Characteristics of follicular and mantle cell lymphoma in Brazil: prognostic impact of clinical parameters and treatment conditions in two hospitals

ABSTRACT Objective: Follicular and mantle cell lymphoma are low-grade B-cell malignancies that lack good responses to chemoimmunotherapy. This study aimed to assess retrospectively clinicopathological features and to determine independent prognostic factors for follicular and mantle cell lymphoma patients treated at two Brazilian medical centers: the Hematology and Hemotherapy Center of the Universidade Estadual de Campinas (Unicamp), a public university hospital, and AC. Camargo Cancer Center, a specialized cancer center. Methods: Two hundred and twenty-seven follicular and 112 mantle cell lymphoma cases were diagnosed between 1999 and 2016. Archived paraffin blocks were retrieved and reviewed. Corresponding demographics and clinical data were recovered from medical charts. Outcome analyses considered both overall and event-free survival. Results: For follicular lymphoma treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) and R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone) regimens, both B-symptoms (p-value < 0.01 for overall and event-free survival) and high-risk Follicular Lymphoma International Prognostic Index (p-value < 0.01 for overall survival) were independently associated to worse prognosis. Maintenance with rituximab improved the prognosis (p-value < 0.01 for overall survival). For mantle cell lymphoma, B-symptoms (p-value = 0.03 for overall survival and event-free survival) and bone marrow infiltration (p-value = 0.01 for overall survival) independently predicted reduced survival, and rituximab at induction increased both event-free and overall survival (p-value < 0.01 in both analyses). Combinations of these deleterious features could identify extremely poor prognostic subgroups. The administration of rituximab was more frequent in the AC. Camargo Cancer Center, which was the institution associated with better overall survival for both neoplasias. Conclusion: This study represents the largest cohort of follicular and mantle cell lymphoma in South America thus far. Some easily assessable clinical variables were able to predict prognosis and should be considered in low-income centers. In addition, the underuse of rituximab in the Brazilian public health system should be reconsidered in future health policies.

Lung cancer in Brazil / Câncer de pulmão no Brasil

ABSTRACT Lung cancer is one of the most incident types of cancer and a leading cause of cancer mortality in Brazil. We reviewed the current status of lung cancer by searching relevant data on prevention, diagnosis, and treatment in the country. This review highlights several issues that need to be addressed, including smoking control, patient lack of awareness, late diagnosis, and disparities in the access to cancer health care facilities in Brazil. We propose strategies to help overcome these limitations and challenge health care providers, as well as the society and governmental representatives, to work together and to take a step forward in fighting lung cancer.

RESUMO O câncer de pulmão é um dos tipos de câncer com maior incidência e uma das principais causas de mortalidade por câncer no Brasil. Revisamos a situação atual do câncer de pulmão por meio de pesquisa de dados relevantes a respeito de prevenção, diagnóstico e tratamento no país. Esta revisão mostra várias questões que precisam de atenção, tais como controle do tabagismo, educação dos pacientes, desconhecimento por parte dos pacientes, diagnóstico tardio e desigualdade de acesso ao tratamento de câncer no Brasil. Propomos estratégias para ajudar a superar essas limitações e desafiamos os profissionais de saúde, a sociedade e os representantes do governo a trabalhar em conjunto e dar um passo à frente na luta contra o câncer de pulmão.

Cetuximab desensitization protocol in two patients with metastatic colorectal cancer after grade 3 infusion reaction to cetuximab

Targeted monoclonal antibodies have become an important therapeutic option for patients with cancer. Cetuximab, a chimeric mouse-human (30:70) immunoglobulin G1 monoclonal antibody against epidermal growth factor receptor, has been approved by the US Food and Drug Administration for the treatment of head and neck and metastatic colorectal cancer (mCRC). Severe (grade 3/4) hypersensitivity-infusion reactions (HIRs) occur in 2-3% of the patients, with fatal outcomes in 0.1%. It is recommended that patients showing severe HIRs to cetuximab should avoid further exposure to it, but in some cases there is no alternative treatment. Two options are currently available for patients with HIRs to cetuximab: desensitization protocol and panitumumab. We describe here two patients with mCRC who successfully underwent a cetuximab desensitization protocol following a severe HIR to cetuximab.

Análise do perfil de expressão gênica em melanomas cutâneos malignos murinos após tratamento sistêmico com o fator de necrose tumoral (TNF) associado ou não a melfalano (MEL) / Gene expression profile of murine malignat melanoma after systemic treatment with with tumor necrosis factor (TNF) associated or not with melphalan (MEL)

ILP (Perfusão Isolada de Membro) com melphalan (MEL) é uma obordagem alternativa no tratamento de melanomas cutâneos avançados, não-ressecáveis, de extremidades, poupando o membro da amputação. ... O objetivo do nosso estudo foi determinar o perfil de expressão gênica do melanoma e sua modificação após tratamento com TNF, MEL ou TMF+MEL. .... Os perfis de expressão gênica das células e dos tumores foram determinados através da estratégia de “microarray”, empregando um “biochip” contendo 16.128 oligonucleotídeos. O tratamento das células de melanoma com MEL durante 48h esteve associado com uma maior taxa de morte celular. O TNF não exerceu nenhuma atividade citotóxica sobre as células de melanoma in vitro. A administração de melfalano promoveu uma menor velocidade de crescimento tumoral (p<0,001), efeito este que não foi modificado pela co-administração de TNF. Entretanto, tumores tratados com TNF apenas ou em combinação com MEL apresentaram mais necrose (p=0,017 e p=0,014, respectivamente) e menos mitoses (p=0,001). Um número menor de mitoses também foi observado em resposta a MEL. O tratamento com MEL ou MEL+TNF esteve associado com aumento da sobrevida livre de progressão. ... Um grupo de genes grande teve sua expressão modulada pelo tratamento in vitro. Entre estes, nós identificamos Aff1, um regulador do ciclo celular, positivamente regulado por MEL. O mesmo efeito foi observado in vivo para este gene em especial. Da comparação entre os perfis de expressão gênica dos tumores por ANOVA, nós identificamos 118 genes diferencialmente expressos com p<0,05. Entre os elementos diferencialmente expressos estão genes que codificam proteínas envolvidas em adesão celular (Pecam1, Pard3, Dlg5), apoptose (Bcl11l), vias de sinalização (Arhgef6, Flt-1), regulação de transcrição (Tcfe3, Ifi202b, Irak1bp1, Fabp4,Trp73, Trim24), ciclo celular (Cdc7, Aff1), metabolismo de drogas (Akr1b7), potencial metastático (Trpm1, Mib2) e várias outras funções biológicas...

ILP (Isolated Limb Perfusion) with melphalan (MEL) is an alternative approach in the treatment of non-resectable locally advanced cutaneous melanomas of extremity, sparing the limb from amputation. ILP is a locoregional procedure to deliver high doses of drugs to a limb with minimal systemic and mild local toxicity. The association with the Tumor Necrosis Factor (TNF) improves total complete response rates from 40-50% to 70-90%. The molecular mechanisms underlining this synergistic effect are poorly understood. The aim of our study was to determine the gene expression profile of melanoma and its alterations after the treatment with TNF, MEL and TNF+MEL. To reach this objective B16F1 and B16F10 cells were exposed to MEL (36,9µM), TNF (10ng/ml) or both during 3 hours for microarray assays or for 24h, 48h and 72h for citoxicity assays. At same time, 6-8 weeks-old male C57BL6 mice were injected subcutaneously, on both flanks, with 5,0x105 of B16F10 and B16F1 melanoma cells. Animals bearing tumors of 1,0±0,3cm2 (n=9-10 mice/group) received an intravenous injection of TNF (0,05µg/Kg), MEL (12mg/Kg), TNF+MEL or saline (control). One of the tumors was surgically removed 3h after for RNA extraction and histology and the other one was left for growth measurements. Gene expression profiles from cells and tumors were determined by microarray strategy using a biochip containing 16.128 oligonucleotides. Treatment of melanoma cells with MEL for 48h was associated with a significantly higher cell death rate. TNF exerted no cytotoxic effects on melanoma cells in vitro. The administration of melphalan led to slower tumor growth rate (p<0,001), effect that was not modified by the TNF co-administration. Nevertheless, tumors treated with TNF alone or in combination with MEL presented more necrosis (p=0,017 and p=0,014, respectively) and less mitosis (p=0,001). Less mitosis was also observed in response to MEL alone. Treatment with MEL or MEL+TNF was associated with a longer progression free survival. Three-hourtreatment with MEL or TNF did not affect vascular density. A whole set of genes had its expression modulated by treatment in vitro. Amongst them, we identified Aff1, a regulator of cell proliferation, as positively regulated by MEL. The same effect was observed in vivo for this specific gene. From the comparison between the gene expression profile by ANOVA, we identified 118 genes differentially expressed with p<0,05. Among the differentially expressed elements are genes coding for proteins involved in cell adhesion (Pecam1, Pard3, Dlg5), apoptosis (Bcl11l), signaling pathways (Arhgef6, Flt-1), regulation of transcription (Tcfe3, Ifi202b, Irak1bp1, Fabp4,Trp73, Trim24), cell cycle (Cdc7, Aff1), drug metabolism (Akr1b7), metastatic potential (Trpm1, Mib2) and many other diverse biological functions. Supported by: FAPESP (AU)