ABSTRACT
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.
Subject(s)
Humans , Costs and Cost Analysis/trends , Dacarbazine/administration & dosage , Dacarbazine/therapeutic use , Molecular Targeted Therapy/methods , Molecular Targeted Therapy/trends , Melanoma/drug therapy , Melanoma/epidemiology , Skin Neoplasms/drug therapy , Unified Health System , Public Health/trends , Health Care Costs/trends , Neoplasm Metastasis/drug therapy , Antineoplastic Agents/economicsABSTRACT
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.
Subject(s)
Animals , Male , Rats , Peritoneal Neoplasms/drug therapy , Peritoneum/pathology , Melanoma/drug therapy , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Peritoneal Neoplasms/surgery , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/secondary , Peritoneum/drug effects , Random Allocation , Regression Analysis , Dacarbazine/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Neoplasm Grading , Nivolumab , Hyperthermia, Induced , Melanoma/secondary , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic useABSTRACT
O linfoma é uma neoplasia originária do sistema linfático, a partir de células linfocitárias. A sintomatologia mais comum é febre, tosse, sudorese noturna, perda de peso, fraqueza e linfoadenopatia indolor. A etiologia ainda permanece desconhecida, tendo sido relacionada ao vírus Epstein-Barr. O diagnóstico se baseia na visualização das células de Reed-Sternberg. O esquema adriamicina, bleomicina, vinblastina e dacarbazina (ABVD) ainda é o tratamento preconizado, associado ou não à radioterapia. Relatamos um caso de linfoma de Hodgkin de apresentação atípica, cujo diagnóstico só foi possível por esplenectomia.(AU)
The lymphoma is a cancer of the lymphatic system originating from lymphocyte cells. The most common symptoms are fever, cough, night sweats, weight loss, weakness, and painless lymphadenopathy. The etiology remains unknown, having been related to the Epstein Barr virus. The diagnosis is based on visualization of Reed Sternberg cells. The adriamycin, bleomicin, vinblastine and dacarbazine (ABVD) regimen is still the preferred treatment, with or without radiation therapy. We report a case of Hodgkin's lymphoma of atypical presentation, the diagnosis of which was only possible through splenectomy.(AU)
Subject(s)
Humans , Male , Aged , Antineoplastic Combined Chemotherapy Protocols , Cyclophosphamide/administration & dosage , Hodgkin Disease/diagnosis , Hodgkin Disease/drug therapy , Reed-Sternberg Cells , Vinblastine/administration & dosageABSTRACT
Objective To evaluate the antitumor effect of dacarbazine (DTIC) on B16-F1 melanoma after CDK2 gene silencing.Methods Cultured B16-F1 melanoma cells were divided into 4 groups:control group receiving no treatment,CDK2-shRNA group infected with a recombinant lentivirus pUL-CDK2-shRNA,DTIC group cultured in 96-well plates followed 12 hours later by the treatment with 250 μmol/L DTIC,CDK2-shRNA + DTIC group infected with pUL-CDK2-shRNA followed 12 hours later by the treatment with 250 μmol/L DTIC.MTT assay was performed to evaluate the growth inhibition of B16-F1 melanoma cells,and coefficient of drug interaction (CDI) was calculated.AnnexinV-FITC/PI double staining was conducted to detect cell apoptosis.C57BL/6 mice were subcutaneously injected with B16-F1 cells at exponential growth phase into the right groin to establish melanoma-bearing mouse models.Twenty mouse models were randomly and equally divided into 4 groups:control mouse group injected with phosphate-buffered solution (PBS) into tumors,CDK2-shRNA mouse group injected with pUL-CDK2-shRNA into tumors,DTIC mouse group injected with DTIC into the abdominal cavity,and CDK2-shRNA + DTIC mouse group treated with pUL-CDK2-shRNA and DTIC.The animal experiment lasted 18 days,and the tumor growth curve was drawn.After 18-day treatment,all the mice were sacrificed,and tumors were isolated and weighed.The tumor growth inhibition rate was calculated,and the tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL).Results After 72-hour culture,compared with the control group,the CDK2-shRNA group,DTIC group,and CDK2-shRNA + DTIC group showed significantly decreased relative cell survival rates (40.6％ ± 2.8％,45.2％ ± 3.7％,28.7％ ± 2.1％,respectively;F =458.04,P ＜ 0.05),but significantly increased cell apoptosis rates (25.1％ ± 3.3％,15.6％ ± 2.2％,45.6％ ± 3.5％,respectively;F =115.46,P ＜ 0.05).Additionally,CDK2-shRNA + DTIC group showed significantly lower relative cell survival rates (P ＜ 0.01),but higher cell apoptosis rates (P ＜ 0.01) compared with the DTIC group.The CDI value was less than 0.7.On the sixth day after the in vivo treatment,the tumor volumes in the control mouse group,CDK2-shRNA mouse group,DTIC mouse group,and CDK2-shRNA + DTIC mouse group were (185.44 ± 68.97) mm3,(83.91 ± 14.33) mm3,(123.70 ± 20.85) mm3,and (34.54 ± 10.72) mm3 respectively.From then on,the CDK2-shRNA mouse group,DTIC mouse group,and CDK2-shRNA + DTIC mouse group showed significantly decreased tumor growth rates compared with the control mouse group (F =11.819,P ＜ 0.05),and the tumor growth rate was significantly lower in the CDK2-shRNA + DTIC mouse group than in the DTIC mouse group (P =0.04).The calculated tumor growth inhibition rates in the CDK2-shRNA mouse group,DTIC mouse group and CDK2-shRNA + DTIC mouse group were 52.2％,41.2％ and 86.4％ respectively.Compared with the control mouse group,the CDK2-shRNA mouse group,DTIC mouse group,and CDK2-shRNA + DTIC mouse group showed significantly increased tumor cell apoptosis indice (32.93％ ± 3.72％,21.62％ ± 3.54％,63.29％ ± 4.74％ respectively;F =222.25,P ＜ 0.05).Moreover,the tumor cell apoptosis index was significantly higher in the CDK2-shRNA + DTIC mouse group than in the DTIC mouse group (P ＜ 0.01).Conclusion CDK2 gene silencing can enhance the inhibitory effect of DTIC on the growth of melanoma,and show a synergistic effect with DTIC,likely by increasing the apoptosis of tumor cells.
ABSTRACT
Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8⁺ T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8⁺ T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8⁺ T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8⁺ T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators.
Subject(s)
Humans , Male , Middle Aged , Asian People , Brain , Cell Death , Dacarbazine , Immunohistochemistry , Lung , Lymph Node Excision , Melanoma , Neoplasm Metastasis , Skin , Spleen , T-LymphocytesABSTRACT
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.