Second-Line Chemotherapy in Recurrent Glioblastoma: A 2-Cohort Study.

BACKGROUND: Glioblastoma (GB) is the most common malignant primary central nervous system tumor in adults. Standard-of-care therapy includes surgical resection, radiotherapy and temozolomide, but nearly all patients experience disease progression. The purpose of this study was to describe 2 cohorts of patients with recurrent GB submitted to second-line treatment with procarbazine/lomustine/vincristine (PCV) or bevacizumab/irinotecan (BI). MATERIAL AND METHODS: Retrospective analysis of GB patients treated in our center with PCV or BI, after progression with temozolomide, between 2004 and 2012. RESULTS: Among 60 patients, 41 were treated with BI and 19 with PCV. According to the Macdonald criteria, the overall response rate in the BI group was 66% (n = 27) while it was 11% (n = 2) in the PCV group. The median progression-free survival was 5 and 3 months in the BI and PCV group, respectively. The median overall survival (OS) since second-line chemotherapy was 9 months in the BI group and 5 months in the PCV group. The latter group had a worse toxicity profile (grade 3-4: 52.6% vs. 22.0%; grade 1-2: 89.5% vs. 68.3%). CONCLUSIONS: The BI cohort had higher response rates, almost twice the OS and a lower degree of toxicity in contrast to the PCV group. The small number of patients and historical cohorts limits these comparisons.

Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer.

Amplification or deletion of the topoisomerase IIα (TOP2A) gene in breast cancer has been related with responsiveness to anthracyclines-based chemotherapy. The purpose of this study was to evaluate the predictive value of TOP2A gene for the efficacy of neo-adjuvant anthracycline in a population with locally advanced breast cancer. Sixty-two patients were included, and the status of TOP2A gene was determined by in situ hybridization method. Treatment efficacy was determined by clinical and pathological response and overall survival. TOP2A gene alterations were found in 22.6% (21.0% of cases with amplification and 1.6% with deletion), and these tumors were biologically more aggressive, with higher nuclear grade, more frequently with HER2 amplification and inflammatory type. Also in these tumors response to chemotherapy appeared to be increased. There was a higher clinical and pathological response rate (complete pathological response of 21.4% vs. 8.3%), a trend toward longer progression-free survival (82.51 vs. 63.12 months) and a trend to increased overall survival (92.08 months; 95% CI 82.81-101.35 vs. 73.40 months; 95% CI 63.44-83.36; p=0.113). These results corroborate that the TOP2A gene alterations may play an important role in determining anthracycline sensitivity in breast cancer.

PNET with neuroendocrine differentiation of the lung: Report of an unusual entity.

Ewing's sarcoma/primitive neuroectodermal tumor (PNET) has been the subject of recent reports describing morphologic variants (adamantinoma-like, large cell, spindle cell, sclerosing, clear cell, and vascular-like) of the most classic form, as well as cases displaying unusual morphologic differentiation and atypical immunohistochemical features. We report a case of an uncommon lung tumor in a 20-year-old female, morphologically and molecularly consistent with an Ewing's sarcoma/PNET tumor with foci of squamous differentiation, and peculiar expression of vimentin, high-molecular-weight keratins, p63, synaptophysin, and chromogranin. This case raises a challenging differential diagnostic problem with therapeutic implications: Should the patient be treated following the protocols for Ewing's sarcoma/PNET tumors or as for lung carcinoma with neuroendocrine features? The patient we report here was treated with neoadjuvant chemotherapy for Ewing's sarcoma/PNET according to Euro Ewing 99 study protocol followed by surgery and has no evidence of disease 15 months after the initial diagnosis. This highlights the importance of achieving the correct diagnosis of these atypical tumors using all clinical, morphological, and ancillary methods available to allow for their correct and timely treatment.

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide.

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide / Síndrome de Cushing ectópico causado por um tumor pulmonar secretor de ACTH em tratamento com octreotide

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

A secreção ectópica de ACTH é uma síndrome rara associada habitualmente à hipercortisolemia grave. A remoção cirúrgica do tumor é o tratamento de primeira linha, sempre que seja exequível. Homem com 33 anos, internado em 1993 com manifestações clínicas sugestivas de síndrome de Cushing, apresentava valores elevados de ACTH plasmática e excreção urinária de cortisol livre muito aumentada, sem supressão na prova com dose alta de dexametasona; RM hipofisária sem alterações; cateterismo bilateral dos seios petrosos inferiores sem gradiente central-periférico de ACTH. A CT de tórax mostrou um nódulo de 1,7 cm no pulmão esquerdo. O diagnóstico de carcinoma neuroendócrino produtor de ACTH foi feito com base nos resultados citológico, imunocitoquímico e ultraestrutural, juntamente com a presença de metástases ósseas. Foi inicialmente submetido à quimioterapia e encontra-se em tratamento com octreotide LAR desde 1998, apresentando resposta clínica, bioquímica e imagiológica favorável. Destacamos a excelente resposta a longo prazo à terapêutica com octreotide LAR, sem taquifilaxia, provavelmente devido ao seu efeito antiproliferativo.

Downregulation of RKIP is associated with poor outcome and malignant progression in gliomas.

Malignant gliomas are highly infiltrative and invasive tumors, which precludes the few treatment options available. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying gliomas aggressive phenotype and poor prognosis. The Raf Kinase Inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. Its role in the prognosis and tumourigenesis of gliomas remains unclear. In the present study, we found that RKIP protein is absent in a low frequency (10%, 20/193) of glioma tumors. Nevertheless, the absence of RKIP expression was an independent prognostic marker in glioma. Additionally, by in vitro downregulation of RKIP, we found that RKIP inhibition induces a higher viability and migration of the cells, having no effect on cellular proliferation and angiogenesis, as assessed by in vivo CAM assay. In conclusion, this is the largest series studied so far evaluating the expression levels of this important cancer suppressor protein in glioma tumors. Our results suggest that in a subset of tumors, the absence of RKIP associates with highly malignant behavior and poor survival of patients, which may be a useful biomarker for tailored treatment of glioma patients.

Bevacizumab for the first-line treatment of human epidermal growth factor receptor 2-negative advanced breast cancer.

PURPOSE OF REVIEW: Breast cancer is the most common cancer in women worldwide and its incidence is increasing as a result of the continued adoption of lifestyles associated with increased risk factors. Approximately, 75% of breast cancers do not express the human epidermal growth factor receptor 2 (HER2), including hormone receptor-positive and triple-negative tumors. HER2-negative breast cancers are resistant to, or eventually become resistant to, existing targeted treatments such as HER2-targeted agents and hormone therapies, and, as a consequence, are associated with poorer outcomes than HER2-positive breast cancer. Bevacizumab is a humanized monoclonal antibody that recognizes vascular endothelial growth factor-A, a rate-limiting step in pathological angiogenesis such as tumor growth. As angiogenic pathways become more complex as breast cancer progresses, angiogenesis inhibitors should be initiated earlier in the disease course. This review will discuss the evidence for bevacizumab as first-line therapy in metastatic breast cancer, with a particular focus on patients with HER2-negative disease. RECENT FINDINGS: Bevacizumab, when administered in combination with first-line standard chemotherapy, significantly increases progression-free survival and overall response rate in patients with metastatic breast cancer. SUMMARY: Novel targeted therapies that are appropriate to HER2-negative breast cancer, such as bevacizumab, may represent valuable therapeutic options in the clinical management of metastatic breast cancer.

Prognostic value of MGMT promoter methylation in glioblastoma patients treated with temozolomide-based chemoradiation: a Portuguese multicentre study.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The identification of novel molecular prognostic markers of GBM has recently been an area of great interest in neuro-oncology. The methylation status of the MGMT gene promoter is currently a promising molecular prognostic marker, but some controversial data have precluded its clinical use. We analyzed MGMT methylation by methylation-specific PCR in 90 GBM patients from four Portuguese hospitals, uniformly treated with radiotherapy combined with concomitant and adjuvant temozolomide (Stupp protocol). The Kaplan-Meier method was used to construct survival curves, and the log-rank test and a Cox-regression model were used to analyze patient survival. The methylation status of MGMT was successfully determined in 89% (80/90) of the tumors. The frequency of tumoral MGMT promoter methylation was 47.5%. The median overall survivals (OSs) were 16 months (95% CI 12.2-19.8) and 13 months (95% CI 13.3-18.7) for patients whose tumors had a methylated or unmethylated MGMT, respectively. Univariate and multivariate analyses did not show any statistically significant association between MGMT methylation status and patient OS (P=0.583 by the log-rank test; P=0.617 by the Cox-regression test) or progression-free survival (P=0.775 by the log-rank test; P=0.691 by the Cox-regression test). None of the patient clinical features were significantly correlated with survival. This is the first study to report the frequency of MGMT methylation among Portuguese GBM patients. Our data did not show statistically significant associations between MGMT promoter methylation and the outcome of GBM patients treated with temozolomide. Additional robust prospective studies are warranted to clarify whether the MGMT status should be used in clinical decisions.

[Cost of cancer care in Portugal]. / Custo do tratamento do cancro em Portugal.

INTRODUCTION: Cancer is the second most important cause of death in Portugal, following cardiovascular diseases (CVD), and shows a constant progressive increase in the proportional share of total deaths. In Portugal, as in most countries, the health care budget is under constant cost-containment pressures. In this context it is necessary to verify if enough resources have been allocated to the disease in terms of health care expenditure. The main objective of this study is to estimate the cost of cancer care in Portugal and to compare it to similar data in Europe and the United States of America (USA), to the cost of CVD. The secondary objective is to evaluate the cost of pharmaceuticals used in the treatment of cancer in Portugal, both in relation to total pharmaceutical expenditure and to other therapeutic areas. METHODS: Three main sources of information were used: comprehensive literature review, primary and secondary data sources, and a modified Delphi Panel, which was used to fill in gaps in the information derived from the data sources and the literatura review. The burden of cancer was measured through the Disability-adjusted life-year (DALY) and, in order to determine the costs of cancer, detailed information on the costs of medical visits and of inpatient episodes based on Diagnosis Related Groups (DRG), in 2006, was used. To estimate the total cost of cancer, we used a combination of top down (breaking global expenditure data to specific levels) and bottom up methodology (based on the sum of different components). RESULTS: Based on 2006 data on direct medical care expenditures in Portugal, we found that 565 million euro were spent on cancer in comparison to 1 320 million on CVD representing 3.91% and 9.14% of total cost on health respectively. When we break down total expenditure on drugs by therapeutic area we find that CVD drugs represent about 21.6% of total drug costs in Portugal and cancer drugs represent about 5.6% of the total. Oncology drugs represent 32% of the total expenditure on cancer, while CVD drugs represent 54% of the total expenditure on CVD. In comparison, in terms of BoD in Portugal, 18.6% of DALY's were associated with CVD and 15.3% with cancer. CONCLUSION: Considering the burden of disease (BoD) of CVD and cancer in Portugal, we can state that the expenditure allocated to cancer is significantly lower than expected. Using the criterion of expenditure according to need, we observed that there is an imbalance of expense/BoD in oncology indicating that cancer seems to be underfunded in Portugal. Even considering that this shouldn't be the only criterion to determine the volume of expense in a certain therapeutic area, the differential observed in this study is sufficiently high to deserve attention from the decision-makers.

[Biosimilars in oncology]. / Biossimilares em oncologia.

The development of biotechnology drugs represents one of the great advances in medical therapy and it was observed an exponential growth in its use. The resource to these drugs in Oncology and Hematology is no exception and it soon became an essential element of an integrated and directed therapy strategy. The expiry of the first biotechnology drugs patents has opened the door for the development and marketing of biosimilars, which entry in the Portuguese market was recently approved. This article was built on the analysis of the available state-of-the-art information on biotechnology drugs, biosimilars and current legislation and it expresses the opinion of Oncology and Hematology experts about the substituition of biological drugs by biosimilars in clinical practice.

[Guidelines for prevention of febrile neutropenia]. / Orientações para a prevenção da neutropenia febril em doentes submetidos a quimioterapia.

Neutropenia and febrile neutropenia are common consequences of some cytotoxic chemotherapy regimens. This situation leads to modifications of the therapeutic regimen, conducting to either dose reduction or cycle delays. Granulocyte colony stimulating factors are commonly used to minimize chemotherapy cytotoxic effect on the granulocytic series. The objective of this study is to assess the available evidence in what concerns the efficacy and safety of granulocyte colony stimulating factors, in several settings of their use. An extensive bibliographic review was performed, including clinical trials, observational studies, systematic reviews, and international guidelines for neutropenia prophylaxis, which aims to establish recommendations on their use, in adequacy to the National reality.