing 0.70 to 1.53% of total SUS annual outpatient drugs expenditure; in best and worst scenario, results ranged from R$ 289,160,835.00 to R$ 1,107,081,926.00. Conclusion: the use of target therapy compared to dacarbazine implies an excessive impact on the budget, this bring unfovorable to its possible incorporation.

Aconselhamento telefônico: identificação de sintomas em pacientes com linfoma em quimioterapia antineoplásica / Consulta telefónica: identificación de síntomas en pacientes con linfoma en quimioterapia antineoplásica / Telephone counseling: identification of symptoms in patients with lymphoma undergoing antineoplastic chemotherapy

Resumo Objetivo Identificar os sinais e sintomas apresentados por pacientes com Linfoma de Hodgkin submetidos ao protocolo quimioterápico composto por Doxorrubicina, Bleomicina, Vimblastina e Dacarbazina (ABVD) por meio de aconselhamento telefônico e comparar os escores de gradação dos sinais e sintomas apresentados nos ciclos do protocolo. Métodos Descritivo, prospectivo, quantitativo. Sete pacientes receberam aconselhamento telefônico, em 24 tempos de chamadas programadas e não programadas, correspondentes a 6 ciclos de quimioterapia com protocolo ABVD. Utilizou-se o Inventário de Sintomas do M.D Anderson e o Critério Comum de Terminologia para Eventos Adversos, para a gradação dos sintomas e um protocolo de condutas. Realizou-se análise descritiva e analítica. Resultados Duzentas e oitenta e seis chamadas telefônicas geraram1.870 queixas sintomáticas. Nas chamadas programadas, as queixas com maior prevalência foram fadiga, preocupações, falta de apetite, vômitos e náuseas. Quanto a interferência nas atividades de vida diária, os itens relacionados a atividades em geral, no trabalho e dificuldade para caminhar, além de alterações no humor foram relatados em maior frequência. Nas chamadas não programadas, a falta de apetite e desregulação menstrual foram as queixas mais recorrentes. Na análise da progressão dos sintomas, observou-se aumento de náuseas e vômitos (p=0,02), diminuição da fadiga e falta de ar (p≤0,03), melhora do sono (p=0,02) e diminuição do estresse (p=0,02). Conclusão A fadiga, náusea, vômito e alteração nas atividades de trabalho foram relatados frequentemente. Houve progressão de náuseas e vômitos, mas regressão da fadiga e do estresse. O aconselhamento telefônico permitiu a comunicação e o manejo rápido de um número expressivo de sintomas.

Resumen Objetivo Identificar los signos y síntomas presentados por pacientes con linfoma de Hodgkin sometidos al protocolo quimioterápico compuesto por doxorrubicina, bleomicina, vinblastina y dacarbazina (ABVD) mediante consulta telefónica, y comparar los puntajes de graduación de los signos y síntomas presentados en los ciclos del protocolo. Métodos Descriptivo, prospectivo, cuantitativo. Siete pacientes recibieron asesoramiento telefónico en 24 momentos de llamadas programadas y no programadas, correspondientes a 6 ciclos de quimioterapia con protocolo ABVD. Se utilizó el Inventario de Síntomas de M. D. Anderson y el Criterio de Terminología Común para Efectos Adversos, para la puntuación de lis síntomas, y un protocolo de conductas. Se realizó análisis descriptivo y analítico. Resultados Doscientas ochenta y seis llamadas telefónicas determinaron 1.870 quejas sintomáticas. En las llamadas programadas, las quejas más prevalentes fueron: fatiga, preocupaciones, falta de apetito, vómitos y náuseas. Respecto a interferencia en actividades cotidianas, los ítems relacionados con actividad en general, laboral y dificultad para caminar, además de cambios del humor, fueron informados con mayor frecuencia. En llamadas no programadas, la falta de apetito y la irregularidad menstrual resultaron las quejas más habituales. En el análisis de progresión de los síntomas se observó aumento de náuseas y vómitos (p=0,02), disminución de fatiga y falta de aire (p≤0,03), mejora del sueño (p=0,02) y disminución del estrés (p=0,02). Conclusión Hubo informe frecuente de fatiga, náuseas, vómitos y cambios en actividades laborales. Existió progresión de náuseas y vómitos, y regresión de fatiga y estrés. La consulta telefónica permitió comunicación y rápido manejo de una expresiva cantidad de síntomas.

Abstract Objective To identify through telephone counselling the signs and symptoms presented by patients with Hodgkin's Lymphoma undergoing chemotherapy with the protocol composed by doxorubicin, bleomycin, vinblastine and dacarbazine and to compare severity scores of the signs and symptoms presented in the cycles of the protocol. Methods Descriptive, prospective, quantitative study. Seven patients received telephone counselling in 24 scheduled and unscheduled calls, corresponding to 6 ABVD chemotherapy cycle. The MD Anderson Symptom Inventory and the Common Terminology Criteria for Adverse Events were used for scoring the symptoms, along with a conduct protocol. A descriptive and analytical analysis was conducted. Results Two hundred and eighty-six telephone calls generated 1,870 symptomatic complaints. In scheduled calls, the most prevalent complaints were fatigue, distress, lack of appetite, vomiting and nausea. As for the interference in daily life activities, the items related to general activities, work, difficulty walking, and mood changes were reported more frequently. In unscheduled calls, lack of appetite and irregular menstruation were the most recurring complaints. The analysis of the progression of symptoms showed an increase in nausea and vomiting (p=0.02), decrease in fatigue and shortness of breath (p≤0.03), improvement in sleep (p=0.02) and decrease of stress (p=0.02). Conclusion Fatigue, nausea, vomiting and alterations in work activities were frequently reported. There was progression of nausea and vomiting but regression of fatigue and stress. Telephone consultation allowed a rapid communication and management of an expressive number of symptoms.

Genetic variants related to angiogenesis and apoptosis in patients with glioma / Variantes genéticas relacionadas à angiogênese e apoptose em pacientes com glioma

ABSTRACT Background Glioma, the most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. The objectives of this study were to evaluate the association of genetic polymorphisms related to angiogenesis and apoptosis with gliomas, as well as comorbidities, lifestyle, clinical profile, survival and response to treatment (temozolomide [TMZ] and radiotherapy [RT]) in patients with the disease. Methods In a total of 303 individuals, genotypes were performed by real-time PCR, and clinical data, lifestyle and comorbidities were obtained from medical records and questionnaires. The significance level was set at 5%. Results Smoking, alcohol consumption, systemic arterial hypertension, diabetes mellitus and body mass index prevailed among patients, compared to controls (p < 0.05). The heterozygous genotype rs1468727 (T/C) and the homozygous genotype rs2010963 (G/G) (p > 0.05) were observed in both groups. Lifestyle and comorbidities showed independent risk factors for the disease (p < 0.0001, p = 0.0069, p = 0.0394, respectively). Patients with low-grade gliomas had a survival rate of 80.0 ± 1.7% in three years. For the combination of TMZ+RT, survival was 78.7 ± 7.6% in 20 months, compared to TMZ only (21.9 ± 5.1%, p = 0.8711). Conclusions Genetic variants were not associated with gliomas. Specific lifestyle habits and comorbidities stood out as independent risk factors for the disease. Low-grade gliomas showed an increase in patient survival with TMZ+RT treatment.

RESUMO Introdução Glioma, tumor cerebral maligno, é altamente agressivo e associado a mau prognóstico. Os objetivos deste estudo foram avaliar a associação de polimorfismos genéticos relacionados a angiogênese e apoptose em pacientes com glioma, bem como suas comorbidades, hábitos de vida, perfil clínico, sobrevida e resposta ao tratamento (temozolomida [TMZ] e radioterapia [RT]). Métodos 303 indivíduos foram genotipados por PCR em tempo real, e foram coletados dados clínicos, hábitos de vida e comorbidades. Admitiu-se nível de significância para valor p < 0,05. Resultados Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal prevaleceram entre os pacientes, comprados aos controles (p < 0,05). O genótipo heterozigoto rs1468727 (T/C) e homozigoto rs2010963 (G/G) (p > 0,05) foram observados em ambos os grupos. Tabagismo, elitismo, hipertensão arterial sistêmica, diabetes mellitus e índice de massa corporal apresentaram fatores de risco independentes para a doença (p < 0.0001, p = 0.0069, p = 0.0394, respectivamente). Os pacientes com gliomas de baixo grau apresentaram sobrevida de 80,0 ± 1,7% em três anos. Para a combinação de RT e TMZ, a sobrevida foi de 78,7±7,6% em 20 meses, em comparação com TMZ (21,9 ± 5,1%, p = 0,8711). Conclusões As variantes genéticas não estiveram associadas aos gliomas. Hábitos de vida e comorbidades específicas destacaram-se como fatores de risco independentes para a doença. O tratamento com TMZ + RT mostrou aumento na sobrevida dos pacientes.

Necrolisis epidérmica tóxica en el curso de un síndrome hemofagocítico secundario a linfoma de Hodgkin: caso clínico / Toxic epidermal necrolysis during a hemophagocytic syndrome secondary to Hodgkin lymphoma: report of one case

Toxic epidermal necrolysis (TEN) is a lethal entity, characterized by extensive epidermal necrosis and multiorgan failure. Hemophagocytic syndrome (HFS) is also a rare and lethal syndrome characterized by hyperinflammation that leads to the appearance of fever, pancytopenia, organomegaly and hemophagocytosis. The concomitance of these diseases is extremely uncommon. We report a 38 years old female, who during the course of a HFS secondary to Hodgkin Lymphoma (HL), presented a TEN secondary to antibiotics. She was admitted due to a consumptive syndrome, lymphadenopathy, visceromegaly and severe pancytopenia. Laboratory and bone marrow tests confirmed HFS. Due to constant fever, imipenem was indicated. On the third day she started with pain and skin rash. She evolved with positive Nikolsky sign. Cutaneous biopsy was concordant with extensive TEN, which was managed with intravenous immunoglobulin and dexamethasone. A complete response and normalization of the blood count were achieved. Finally, the lymph node biopsy showed HL of mixed cellularity type, which was managed with 8 cycles of ABVD chemotherapy, achieving complete remission.

High frequency of primary refractory disease and low progression-free survival rate of Hodgkin's lymphoma: a decade of experience in a Latin American center

Abstract Background: Reports dealing with clinical outcomes of classical Hodgkin's lymphoma in low- to middle-income countries are scarce and response to therapy is poorly documented. This report describes the characteristics and clinical outcomes of patients with classical Hodgkin's lymphoma from a single institution in Latin America. Method: A retrospective study was conducted over ten years of patients with classical Hodgkin's lymphoma treated at a referral center. Progression-free and overall survival rates were estimated by Kaplan-Meier analysis. The univariate Cox regression model was used to estimate associations between important variables and clinical outcomes. Main results: One hundred and twenty-eight patients were analyzed. The mean age was 28.5 years. The five-year progression-free and overall survival were 37.3% and 78.9%, respectively. Of the whole group, 55 (43%) were primary refractory cases. Only 39/83 (47%) patients with advanced disease vs. 34/45 (75.6%) in early stages (p-value = 0.002) achieved complete remission. Those with advanced disease had a five-year overall survival of 68.7% vs. 91.8% for early disease (p-value = 0.132). Thirty-one patients relapsed (24.2%) and 20 (64.5%) received a transplant. The hazard ratio for progression with bone marrow infiltration was 2.628 (p-value = 0.037). For death, an International Prognostic Score ≥4 had a hazard ratio of 3.355 (p-value = 0.050) in univariate analysis. Two-thirds of classical Hodgkin's lymphoma patients diagnosed at advanced stages had a low progression-free survival but an overall survival similar to high-income countries. Conclusion: Patients diagnosed with classical Hodgkin's lymphoma in Northeastern Mexico had a significantly low progression-free survival rate and presented with advanced disease, underscoring the need for earlier diagnosis and improved contemporary therapeutic strategies in these mainly young productive-age Hodgkin's lymphoma patients.

Effects of nivolumab in peritoneal carcinamatosis of malign melanoma in mouse model

Abstract Purpose: To evaluate the efficacy of nivolumab and comparison with dacarbazine (DTIC) on peritoneal carcinomatosis of malignant melanoma in mouse model. Methods: Mouse skin melanoma cells was injected under the capsule of the peritoneal surface in the left side of the abdomen. On postoperative day ten, mouses randomised into three groups. Group 1: Control, Group 2: HIPEC (Hyperthermic intraperitoneal chemotherapy) with DTIC and Group 3: HIPEC with Nivolumab. After the sacrification on postoperative day fifteen, peritoneum evaluated macroscopically and histopathologically by using peritoneal regression grading score (PRGS). Results: In the 15th day exploration, all animals developed extensive intraperitoneal tumor growth in Group 1. In Group 2 and Group 3 median tumor size was 0.7±0.3cm and 0.3±0.2cm respectively (p: 0.023). Peritoneal carcinomatosis index (PCI) were significantly lower in Group 3 than other groups (p: 0.019). The lowest total tumor nodules in group 3 was 4 ± 2. The PGRS score was found significantly lower in Group 3 than other groups (p: 0.03). Lymphocytic response rate was found higher in the Group 3. Conclusions: It has been found that nivolumab significantly better than DTIC on peritoneal metastases of malign melanoma in mouse models. Nivolumab treatment gives promising results with pathological evidence in the treatment of metastatic disease of malignant melanoma.

Excelente respuesta a tratamiento con ABVD en pacientes con linfoma de Hodgkin localizado / Response to ABVD chemotherapeutic protocol in patients with early stage Hodgkin’s lymphoma

Background: Recent trials show that > 90% of patients with early stage Hodgkin`s Lymphoma (ESHL) can be cured, especially when using the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapeutic (CT) protocol. The use of radiotherapy (RT) is variable and can be selected according to the presence of specific risk factors, including PET-CT, as recently reported. Aim: To report the experience in the treatment of ESHL. Material and Methods: Retrospective and descriptive analysis of patients with ESHL treated at the Red de Salud UC-Christus between 2011-2015. Results: Twenty-two patients were treated. In 73%, the tumor was of nodular sclerosis histologic type. Most patients (95%) were in stage II, and 78% had a favorable prognosis according to the Deutsche Hodgkin Studiengruppe (GHSG) criteria. All patients were stratified using PET-CT and treated using the ABVD CT protocol, for 4-6 cycles. Only 5 patients received RT. There was no change of conduct after interim-PET-CT results. Ninety one percent of patients achieved complete response and there were two cases of refractory disease. Both cases underwent hematopoietic stem cell transplantation. After 17 months of median follow-up, 91% of patients are relapse-free, and only one patient died (5%). Conclusions: ABVD offers excellent results for ESHL patients. The benefit of PET-CT should be evaluated with prospective protocols, aiming to select patients needing RT or to reduce the number of CT cycles.

Nuevas posibilidades terapéuticas en melanoma metastásico / Novel therapeutics possibilities for metastatic melanoma

El melanoma ha experimentado un aumento constante en su tasa de incidencia en las últimas cinco décadas a nivel mundial. El pronóstico del paciente con melanoma se relaciona con el estadio de la enfermedad al momento del diagnóstico, con una sobrevida global media de 6,2 meses en pacientes con melanoma metastásico. El avance en las investigaciones sobre la biología y el comportamiento tumoral permitió el desarrollo de nuevas terapias con distintos mecanismos de acción y mayor eficacia. En esta revisión se abordan las terapias biológicas en melanoma metastásico, su mecanismo de acción y principales resultados en ensayos clínicos. (AU)

Melanoma has experienced a consistent increase in incidence over the past five decades worldwide. The prognosis of patients with melanoma is related to the stage of disease at diagnosis, with a median overall survival of 6.2 months in metastatic melanoma. Progress in research on tumor biology allowed the development of new therapies with different mechanisms of action and greater efficiency. In this review, biologic therapies in metastatic melanoma, its mechanism of action and main results in clinical trials are discussed. (AU)

The efficacy of 2-nitrovinylfuran derivatives against Leishmania in vitro and in vivo

Despite recent advances in the treatment of some forms of leishmaniasis, the available drugs are still far from ideal due to inefficacy, parasite resistance, toxicity and cost. The wide-spectrum antimicrobial activity of 2-nitrovinylfuran compounds has been described, as has their activity against Trichomonas vaginalis and other protozoa. Thus, the aim of this study was to test the antileishmanial activities of six 2-nitrovinylfurans in vitro and in a murine model of leishmaniasis. Minimum parasiticide concentration (MPC) and 50% inhibitory concentration (IC50) values for these compounds against the promastigotes of Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis were determined, as were the efficacies of two selected compounds in an experimental model of cutaneous leishmaniasis (CL) caused by L. amazonensis in BALB/c mice. All of the compounds were active against the promastigotes of the three Leishmania species tested. IC50 and MPC values were in the ranges of 0.8-4.7 µM and 1.7-32 µM, respectively. The compounds 2-bromo-5-(2-bromo-2-nitrovinyl)-furan (furvina) and 2-bromo-5-(2-methyl-2-nitrovinyl)-furan (UC245) also reduced lesion growth in vivo at a magnitude comparable to or higher than that achieved by amphotericin B treatment. The results demonstrate the potential of this class of compounds as antileishmanial agents and support the clinical testing of Dermofural(r) (a furvina-containing antifungal ointment) for the treatment of CL.

Combination hyperbaric oxygen and temozolomide therapy in c6 rat glioma model / Terapia combinada de oxigênio hiperbárico e temozomida no modelo C6 de glioma em ratos

PURPOSE: Temozolomide (TMZ) has anti-tumor activity in patients with malignant glioma. Hyperbaric oxygen (HBO) may enhance the efficacy of certain therapies that are limited because of the hypoxic tumor microenvironment. We examined the combined effects of TMZ-HBO in a rat glioma model. METHODS: After stereotactic injection of C6/LacZ rat glioma cells into the Wistar rats brain, the rats were randomly assigned to three treatment groups [group 1, control treatment; group 2, TMZ alone; group 3, a combination of TMZ and HBO]. Rats were sacrificed 18 days after treatment, and number of intra-/peri-tumoral vessels, microendothelial proliferations, immunohistochemistry and necrotic area were evaluated. RESULTS: Tumoral tissue was stained only sparsely with GFAP. Temozolomide treatment was significantly decreased in tumor tissue intratumoral vessel number / total tumor area level. The level of Ki67 was significantly decreased in the tumor tissue of the group 3. Additionally, the total necrotic area / total tumor volume (%) was decreased significantly in tumor tissue of the group 3 rats compared to group1 and 2. CONCLUSION: The combination of hyperbaric oxygen with temozolomide produced an important reduction in glioma growth and effective approach to the treatment of glioblastoma.

OBJETIVO: A temozolomida (TMZ) tem atividade anti-tumoral em pacientes com glioma maligno. Oxigênio hiperbárico (HBO) pode aumentar a eficácia de terapias que são limitadas devido a um microambiente do tumor hipóxico. Foram examinados os efeitos combinados de TMZ-HBO em um modelo de glioma em rato. MÉTODOS: Após a injeção estereotáxica de células de glioma de rato C6/LacZ no cérebro de ratos Wistar, os ratos foram distribuídos aleatoriamente em três grupos de tratamento: Grupo 1: tratamento de controle. Grupo 2: TMZ sozinho. Grupo 3: uma combinação de TMZ e HBO. Os ratos foram sacrificados 18 dias após o tratamento. Foram avaliados o número de vasos intra-/peri-tumoral, proliferação microendotelial, imunohistoquímica e área necrótica . RESULTADOS: O tecido tumoral foi marcado apenas esparsamente com GFAP. O tratamento com temozolomida diminuiu significativamente o tecido intratumoral e a área total do tumor. O nível de Ki67 foi significativamente diminuído no tecido do tumor do grupo 3. Além disso, a superfície necrótica total / volume total do tumor (%) diminuiu significativamente no tecido do tumor do grupo 3 em comparação com grupo 1 e 2. CONCLUSÃO: A combinação de oxigênio hiperbárico com temozolomida produziu uma redução importante no crescimento do glioma podendo ser abordagem eficaz para o tratamento do glioblastoma.

Temozolomide in aggressive pituitary adenomas and carcinomas

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the available publications regarding the use of temozolomide for the treatment of pituitary tumors was performed. To date, 46 cases of adenohypophysial tumors that were treated with temozolomide, including 30 adenomas and 16 carcinomas, have been reported. Eighteen of the 30 (60%) adenomas and 11 of the 16 (69%) carcinomas responded favorably to treatment. One patient with multiple endocrine neoplasia type 1 and an aggressive prolactin-producing adenoma was also treated and demonstrated a good response. No significant complications have been attributed to temozolomide therapy. Thus, temozolomide is an effective treatment for the majority of aggressive adenomas and carcinomas. Evidence indicates that there is an inverse correlation between levels of O6-methylguanine-DNA methyltransferase immunoexpression and therapeutic response. Alternatively, high-level O6-methylguanine-DNA methyltransferase immunoexpression correlates with an unfavorable response. Here, we review the use of temozolomide for treating pituitary neoplasms.

Autologous hematopoietic stem cell transplantation in classical Hodgkin's lymphoma

BACKGROUND: Hodgkin's lymphoma has high rates of cure, but in 15 percent to 20 percent of general patients and between 35 percent and 40 percent of those in advanced stages, the disease will progress or will relapse after initial treatment. For this group, hematopoietic stem cell transplantation is considered one option of salvage therapy. OBJECTIVES: To evaluate a group of 106 patients with Hodgkin's lymphoma, who suffered relapse or who were refractory to treatment, submitted to autologous hematopoietic stem cell transplantation in a single transplant center. METHODS: A retrospective study was performed with data collected from patient charts. The analysis involved 106 classical Hodgkin's lymphoma patients who were consecutively submitted to high-dose chemotherapy followed by autologous transplants in a single institution from April 1993 to December 2006. RESULTS: The overall survival rates of this population at five and ten years were 86 percent and 70 percent, respectively. The disease-free survival was approximately 60 percent at five years. Four patients died of procedure-related causes but relapse of classical Hodgkin's lymphoma after transplant was the most frequent cause of death. Univariate analysis shows that sensitivity to pre-transplant treatment and hemoglobin < 10 g/dL at diagnosis had an impact on patient survival. Unlike other studies, B-type symptoms did not seem to affect overall survival. Lactic dehydrogenase and serum albumin concentrations analyzed at diagnosis did not influence patient survival either. CONCLUSION: Autologous hematopoietic stem cell transplantation is an effective treatment strategy for early and late relapse in classical Hodgkin's lymphoma for cases that were responsive to pre-transplant chemotherapy. Refractory to treatment is a sign of worse prognosis. Additionally, a hemoglobin concentration below 10 g/dL at diagnosis of Hodgkin's lymphoma has a negative impact on the survival of patients after transplant. As far as we know this relationship has not been previously reported.

Influência do CD 20 na refratariedade do linfoma de Hodgkin clássico ao tratamento inicial com o esquema ABVD, no Ceará, Brasil / Influence of CD 20 antigen expression in the refractoriness of classical Hodgkin lymphoma in the first line treatment with ABVD protocol in Ceará state, Brazil

INTRODUÇÃO: A significância prognóstica do marcador imunológico CD 20 no linfoma de Hodgkin clássico (LHc) ainda é incerta, particularmente no que se refere à refratariedade ao tratamento inicial. OBJETIVOS: Avaliar a influência da positividade do marcador CD 20 na refratariedade do LHc ao tratamento poliquimioterápico inicial, com o esquema doxorubicina 25 mg/m², bleomicina 10 mg/m², vinblastina 6 mg/m² e dacarbazina 375 mg/m² (ABVD), no Ceará, Brasil. MATERIAL E MÉTODOS: Estudo analítico incluindo 97 pacientes com diagnóstico de LHc firmado entre janeiro de 2000 e dezembro de 2004. A análise foi realizada avaliando variáveis demográficas, clínicas e laboratoriais. RESULTADOS: Foi evidenciada uma positividade do CD 20 em 38,1 por cento dos pacientes. Na análise bivariada, CD 20 positivo (razão de chance [RC] = 4,02; intervalo de confiança [IC] = 1,09 - 8,54; p = 0,02), a presença de sintomas B (RC = 4,02; IC = 1,18-17,51; p = 0,01) e a elevação da desidrogenase lática (mediana não-refratários 248,5 [200,5 - 389,5]; mediana refratários 356 [208,5 - 545]; p = 0,03) apresentaram relação de pior prognóstico quanto à refratariedade. Na regressão logística, o CD 20 positivo (RC ajustada = 3,6; IC = 0,99 - 13,09; p = 0,05) e a presença de sintomas B (RC ajustada = 5,41; IC = 1,16 - 25,34; p = 0,03) continuaram apresentando pior prognóstico. DISCUSSÃO: Esses dados coincidem com a literatura, em que a positividade do marcador CD 20 está relacionada com pior resposta ao tratamento com ABVD. CONCLUSÃO: Os nossos dados indicam que o tratamento com ABVD não é completamente adequado para a abordagem terapêutica inicial deste subgrupo de pacientes e novas pesquisas precisam ser realizadas no sentido de aperfeiçoar o tratamento destes pacientes.

INTRODUCTION: The prognostic value of CD20 antigen expression in classical Hodgkin lymphoma (cHL) is uncertain, particularly regarding the refractoriness to first-line treatment. OBJECTIVES: To assess the influence of CD20 positiveness on the refractoriness of cHL to first-line chemotherapy with ABVD protocol in Ceará State, Brazil. MATERIAL AND METHODS: Analytical study including 97 patients diagnosed with cHL between January/2000 and December/2004. The analysis was performed evaluating demographic, clinical and laboratory variables. RESULTS: CD20 antigen expression was positive in 38.1 percent of the patients. In the bivariate analysis, CD20 antigen expression (OR = 4.02; CI = 1.09 - 8.54; p = 0.02), the presence of B-symptoms (OR = 4.02; CI = 1.18-17.51; p = 0.01) and an elevated lactate dehydrogenase level (median not refractory 248.5 [200.5 - 389.5]; median refractory 356 [208.5-545]; p = 0.03) showed worse prognosis as to refractoriness. In the logistic regression analysis, the presence of CD 20 (OR = 3.6; CI = 0.99-13.09; p = 0.05) and B-symptoms (OR = 5.41; CI = 1.16-25.34; p = 0.03) continued to show worse prognosis. DISCUSSION: These findings coincide with literature data indicating that CD 20 antigen expression is associated with low response to treatment with ABVD. CONCLUSION: Our data show that the treatment with ABVD is not totally appropriate for the initial therapeutic approach in this subgroup of patients and that further studies are required to optimize their treatment.

O microambiente tumoral como alvo terapêutico: avaliação do efeito de antagonistas do receptor de bradicinina tipo 1 em melanoma murino / Tumor microenvironment as therapeutic target: evaluation of the effect of bradkinin receptor 1 antagonists in murine melanoma

O microambiente tumoral tem sido considerado um importante alvo para terapias anticâncer. Recentemente, o receptor de bradicinina tipo 1 (BKR1), o qual é expresso em leucócitos e células endoteliais, foi implicado na progressão de diversos cânceres, incluindo o melanoma... Dois diferentes métodos foram utilizados na seleção de genes diferencialmente expressos (differentially expressed genes -DEGs): o test “t de Student” e o teste Limma. Um total de 87 DEGs foram selecionadas com fold change >1,5 e valor de p<0,05. Alguns desses genes, envolvidos em importantes processos como angiogênese, invasão, metástase e quimioresistência, têm sido validados por PCR em tempo real, como: transglutaminase-2, HSP-1b, neuropilina-2, serpine 1, fator de crescimento do tecido conjuntivo (Ctgf) e serglicina. Em um segundo conjunto de experimentos foi avaliado o efeito de antagonistas de BKR1 em alterações de permeabilidade vascular e distribuição de droga fluorescente (doxorrubicina) no microambiente do tumor. Os antagonistas de BKR1, R-954 e R-715, causaram redução da penetração de doxorrubicina no microambiente tumoral após tratamento por 2 horas, precedido ou não de tratamento crônico (diário), entretanto após 6 horas de tratamento foi observado um aumento da quantidade de doxorrubicina, comparado ao controle, seguido de redução após 24 horas de tratamento. Já em tumores EMT6 (sarcoma mamário murino) após 2 horas de tratamento com esses antagonistas foi possível observar um aumento da quantidade de doxorrubicina no microambiente tumoral. Esses resultados sugerem mecanismos pelos quais as complexas interações entre as células tumorais e as células do hospedeiro podem resultar na resistência tumoral aos quimioterápicos e a consequente falha dos tratamentos convencionais.

Tumor microenvironment has been considered an important target for anticancer therapies. Recently, the bradykinin receptor type 1 (BKR1), which is expressed on leukocytes and endothelial cells, has been implicated in the progression of several cancers, including melanoma. In this work we have shown that there is a delay in BKR1 knockout mice melanoma engraftment and we also observed higher survival rates in these animals compared to wild type mice. We have investigated the effects of selectives BKR1 antagonists evaluating its combination with the chemotherapeutic agent dacarbazine (DTIC). B16-F10 melanoma cells were injected subcutaneously in C57bl/6 mice, which were treated with DTIC (2mg/kg) every 3 days, R-954 (1mg/kg) daily, DTIC plus R-954 or PBS, as control. Mice were sacrificed at day 12 of treatment; tumors were excised and processed for RNA extraction. Treatments with R-954, DTIC or R-954 plus DTIC did not reduced tumor mass. However, the combined treatment increased the global survival of mice bearing tumor. Microarray experiments were performed using GeneChip Mouse 430 (Affymetrix). Data was normalized using the RMA method. Two different methods were employed for selection of differentially expressed genes (DEGs):the Student's T-test and the Limma package. A total of 87 DEGs were identified with fold change>1,5 and p value<0,05. Some of these genes, involved in important process as angiogenesis, invasion, metastasis and chemoresistance, had been validated by real time PCR as; transglutaminase-2, HSP-1b, neuropilin-2, serpine 1, connective tissue growth factor and serglycin. In a second set of experiments we evaluated the effect of antagonists BKR1 in vascular permeability alterations and distribution of fluorescent drug (doxorubicin) in tumor microenvironment. BKR1 antagonists, R-954 and R-715, caused a reduction of the penetration of doxorubicin in the tumor microenvironment after treatment for 2 hours, followed or not by chronic treatment (daily), but after 6 hours of treatment was observed an increase in the amount of doxorubicin, compared to the control, followed by reduction after 24 hours of treatment. However, in EMT6 tumors (murine mammary sarcoma) after 2 hours of treatment with these antagonists we observed an increased amount of doxorubicin in tumor microenvironment. These results suggest mechanisms by which the complex interactions between tumor and BKR1 positive host cells may result in tumor resistance to chemotherapeutic agents and the consequent failure of regular treatments.

Melanoma de ano / Melanoma of the anus

Objetivo: Las lesiones malignas del ano no son frecuentes. Entre 0,1 a 1 por ciento de estas corresponden a melanomas primarios de ano y en ellos se destacan su diagnóstico tardío, rápida progresión y mal pronóstico. Su tratamiento es todavía discutido. Se presenta un caso de melanoma primario de ano con revisión de la literatura. Pacientes y Métodos: Mujer de 69 años, sin antecedentes médico-quirúrgicos, consultó por hemoproctorragia y tumoración anal de 6 meses de evolución, de 6 cm de diámetro, indolora, de coloración oscura. Se realizó biopsia incisional. La anatomía patológica informó “melanoma”. La TAC de abdomen y pelvis demostró múltiples imágenes nodulares en hígado. Se realizó resección local. Resultados: Evolucionó favorablemente. Alta al 2º día. Se realizó adyuvancia con Dacarbazina (TTIC). Óbito a los 16 meses, con metástasis pulmonares. Conclusiones: El melanoma primario de ano es infrecuente. Su tratamiento es discutido, prefiriéndose la resección local en los pacientes con enfermedad avanzada por presentar ésta menor morbilidad con igual tasa de sobrevida.

Objective: The malign injuries of the anus are rare. Between 0,1 to 1 per cent of these correspond to melanoma primary of anus and in them stand out its diagnose delayed, fast progression and badly foretell. Its treatment still is discussed. A primary case of melanoma ofthe anus with revision of literature appears. Patients and methods: Woman of 69 years old without surgical or medical antecedents. She consult by bleeding and anal tumor of 6 months of evolution, of 6 cm, painless, of dark coloration. We are made incisional biopsy. The pathology informed melanoma. CT of abdomen and pelvis showed many images cleared in liver. We are made wide local excision with a negative margin. Results: She evolves favorably, whit hospital stay of two days. We are made adyuvancy with Dacarbazyne (TTIC). Development pulmonary metastasis. She was death 16 months after surgical treatment. Conclusions: Primary melanomas of the anus are infrequent. The treatment is discussed, preferring wide local resection in patients with disease outpost to present this one, smaller morbidity and equal rate of survival.

Linfoma de Hodkin en Chile: Experiencia de 15 años del Programa Nacional de Cáncer del Adulto / Hodgkin lymphoma in Chile: Experience of the national adult cancer program

Background: Hodgkin lymphoma is a highly curable disease. Aim: To evaluate the clinical characteristics and the treatment results of Hodgkin lymphoma patients of the National Cancer Program in Chile. Patients and methods: Prospective assessment of 682 patients treated in 18 adult cancer centers. Progression free survival (PFS) and overall survival (OS) were calculated. Median follow up was 127, 95, 87, 72 and 50 months for C-MOPP, radiotherapy (RT), C-MOPP/ABV, NOVP and ABVD, respectively. Results: Median age was 37 years (15-84). Nodular sclerosis and mixed cellularity were equally expressed. Advanced stages (III & IV) were present at diagnosis in 61 percent of cases. Age over 40 was an adverse prognostic factor (p <0.001). The rate of PFS at 5 and 10 years for early stages was 73 percent and 66 percent with RT, 80 percent and 74 percent with C-MOPP+RT, 73 percent and 71 percent with C-MOPP/ABV, 59 percent and 59 percent with NOVP+RT, and 81 percent with ABVD+RT, at 5 years, being significantly lower for NOVP (p =0.02). The rate of OS at 5 and 10 years for advanced stages was 82 percent and 70 percent with RT, 82 percent and 76 percent with C-MOPP+RT, 82 percent and 80 percent with C-MOPP/ABV, 68 percent and 60 percent with NOVP, and 85 percent with ABVD at 5 years, also significantly lower for NOVP (p =0.04). For advanced stages, the rate of PFS at 5 and 10 years was 49 percent and 43 percent with C-MOPP, 69 percent and 62 percent with C-MOPP/ABVD or C-MOPP/ABV, and 71 percent at 5 years with ABVD, significantly lower for C-MOPP (p =0.01). The rate of OS at 5 and 10 years was 52 percent and 46 percent with C-MOPP, 70 percent and 63 percent with C-MOPP/ABVD or C-MOPP/ABV and 76 percent with ABVD at 5 years, significantly lower for C-MOPP (p =0.0002). Conclusions: Age over 40 years was an adverse prognostic factor. C-MOPP/ABVD, C-MOPP/ABV and ABVD had comparable results and reached a high tumor control and overall survival in both early...

Meningitis linfomatosa como sitio de recaída en la enfermedad de Hodgkin / Limphomatous meningitis as recurrence site in Hodgkin's disease

Intracraneal manifestations of Hodgkin's Disease (HD) are extremely rare, with an estimated incidence rate of approximately 0.5%. They can be classified as: 1) treatment-related leucoencephalopathy, 2) central nervous system infections, 3) paraneoplasic syndromes and 4) intracraneal lymphomas, which could be sub-classified into intraparenchymal or intradural masses. We describe a case of a 40 year-old male with mixed cellularity type HD who developed neurological manifestations as relapsed disease. Magnetic resonance imaging suggested leptomeningeal metastases and atypical cells were found in cerebrospinal fluid. The patient died from progressive disease refractory to third line chemotherapy. There are less than 50 similar cases reported in the literature. We review the clinical features and differential diagnosis of leptomeningeal metastases in Hodgkin's disease.

Gliomas de bajo grado: viejas controversias, nuevas evidencias / Low grade glioma: old controversies, new evidences

Many aspects of the management of low-grade gliomas have been controversial. Warren Mason reviews the new evidence addressing some of them in the article Advances in the management of low-grade gliomas, published in Can J. Neurol. Sci. 2005. This information should be specially useful for tailoring therapies to each particular situation. The presence of an oligodendroglial component and 1p and 19q deletions confers a better prognosis and better response rates to chemotherapy and radiotherapy. Delaying interventions in stable, asymptomatic patients does not seem to affect overall survival. More extensive resections are associated to longer and better quality survival. Early radiotherapy prolongs time to progression, but not overall survival as compared to delayed radiotherapy. The optimal dose is in the range between 45Gy and less than 59.4 Gy. Chemotherapy produces responses in most of these patients.