Immunohistochemical evidence of melatonin protection on lung tissue during chemotherapy / Evidencia inmunohistoquímica de la protección de la melatonina en el tejido pulmonar durante la quimioterapia

SUMMARY: The present study investigated the possible protective effects of melatonin on Bleomycin, Cisplatin and etoposide (BEP) chemotherapy regimens using immunohistochemistry. Forty male Wistar rats were divided into four groups of ten as; group 1 as untreated control; group 2 as BEP group which received the three cycles of 21 days' regimen each of 0.5¥ dose levels ofBEP (bleomycin 0.75 mg/kg, etoposide 7.5 mg/kg and cisplatin 1.5 mg/kg). Rats in the group 3 (MEL group) received 10 mg/kg/day melatonin once daily. Group 4 received the melatonin (30 min before the BEP injections) and BEP as in groups 2. Proliferating cell nuclear antigen (PCNA) staining was used to detect cell proliferation and caspase-3, caspase-9 and Caspase-8 were detected to investigate apoptosis. PCNA immunostaining in alveolar epithelium, alveolar macrophages and bronchus was weak to moderate in BEP group. However, diffuse and strong caspase immunoreactions for caspase-3, caspase 8- and caspase-9 were detected in the bronchioles epithelium, vascular endothelium, alveolar luminal macrophages in the BEP group. PCNA and caspase immunoreactivities in MEL and Mel + BEP groups were close to the control one. The surface are in the BEP group was significantly reduced as compared to the control one ((P0.05). It can be concluded that BEP regimen can affects negatively on lung tissue and melatonin inhibits lung tissue injuries during BEP chemotherapy.

El presente estudio investigó los posibles efectos protectores de la melatonina en los regímenes de quimioterapia con bleomicina, etopósido y cisplatino (BEP) mediante inmunohistoquímica. Cuarenta ratas Wistar macho se dividieron en cuatro grupos de diez: grupo 1, control sin tratar; grupo 2, quimioterapia con una dosis de 0,5x de BEP (0,75 mg/kg de bleomicina, 7,5 mg/ kg de etopósido y 1,5 mg/kg de cisplatino) con tres ciclos de 21 días cada uno. Las ratas del grupo 3 (grupo MEL) recibieron 10 mg/kg/día de melatonina una vez al día. El grupo 4 (Mel + BEP) recibió melatonina (30 minutos antes de las inyecciones de BEP) y BEP, como en los grupos 2. Se usó la tinción del antígeno nuclear de células en proliferación (PCNA) para detectar la proliferación celular y, caspasa- 3, caspasa-9 y caspasa-8 para investigar apoptosis. La inmunotinción de PCNA en el epitelio alveolar, los macrófagos alveolares y los bronquios varió de débil a moderada en el grupo BEP. Sin embargo, se detectaron inmunorreacciones difusas y fuertes para caspasa-3, caspasa 8- y caspasa-9 en el epitelio de los bronquiolos, endotelio vascular y macrófagos luminales alveolares. Las inmunorreactividades de PCNA y caspasa en los grupos MEL y Mel + BEP fueron similares a las del control. El área de superficie en el grupo BEP se redujo significativamente en comparación con el control (P0,05). Se puede concluir que la quimioterapia con BEP puede afectar negativamente al tejido pulmonar y la melatonina inhibe las lesiones durante la quimioterapia.

Pneumatosis intestinalis after etoposide-based chemotherapy in a patient with metastatic small cell lung cancer: successful conservative management of a rare condition / Pneumatose intestinal após quimioterapia com etoposídeo em paciente com câncer de pulmão de pequenas células: sucesso com conduta conservadora em uma condição rara

ABSTRACT A 69-year-old male patient, smoker, was diagnosed with small cell lung cancer metastatic to lung, liver and central nervous system. He received chemotherapy with carboplatin AUC 5 on day 1 and etoposide 100mg/m2 on days 1, 2 and 3. During the first cycle, the patient presented with febrile neutropenia and abdominal distension. Chest, abdomen and pelvis computed tomography scan was performed and detected gas dissecting the wall of sigmoid colon extending to the mesosigmoid. Patient had no abdominal pain, nausea, vomiting, and on physical examination he had no peritoneal irritation, tachycardia or hemodynamic instability compatible with perforation or acute abdomen. Therefore, the radiological finding was interpreted as pneumatosis intestinalis caused by chemotherapy with etoposide. Pneumatosis resolved after continuous oxygen therapy. The second cycle was administered after a complete resolution of the clinical condition and etoposide dose was reduced by 30%. The patient experienced a remarkable evolution.

RESUMO Paciente do gênero masculino, 69 anos, fumante, diagnosticado com câncer de pulmão de pequenas células, metastático para pulmão, fígado e sistema nervoso central. Foi administrada quimioterapia com carboplatina AUC 5 no dia 1 e etoposídeo 100mg/m2 nos dias 1, 2 e 3. Durante o primeiro ciclo, o paciente apresentou neutropenia febril e distensão abdominal. Tomografias de tórax, abdome e pelve detectaram gás dissecando a parede do cólon sigmoide, com extensão para o mesossigmoide. O paciente não apresentava dor abdominal, náusea, vômito e não tinha sinais de irritação peritoneal, taquicardia ou instabilidade hemodinâmica compatíveis com perfuração ou abdome agudo. O achado radiológico foi interpretado como pneumatose intestinal causada por etoposídeo. A resolução do quadro ocorreu após suplementação de oxigênio. O segundo ciclo foi administrado após resolução completa do quadro, com redução da dose do quimioterápico em 30%. O paciente evoluiu de forma bastante satisfatória.

Estudo de fase II com doses fracionadas diárias de etoposide oral em pacientes com câncer de mama estádio IV refratário a múltiplos esquemas quimioterápicos / Phase II study of fractionated daily doses of oral etoposide in patients with stage IV breast cancer refractory to multiple chemotherapy regimens

O etoposide é um inibidor da topoisomerase II capaz de produzir respostas objetivas em cerca de 10% das pacientes com câncer de mama metastático após a falha a esquemas convencionais. A administração oral de doses fracionadas de etoposide produz um aumento significativo do tempo de exposição dos tecidos em níveis terapêuticos deste agente, aumentando o seu índice terapêutico. Neste artigo, são descritos os resultados de um ensaio clínico de fase II com etoposide oral em doses fracionadas diárias em 20 mulheres com câncer de mama metastático refratário a múltiplos esquemas quimioterápicos. Foram elegíveis pacientes entre 18-75 anos de idade, desempenho clínico entre 0-2 (ECOG), diagnóstico histopatológico de câncer de mama, doença metastática visceral, sem disfunção de órgãosvitais e sem envolvimento do Sistema Nervoso Central (SNC). A assinatura de um documento de consentimento pelapaciente, segundo as normas da CONEP e do Comitê de Ética da Instituição, era condição necessária para inclusão.O conteúdo da ampola de etoposide para uso endovenoso foi administrado por via oral na dose de 20mg/m2 a cadaoito horas, diluído em veículo ácido (suco de laranja ou uva), diariamente por 14 dias, seguido de sete dias deintervalo. A cada 21 dias, as pacientes foram reavaliadas quanto à toxicidade (critério do NCI-CTC) e, a cada doisciclos (42 dias), quanto à resposta tumoral (critério da RECIST). As pacientes foram tratadas até a progressão, toxicidade limitante ou desejo próprio de interromper o tratamento. Foram incluídas 20 pacientes no estudo, tendo sido analisado um total de 55 ciclos de tratamento, com uma mediana de dois ciclos por paciente (1-10). Os efeitosadversos mais observados foram: náusea (36%), vômitos (24%), mucosite (16%) e neutropenia (14%). Neutropenia febril ocorreu em apenas um caso (2%). Não foram documentadas respostas objetivas. Entretanto, 9 pacientes apresentaram doença estável (45%), algumas com duração prolongada (30+, 21+ e...

Etoposide is an inhibitor of the nuclear topoisomerase II enzyme, which produces objective tumor responses inabout 10% of patients with metastatic breast cancer failing to standard chemotherapy regimens. Fractionatedoral administration of etoposide causes significant increase in tissue drug exposure, leading to a better therapeuticindex. In this paper, the outcomes of a Phase II trial of fractionated oral daily doses of etoposide conducted in20 women with metastatic breast cancer, who progressed following multiple chemotherapy regimens, are described. Eligible patients were those between 18-75 years old, ECOG performance status between 0-2, confirmed histopathological diagnosis of breast cancer, presence of visceral involvement, no vital organs dysfunction and no CNS involvement. A written informed consent was required, in accordance with the local IRB and theMinistry of Health of Brazil. The content of an ampoule for IV use was administered orally, at the dose of 20mg/m2, every eight hours, diluted in a low pH fluid (orange or grape juice), daily for 14 consecutive days,followed by a 7-day rest. Patients were reviewed every 21 days for toxicity (NCI-CTC criteria), and every 42days for tumoral response (RECIST criteria). Patients were treated until tumor progression, dose-limiting toxicityor own desire to interrupt the treatment. Twenty patients were included in the trial, and a total of 55 treatment cycles administered with a median of two cycles per patient (1-10) was evaluated. The most common side-effects were nausea (36%), vomiting (24%), mucositis (16%) and neutropenia (14%). Febrile neutropenia was documented in one case (2%) only. No objective response was documented. However, nine patients showed stable disease (45%), in some cases with prolonged duration (30+, 21+ and 18 weeks). The median duration of stable disease was 15 weeks (9-30+). In summary, this daily fractionated regimen of oral etoposide was welltolerated, producing...

A case of ovarian endodermal sinus tumor diagnosed during pregnancy.

Pregnancy complicated by endodermal sinus tumor of the ovary is extremely rare. The authors present a case report of a pregnant woman with persistent left adnexal mass and subsequently found to have a primary endodermal sinus tumor of the ovary that was diagnosed at 19 weeks of gestation. After left salpingo-oophorectomy had been performed, the patient chose to terminate the pregnancy before the initiation of combination chemotherapy with bleomycin, etoposide, and cisplatin. The response to chemotherapy was not satisfactory. The patient expired after seven cycles of treatment had been completed because of pulmonary fibrosis and the drug toxicity of bleomycin.

Mutagenicity of some topoisomerase II-interactive agents

Among the anticancer drugs currently used in the treatment of human malignancies, as well as several new series of drugs under development, are targeted at topoisomerase II enzymes. Besides of inducing cell death due to both 'mitotic catastrophe' and the induction of apoptosis, topoisomerase-II-targeted drugs can increase the frequency of cells bearing mutations. These cells can develop resistance to the therapeutic agents or may lead to the development of secondary tumours and abnormal reproductive outcomes. This review focuses on the mutagenic properties of the topoisomerase II poisons etoposide, doxorubicin and amsacrine, which are front-line therapies for a variety of malignancies, and genistein, which is prominent in soybean foods and is believed to be a chemopreventative agent that contributes to the low incidence of specific cancers among Asian populations. In addition, the topoisomerase II catalytic inhibitor merbarone that is in clinical trials as an anticancer agent will be discussed. It clear from the present review that, the topoisomerase II-interactive anticancer agents appear to be mutagenic. Therefore, the clinical use of these mutagenic drugs must be weighed against the risks of secondary malignancies in cured patients and persistent genetic damage of their potential offspring

Treatment outcome and cost-effectiveness analysis of two chemotherapeutic regimens (BEP vs. VIP) for poor-prognosis metastatic germ cell tumors.

BACKGROUND: In patients with small-volume disseminated disease of germ cell tumors, cure can be achieved with four cycles of bleomycin, etoposide, and cisplatin (BEP). However, around 20% of these cases are not curable. Strategies to improve cure rates have shown that none of the currently available modalities were superior to the others. Among the most used ones, BEP and VIP (etoposide, cisplatin, and ifosfamide) have been the most studied. However, there are no reports comparing the two, except for a few in abstract forms from southern India. Therefore, we did a treatment outcome and cost-effectiveness analysis of two chemotherapeutic regimens (BEP vs VIP) that are used in poor-prognosis metastatic germ cell tumors. MATERIALS AND METHODS: All male patients with germ cell tumors, diagnosed as having poor risk by IGCCCG, between January 2002 and December 2004 were included in the study. Clinical, laboratory, and other data were recorded. The patients were stratified into two categories on the basis of the type of chemotherapeutic regimen they received. RESULTS: In all, 46 patients were analyzed, with a median follow up of 26.6 months. The baseline characteristics (age, stage, PS, histology, and serum markers) were not different in the two treatment arms. There is no significant difference in the outcome with either of the chemotherapeutic modalities. VIP is less cost effective and more toxic compared to BEP. CONCLUSION: In view of the greater toxicity and cost of therapy, as well as lack of either overall or disease free survival advantage, VIP is not a preferred option for patients with high-risk germ cell tumors in the Indian setting and it is still advisable to treat patients with BEP.

Resultados a largo plazo del tratamiento con quimioterapia y radioterapia en linfoma no Hodgking localizado, de grados intermedio y alto / Long term results for intermediate and high grade localized non Hodgkin lymphoma, treated with chemotherapy and radiotherapy

Background: Treatment of intermediate and high grade non-Hodgkin lymphoma (NHL) includes chemotherapy with or without radiotherapy, depending on the clinical stage. The standard treatment for advanced NHL is 8 cycles of combined chemotherapy, cyclophosphamide, adriamicin, vincristine and prednisone (CHOP). Patients presenting with localized disease are treated with fewer chemotherapy cycles and involved field radiotherapy, with good results. Aim: To evaluate the treatment results including overall survival (OS) and event-free survival (EFS) in localized aggressive NHL patients treated at the Pontificia Universidad Católica de Chile, Clinical Hospital. Patients and Methods: Retrospective analysis of all patients with Ann Arbor stages I and II referred to the hematology and radiotherapy clinic between 1998 and 2003. OS and EFS analysis was made according to the Kaplan and Meier method. Log-rank and Cox methods were used for univariate and multivariate analyses, respectively. Chemotherapy and radiotherapy toxicities were scored according to World Health Organization (WHO) and Radiation Therapy Oncology Group (RTOG) scales, respectively. Results: 39 patients (20 men), aged between 20 to 85 years, were the source for this study. The average follow-up was 51 months (range 6-115). The 5 years OS and EFS were 72,4 percent and 63,3 percent, respectively. On univariate analysis, age over 60 was the only variable that affected negatively OS and EFS. Acute toxicity caused by chemotherapy and radiotherapy was uncommon. Conclusions: Age over 60 was the only independent variable associated with poor prognosis. The number of chemotherapy cycles and the drug combination did not influence the results. These results support the usefullness of a shortened chemotherapy regimen plus involved field radiotherapy.

Extensive deep vein thrombosis as a complication of testicular cancer treated with the BEP protocol (bleomycin, etoposide and cisplatin): case report

CONTEXT: There are no reports in the literature of massive deep venous thrombosis (DVT) associated with cisplatin, bleomycin and etoposide (BEP) cancer treatment. CASE REPORT: The patient was a 18-year-old adolescent with a nonseminomatous germ cell tumor of the right testicle, with the presence of pulmonary, liver, and massive retroperitoneal metastases. Following radical orchiectomy, the patient started chemotherapy according to the BEP protocol (without routine prophylaxis for DVT). On day 4 of the first cycle, massive DVT was diagnosed, extending from both popliteal veins up to the thoracic segment of the inferior vena cava. Thrombolytic therapy with streptokinase was immediately started. On day 2 of thrombolytic therapy, the patient developed acute renal failure, due to extension of the thrombosis to the renal veins. Streptokinase was continued for six days and the outcome was remarkably favorable.

CONTEXTO: Não há relatos na literatura de trombose venosa profunda (TVP) extensa associada ao protocolo de quimioterapia cisplatina, bleomicina e etoposite (BEP). RELATO DO CASO: O paciente era um adolescente de 18 anos com um tumor germinativo não-seminomatoso no testículo direito, com metástases pulmonares, hepáticas e retroperitoneais. Após orquiectomia radical, o paciente começou a receber quimioterapia de acordo com o protocolo BEP (sem profilaxia rotineira para TVP). No quarto dia do ciclo, TVP massiva foi diagnosticada, estendendo-se das veias poplíteas até o segmento inferior da veia cava torácica. Tratamento trombolítico foi iniciado imediatamente com estreptoquinase. No segundo dia da terapia trombolítica, o paciente desenvolveu insuficiência renal aguda, devido ao acometimento das veias renais pela trombose. Estroptoquinase foi mantida por seis dias e o paciente teve evolução surpreendentemente favorável.

A Case of Treatment-Related Myelodysplastic syndrome and Acute Myelogenous Leukemia Following High-Dose Chemotherapy with Autologous Stem Cell Transplantation for Non-Hodgkin's Lymphoma

Treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (t-AML) are now well established as complications of cytotoxic chemotherapy. We experienced a 28-yr-old female patient who developed t-MDS/t-AML with characteristic chromosomal abnormalities including 11q23 chromosomal rearrangement following high-dose chemotherapy with autologous stem cell transplantation (ASCT) for non-Hodgkin's lymphoma. The patient was admitted with bulky abdominal masses of B cell lineage non-Hodgkin's lymphoma. After 2 cycles of systemic chemotherapy of the Vanderbilt regimen, the patient underwent ASCT with high dose chemotherapy of the BEAC regimen. She also received radiation of 48 Gy for the residual periportal lymphadenopathy. The initial cytogenetic analysis of the infused mononuclear cells revealed a normal karyotype. Twenty two months after the ASCT, pancytopenia was noted and her bone marrow aspirate showed dysplastic hemopoiesis with myeloblasts up to 12% of nonerythroid nucleated cells. The patient was diagnosed as t-MDS (refractory anemia with an excess of blasts). Cytogenetic analysis showed complex chromosomal abnormalities including 11q23 rearrangement, which is frequently found in topoisomerase II inhibitor-related hematologic malignancies. Four months later, it was noted that the t-MDS had evolved into an overt t-AML. Cytogenetic analysis showed an evolving pattern with more complex abnormalities. The patient was treated with combination che-motherapy, but her leukemic cells were resistant to the therapy.

Tratamento sistêmico do sarcoma de Kaposi associado a AIDS: estudo clínico e farmacológico com doses fracionadas de etoposida por via oral / Treatment of AIDS related Kaposiïs sarcoma: clinical and pharmacological study with oral etoposide

Os objetivos deste estudo foram: avaliar a atividade antitumoral, a toxicidade e a farmacocinética da etoposida em doses orais fracionadas por um período de tempo prolongado em pacientes com Sarcoma de Kaposi avançado associado a AIDS; determinar o percentual de respostas objetivas alcançado pela etoposida na posologia proposta no estudo; estabelecer o perfil e a gravidade dos efeitos tóxicos apresentados pelos pacientes nesse esquema de administração da etoposida e descrever a farmacocinética da etoposida no plasma dos pacientes incluidos no estudo

Therapy related acute myeloblastic leukemia following gestational trophoblastic tumor: Possible role of high cumulative dose of etoposide

The development of secondary acute myeloblastic leukemia [sAML] following chemotherapy of a gestational trophoblastic tumor [GTT] is rare. Alkylating drugs are known leukemogenic agents and epipodophyllotoxins have been implicated in the causation of a distinct subset of sAML. We report a case of s AML following treatment of a gestational trophoblastic tumor with multiagent chemotherapy including alkylating agents and a high dose of etoposide. The leukemia was characterized as myelomonocytic leukemia [FAB- M4] with a normal chromosomal pattern and without any preceding myelodysplastic phase. The leukemia developed 3 years and 6 months after the first etoposide exposure. Continuous exposure to etoposide following administration of other cytotoxic drugs including alkylating drugs may increase the risk of sAML

Esquemas de quimioterapia y bacteriemias en pacientes adultos con leucemia aguda / Chemotherapy schedules and bacteremias in adult patients with acute leukemia

En un estudio efectuado para evaluar la utilidad de la profilaxis con fluoroquinolonas en pacientes neutropénicos afebriles, se encontró una asociación inesperada entre el esquema de poliquimioterapia utilizado y la posterior documentación de bacteriemias durante los episodios de neutropenia y fiebre. Se analizaron 25 episodios de neutropenia febril secundaria a quimioterapia antileucémica. Los pacientes recibieron etoposide y mitoxantrona o bien citarabina - en dosis estándar, intermedia o alta - asociada a daunomicina o mitoxantrona. El análisis de los datos microbiológicos demostró una mayor incidência de bacteriemias con el uso combinado de antraciclinas y citarabina en dosis intermedia o alta en comparación con la administración de etoposide y mitoxantrona (p = 0,000387). Ambos grupos de pacientes desarrollaron una neutropenia igualmente veloz y severa con una mucositis digestiva equivalente. El esquema de poliquimioterapia fue el único dato que se asoció con la aparición o no de bacteriemias en el episodio de neutropenia febril subsiguiente. Se concluye en que otros efectos - además de la aplasia medular y la mucositis digestiva - podrían ser relevantes en la susceptibilidad a las infecciones que originan los citostáticos.

Quimioterapia postoperatoria con carboplatino y etopósido en niños con meduloblastoma de alto riesgo / Postoperative chemotherapy with carboplatin and etoposide in children with high-risk medulloblastoma

Introducción. Se estudiaron prospectivamente diez pacientes con meduloblastoma de alto riesgo que recibrieron quimioterapia postoperatoria con carboplatino y etopósido previo a radioterapia. Material y métodos. Se realizaron a cada uno de los pacientes estudios de resonancia magnética de cráneo y neuroeje antes de iniciado el tratamiento y al concluir, con el fin de valorar la respuesta tumoral obtenida. Se deretminó el grado de toxicidad hematológica secundaria al tratamiento y se calculó la sobrevida actuarial obtenida. Resultados. Ocho pacientes presentaron una respuesta superior al 50 por ciento; la toxicidad hematológica se presentó en el 34.2 por ciento de los cursos administrados. La sobrevida actuarial obtenida a 18 meses fue del 57 por ciento en el mismo periodo. Conclusiones. La asociación de carboplatino y etopósido empleados en conjunto tienen un buen efecto antitumoral en este tipo de neoplasias con mínimos efectos colaterales y con la posibilidad de mejorar la sobrevida de los pacientes con meduloblastoma de alto riesgo

Avaliaçäo do potencial cardiotóxico do VP-16 através de um modelo experimental utilizando ratas albinas: discussäo de achados anátomo-patológicos / Evaluation of cardiotoxic potential of VP-16 by an experimental model using albine rats: discussion of the anatomopathological findings

A existência de relatos ocasionais de cardiotoxicidade pelo VP-16 motivou os autores a realizarem este estudo. Para tal, um modelo experimental utilizando dois grupos de ratas Albinas (grupo A e grupo B) foi idealizado. Os animais do grupo A foram divididos em sub-grupos de 10 (G1, G2, G3, G4 e G5), sendo tratados com VP-16-213 5mg/kg de peso por via intrapetorineal em ciclos semanais pelo prazo de oito ciclos. O grupo B recebeu soluçäo de cloreto de sódio isotônico (0,9%) pelo mesmo espaço de tempo. Os animais do grupo A foram sacrificados a intervalos de 14 dias, segundo a ordem dos sub-grupos tratados. Os animais do grupo B foram sacrificados ao término do experimento. A avaliaçäo anatomopatológica dos coraçöes de animais do grupo A näo diferiu significativamente entre os sub-grupos, a despeito das doses crescentes da droga. Quando estes achados foram confrontados com os do grupo B, näo foram detectadas diferenças significativas entre as amostras (P menos de 0.05). Isto permite aos autores concluir pela ausência de cardiotoxicidade pela droga, o que sugere que as descriçöes prévias de literatura devam decorrer de fatores näo-associados ao uso de droga