Fusion Cell Markers in Circulating Tumor Cells from Patients with High-Grade Ovarian Serous Carcinoma.

Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.

EVALUATING MMP-2 AND TGFß-RI EXPRESSION IN CIRCULATING TUMOR CELLS OF PANCREATIC CANCER PATIENTS AND THEIR CORRELATION WITH CLINICAL EVOLUTION.

BACKGROUND: Metastasis is common in the diagnosis of pancreatic cancer, and the presence of epithelial-mesenchymal transition markers in circulating tumor cells may suggest worse prognosis. AIM: To correlate the number of circulating tumor cells (CTCs) in the peripheral blood of patients with a locally advanced or metastatic pancreatic tumor and the protein expression involved in epithelial-mesenchymal transition (EMT) in CTCs with clinical characteristics, progression-free survival (PFS) and overall survival (OS). METHOD: This was a prospective study conducted using peripheral blood samples collected at three different times. CTCs were quantified by the ISET test and analyzed by immunocytochemistry. Proteins involved in EMT (vimentin, TGFß-RI and MMP2) were analyzed in all CTCs. RESULTS: Twenty-one patients were included. Median CTCs detected were 22, 20 and 8 CTCs/8 ml blood at baseline, first and second follow-up, respectively. No statistically significant correlation was found in correlating the number of CTCs and the evaluated clinical characteristics, PFS, or OS. There was no difference in PFS and OS among the EMT markers in the groups with and without markers. CONCLUSION: CTC analysis was not relevant in this sample for comparing clinical findings, PFS and OS in patients with pancreatic cancer. However, marker analysis in CTCs could be useful for the MMP-2 and/or TGFß-RI expression, as observed by the separate PFS curve.

Evaluating mmp-2 and tgfß-ri expression in circulating tumor cells of pancreatic cancer patients and their correlation with clinical evolution / Avaliação da expressão de mmp-2 e tgfß-ri em células tumorais circulantes de pacientes com câncer de pâncreas e sua correlação com evolução clínica

ABSTRACT Background: Metastasis is common in the diagnosis of pancreatic cancer, and the presence of epithelial-mesenchymal transition markers in circulating tumor cells may suggest worse prognosis. Aim: To correlate the number of circulating tumor cells (CTCs) in the peripheral blood of patients with a locally advanced or metastatic pancreatic tumor and the protein expression involved in epithelial-mesenchymal transition (EMT) in CTCs with clinical characteristics, progression-free survival (PFS) and overall survival (OS). Method: This was a prospective study conducted using peripheral blood samples collected at three different times. CTCs were quantified by the ISET test and analyzed by immunocytochemistry. Proteins involved in EMT (vimentin, TGFß-RI and MMP2) were analyzed in all CTCs. Results: Twenty-one patients were included. Median CTCs detected were 22, 20 and 8 CTCs/8 ml blood at baseline, first and second follow-up, respectively. No statistically significant correlation was found in correlating the number of CTCs and the evaluated clinical characteristics, PFS, or OS. There was no difference in PFS and OS among the EMT markers in the groups with and without markers. Conclusion: CTC analysis was not relevant in this sample for comparing clinical findings, PFS and OS in patients with pancreatic cancer. However, marker analysis in CTCs could be useful for the MMP-2 and/or TGFß-RI expression, as observed by the separate PFS curve.

RESUMO Racional: A metástase é comum no diagnóstico de câncer de pâncreas; presença de marcadores de transição epitélio-mesenquimal nas células tumorais circulantes (CTCs) podem sugerir pior prognóstico. Objetivo: Correlacionar o número de CTCs no sangue periférico de pacientes com tumor de pâncreas localmente avançado ou metastático e expressão de proteínas envolvidas na transição epitélio-mesenquimal (TEM) nas CTCs com características clínicas, sobrevida livre de progressão (SLP) e global (SG). Método: Estudo prospectivo realizado por meio de coletas de sangue periférico em três tempos distintos. As CTCs foram quantificadas pelo sistema ISET e analisadas por imunocitoquímica. Proteínas envolvidas na TEM (vimentina, TGFß-RI e MMP2) foram analisadas em todas as CTCs. Resultados: Foram incluídos 21 pacientes. A mediana de CTCs detectadas foi de 22, 20 e 8 CTCs/8 ml de sangue no baseline, primeiro e segundo seguimentos, respectivamente. Na correlação entre número de CTCs e as características clínicas levantadas, SLP, SG não houve correlação estatisticamente significante. Nos marcadores de TEM não houve diferença de SLP e SG entre os grupos que apresentaram e não apresentaram marcação. Conclusão: As CTCs não se mostraram relevantes na comparação dos achados clínicos, SLP e SG em pacientes com câncer de pâncreas. No entretanto, pode ser que para a análise de marcador seja útil, como observado pelas curvas separadas de expressão de MMP-2 e TGFß-RI nas CTCs.

Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-ß receptor I in head and neck cancer.

BACKGROUND: Circulating tumor microemboli (CTM) are clusters of circulating tumor cells (CTCs), involved in metastasis, as also transforming growth factor-ß (TGF-ß). The purpose of this study was to verify their role in progression-free survival (PFS). METHODS: Blood from patients with locally advanced head and neck squamous cell carcinoma (HNSCC; n = 53) was analyzed in 2 moments. TGF-ß receptor I (TGF-ßRI) expression was evaluated by immunocytochemistry. RESULTS: Comparing CTM1 (baseline) with CTM2 (first follow-up), patients with CTM1-positive disease who became CTM2-negative were classified as favorable (PFS 20 months). Patients with unfavorable evolution (CTM1-negative/CTM2-positive), had PFS of 17.5 months. Patients always CTM-negative showed PFS of 22.4 months, those always positive, 4.7 months (P < .001). The TGF-ßRI expression in the first follow-up correlated with poor PFS (12 × 26 months; P = .007), being an independent prognostic factor (hazard ratio [HR] = 6.088; P = .033). CONCLUSION: CTM1/2, TGF-ßRI expression, and unfavorable CTM kinetics may represent poor prognosis in locally advanced HNSCC.

Circulating Tumor Cells as Cancer Biomarkers in the Clinic.

It is believed that the development of metastatic cancer requires the presence of circulating tumor cells (CTCs) , which are found in a patient's circulation as rare abnormal cells comingled with billions of the normal red and white blood cells. The systems developed for detection of CTCs have brought progress to cancer treatment. The molecular characterization of CTCs can aid in the development of new drugs, and their presence during treatment can help clinicians determine the prognosis of the patient. Studies have been carried out in patients early in the disease course, with only primary tumors, and the role of CTCs in prognosis seems to be as important as it is in patients with metastatic disease. The published studies on CTCs have focused on their prognostic significance, their utility in real-time monitoring of therapies, the identification of therapeutic and resistance targets, and understanding the process of metastasis . The analysis of CTCs during the early stages, as a "liquid biopsy," helps to monitor patients at different points in the disease course, including minimal residual disease, providing valuable information about the very early assessment of treatment effectiveness. Finally, CTCs can be used to screen patients with family histories of cancer or with diseases that can lead to the development of cancer. With standard protocols, this easily obtained and practical tool can be used to prevent the growth and spread of cancer. In this chapter, we review some important aspects of CTCs , surveying the disease aspects where these cells have been investigated.

Epidemiological Profile and Treatment Outcomes in Young Adults (19-29 Years of Age) Treated for Cancer in a Tertiary Hospital in São Paulo, Brazil.

BACKGROUND: Worldwide, the incidence of cancer in young adults (20-39 years) is increasing, and represents an important cause of mortality in this age group. A retrospective study was undertaken to provide information that may lead to improved treatment outcomes. METHODS: Epidemiological, clinicopathological, treatment, and survival information were retrieved from the electronic database registry of a tertiary referral hospital in São Paulo, Brazil for patients 19-29 years of age diagnosed with cancer between January 2007 and December 2012. RESULTS: There were 960 patients with a median age at diagnosis of 26 years; female patients comprised 59.2%. A previous diagnosis of malignancy was present in 2.3%; 0.4% had malignant tumors that were radiation-associated; regular alcohol use was present in 10.4%; 9% of patients reported tobacco use; a family history of cancer was present in 41.7%. Malignant tumors included carcinomas (45.7%), germ cell and trophoblastic neoplasms (12.3%), and lymphomas (12.1%). Median follow-up was 47.7 months (range: 0.62-100.9 months) during which time 111 patients (13.5%) died. Carcinomas (n = 43, 38.7%), soft tissue sarcomas (n = 18, 16.2%), and leukemias (n = 10, 9.0%) were the most common causes of death. CONCLUSIONS: This study has shown that carcinomas represent the most common malignancy in adolescents and young adults referred to a tertiary cancer center in Brazil and are the most common cause of mortality. Because clinical outcome may be affected by multiple factors in this patient population, further global studies are needed to characterize this population and improve clinical care.

Circulating tumor cells as a new and additional approach to follow-up patients with serous low-grade ovarian adenocarcinoma: a case report and review of the literature

Background: Current methods for follow-up of Ovarian Cancer (OC) are widespread, especially with CA125, which, however, is not a perfect biomarker and thus further investigation for new methods of evaluation are warranted. The feasibility of Circulating Tumor Cells (CTCs) in advanced OC was investigated in this case report. Case presentation: A 19-year-old woman with advanced low-grade serous papillary adenocarcinoma and relapsed disease did not have a CA125 correspondent with disease relapse. CTCs were evaluated, compared with CA125 and with image exams. Relapses were not correspondent to elevations of CA125. CTCs demonstrated usefulness, being proportional to major disease relapse, especially in the peritoneum. CTCs may be used as a complementary diagnosis tool when marginal/small increases in CA-125 levels are observed. Conclusions: In OC, CTCs can be an important tool to predict recurrence, response to treatment and improve the quality of decision-making, in order to offer the best treatment to a determined group of patients (AU)

Is early response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography a predictor of long-term outcome in patients with metastatic colorectal cancer?

BACKGROUND: Identify in advance responder patients to chemotherapy in metastatic colorectal cancer (CRC) would allow prompt interruption of ineffective therapies in non-responder patients. Hence, predictive markers are sought in numerous trials to detect responder patients, including tumor shrinkage measured by imaging methods. Usually, Response Evaluation Criteria in Solid Tumors (RECIST) is used to evaluate tumor response in metastatic CRC, but these criteria are questionable with use of biological agents associated to chemotherapy. Our aim was correlate early metabolic response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ((18)FDG-PET-CT) with long-term outcome in metastatic CRC in first-line therapy. METHODS: We prospectively evaluated 36 patients with metastatic CRC in first-line treatment with 5-fluorouracil, leucovorin (folinic acid), oxaliplatin (FOLFOX) or 5-fluorouracil, leucovorin (folinic acid), irinotecan (FOLFIRI) associated with cetuximab or bevacizumab. (18)FDG-PET-CT was performed at baseline and after two cycles of chemotherapy. The early metabolic response [standardized uptake value (SUV)] was measured to identify responder and non-responder patients and correlated with overall survival (OS) and progression-free survival (PFS). RESULTS: Median age was 58.5 years (range, 41-74 years). PFS was 15.5 months for responder and 13.3 months for non-responder (P=0.42), OS was 55.7 months for responder and not reached for non-responder. There was no correlation between delta-SUV and clinical and pathological variables analyzed. In the subgroup of patients who did not undergo resection of metastasis (45%), PFS was higher for responders (15.3×6.8 months, P=0.02). CONCLUSIONS: According to our findings, early response by (18)FDG-PET-CT was not a predictor of long-term outcome for patients with metastatic CRC treated in the first-line chemotherapy with a monoclonal antibody.

MRP1 expression in CTCs confers resistance to irinotecan-based chemotherapy in metastatic colorectal cancer.

Circulating tumor cells are important markers of tumor progression and can reflect tumor behavior in metastatic colorectal cancer (mCRC). Identification of proteins that confer resistance to treatment is an important step to predict response and better selection of treatment for patients. Multidrug resistance-associated protein 1 (MRP1) and Multidrug resistance-associated protein 4 (MRP4) play a role in irinotecan-resistance, and Excision Repair Cross-Complementation group 1 (ERCC1) expression can confer resistance to platinum compounds. Here, we included 34 patients with mCRC and most of them received FOLFIRI or FOLFOX chemotherapy (91.1%). CTCs were isolated by ISET(®) Technology and identified in 30 patients (88.2%), with a median of 2.0 CTCs/mL (0-31.0). We analyzed the immunocytochemical expression of MRP1, MRP4 and ERCC1 only in patients who had previously detectable CTCs, accordingly to treatment received (n = 19, 15 and 13 patients, respectively). Among patients treated with irinotecan-based chemotherapy, 4 out of 19 cases with MRP1 positive CTCs showed a worse progression free survival (PFS) in comparison to those with MRP1 negative CTCs (2.1 months vs. 9.1 months; p = 0.003). None of the other proteins studied in CTCs had significant association with PFS. We analyzed also histological sections of primary tumors and metastases by immunohistochemistry, and found no association with clinicopathological characteristics or with PFS. Our results show MRP1 as a potential biomarker of resistance to treatment with irinotecan when found in CTCs from mCRC patients. This is a small proof-of-principle study and these early findings need to be validated in a larger cohort of patients.

Noncurative Resection for Gastric Cancer Patients: Who Could Benefit? : Determining Prognostic Factors for Patient Selection.

BACKGROUND: Resections have long been recommended for patients with incurable gastric cancer. However, high morbidity rates and more efficient chemotherapy regimens have demanded more accurate patient selection. The aim of this study was to analyze the results of gastric cancer patients treated with noncurative resection in a single cancer center. METHODS: Medical charts of patients treated with a noncurative resection between January 1988 and December 2012 were analyzed. Individuals who had M1 disease were included, along with those with no metastasis but who had an R2 resection. Morbidity, mortality, and survival prognostic factors were analyzed. RESULTS: In the period, 192 patients were resected, 159 with previously diagnosed metastatic disease and the other 33 having resection with macroscopic residual disease (R2). A distal gastrectomy was performed in 117 patients and a total resection in 75, with a more limited lymph node dissection in 70 % of cases. A multivisceral resection was deemed necessary in 42 individuals (21.9 %). Overall morbidity was 26.6 % and 60-day mortality was 6.8 %. Splenectomy was the only independent prognostic factor for higher morbidity. Median survival was 10 months, and younger age, distal resection, and chemotherapy were independent prognostic factors for survival. A prognostic score obtained from these factors identified a 20-month median survival in patients with these favorable characteristics. CONCLUSION: Noncurative surgery may be considered in selected gastric cancer patients as long as it has low morbidity and allows the realization of chemotherapy.

Aortic dissection during antiangiogenic therapy with sunitinib. A case report / Dissecção de aorta em terapia anti-angiogênica com sunitinibe. Um relato de caso

CONTEXT: Sunitinib is an antiangiogenic drug that has been approved for treating metastatic renal cancer. Its action as a tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) and other angiogenesis receptors may lead to adverse effects such as hypertension and heart failure. However, reports in the literature on an association between sunitinib therapy and acute aortic dissection are rare. CASE REPORT: We report the case of a 68-year-old man with metastatic renal carcinoma who developed acute aortic dissection during sunitinib therapy. He had no history of hypertension or any other risk factor for aortic dissection. After aortic dissection had been diagnosed, sunitinib was withdrawn and an aortic endoprosthesis was placed. Afterwards, the patient was treated clinically with antihypertensive drugs and new therapy for renal cancer consisting of temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway. CONCLUSION: Hypertension is a common event when antiangiogenic drugs are used in oncology. However, knowledge of other severe cardiovascular events that may occur in these patients, such as acute aortic dissection, is important. Adequate control over arterial pressure and frequent monitoring of patients during the first days of antiangiogenic therapy is essential for early diagnosis of possible adverse events. .

CONTEXTO: Sunitinibe é uma droga antiangiogênica aprovada para tratamento de câncer renal metastático. Sua ação como inibidor de tirosina quinase de receptores de fatores de crescimento do endotélio vascular (VEGFR) e de outros receptores de angiogênese pode levar a eventos adversos como hipertensão e insuficiência cardíaca. No entanto, é escassa na literatura a associação da terapia com sunitinibe e dissecção aguda de aorta. RELATO DE CASO: Relatamos o caso de um paciente do sexo masculino de 68 anos com câncer renal metastático que desenvolveu dissecção aguda de aorta durante tratamento com sunitinibe. O paciente não tinha histórico prévio de hipertensão nem outro fator de risco para dissecção de aorta. Após diagnóstico da dissecção de aorta, a droga foi suspensa e o paciente foi submetido à colocação de endoprótese na aorta, evoluindo posteriormente com controle clínico da pressão arterial e nova terapia para câncer renal com tensirolimo, um inibidor da via proteína alvo da rapamicina em mamíferos (mTOR). CONCLUSÕES: A hipertensão é um evento comum com uso de drogas antiangiogênicas na oncologia. No entanto, é importante o conhecimento de outros eventos cardiovasculares graves, como dissecção aguda de aorta, que podem ocorrer nesses pacientes. Controle adequado da pressão arterial e monitorização frequente dos pacientes nos primeiros dias de terapia antiangiogênica são essenciais para diagnóstico precoce de possíveis eventos graves. .

Thymidylate synthase expression in circulating tumor cells: a new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients.

Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5-FU resistance predictor biomarker if analyzed in CTCs from mCRC patients.

Aortic dissection during antiangiogenic therapy with sunitinib. A case report.

CONTEXT: Sunitinib is an antiangiogenic drug that has been approved for treating metastatic renal cancer. Its action as a tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) and other angiogenesis receptors may lead to adverse effects such as hypertension and heart failure. However, reports in the literature on an association between sunitinib therapy and acute aortic dissection are rare. CASE REPORT: We report the case of a 68-year-old man with metastatic renal carcinoma who developed acute aortic dissection during sunitinib therapy. He had no history of hypertension or any other risk factor for aortic dissection. After aortic dissection had been diagnosed, sunitinib was withdrawn and an aortic endoprosthesis was placed. Afterwards, the patient was treated clinically with antihypertensive drugs and new therapy for renal cancer consisting of temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway. CONCLUSION: Hypertension is a common event when antiangiogenic drugs are used in oncology. However, knowledge of other severe cardiovascular events that may occur in these patients, such as acute aortic dissection, is important. Adequate control over arterial pressure and frequent monitoring of patients during the first days of antiangiogenic therapy is essential for early diagnosis of possible adverse events.

Cytokeratin-based CTC counting unrelated to clinical follow up.

BACKGROUND: Circulating tumor cells (CTCs) have been reported to be a relevant prognostic biomarker in metastatic patients. However, their clinical use and impact is still under debate. We have thus comparatively and kinetically assessed two CTC detection methods according to the patient's clinical follow up. METHODS: CTC counting and characterization were repeatedly performed during follow up in a patient with metastatic undifferentiated non-small cell lung cancer by using cytokeratin (CK)-dependent immunomagnetic separation (Miltenyi) and CK-independent, size-based isolation [isolation by size of tumor cells (ISET)] (Rarecells). RESULTS: Comparison between the two methods showed a parallel increase of CTC detected by ISET and worsening of the clinical status, while CK-dependent CTC numbers were decreasing, misleadingly suggesting a response to treatment. ISET results were in agreement with the clinical follow up showing Circulating tumor microemboli (CTM) and CTC expressing a mesenchymal marker with absence of epithelial markers. CONCLUSIONS: This case report study shows the interest of a comparative and kinetic analysis of different methods for CTCs detection combined with their evaluation according to the clinical follow up. Our results should open up an area for future research and validation in larger clinical cohorts.

The influence of transforming growth factor-α, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer.

AIMS: Determination of prognostic parameters that are predictive of survival of gastric cancer (GC) may allow better identification of patients who could benefit from current chemotherapy regimens. To assess the correlation between tumour progression and epithelial-mesenchymal transition (EMT), we assayed the expression levels of selected molecules involved in EMT [CD44, transforming growth factor (TGF)-α, cyclooxygenase-2 (COX-2), matrix metalloproteinase (MMP)-7, MMP-9 and C-X-C chemokine receptor (CXCR4)], and correlated these with overall patient survival (OS) and disease stage. METHODS AND RESULTS: Medical records and pathological biopsy results of 137 patients with GC were evaluated retrospectively. Spearman's correlation analysis showed that expression of CXCR4 was correlated significantly with the expression of all other proteins studied. In contrast, COX-2 expression correlated significantly with the expression of only MMP-7 (P = 0.011), MMP-9 (P = 0.015) and CXCR4 (P = 0.013). We observed significant negative correlations between OS and the expression of TGF-α (P = 0.017), COX-2 (P < 0.001), CXCR4 (P = 0.010), MMP-7 (P = 0.020) and MMP-9 (P = 0.015). On multivariate analysis, only COX-2 was an independent prognostic factor for OS [hazard ratio (HR) = 3.34; 95% confidence interval (CI): 1.43-9.75; P = 0.002). CONCLUSIONS: COX-2, TGF-α, MMP-7, MMP-9 and CXCR4 are associated with poor OS in gastric cancer.

Circulating tumor cells: basic concepts and some clinical applications

The spread of cancer requires the presence of circulating tumor cells (CTCs), which are rare cells surrounded by billions of normal hematopoietic cells in the bloodstream. It is believed thatCTCs tend to metastasize to certain organs, thus, their presence may determine invasive tumor behavior. Generally, these cells are undetectable by conventional histopathological analysisand imaging exams with high resolution. Therefore, more sensitive immunohistochemical and molecular assays have been developed that have allowed the specific detection of metastatic tumor cells in regional lymph nodes, peripheral blood and bone marrow. This article reviews theliterature regarding CTCs and tumors of the breast, colorectal, pancreas and lung as it pertains to forms of detection and clinicopathological correlations, in addition to future outlooks

Meningeal carcinomatosis in breast cancer: prognostic factors and outcome.

Meningeal carcinomatosis (MC) occurs in up to 5% of breast cancer patients. Few studies have evaluated prognostic markers in breast cancer patients with MC. Our aim was to describe the treatment of breast cancer patients with MC, and identify prognostic factors related to survival. Sixty breast cancer patients that had a diagnosis of MC between January 2003 and December 2009 were included. The median age was 46 years (range 27-76). Most patients had invasive ductal carcinoma (78.3%) and high histological/nuclear grade (61.7/53.3%). Estrogen and progesterone receptors were positive in 51.7 and 43.3% of patients, respectively, and 15% were HER-2-positive. Symptoms at presentation were headache, cranial nerve dysfunction, seizures, and intracranial hypertension signals. Diagnosis was made by CSF cytology in 66.7% of cases and by MRI in 71.7%. Intrathecal (IT) chemotherapy was used in 68.3% of patients, and 21.6% received a new systemic treatment (chemo- or hormone therapy). Median survival was 3.3 months (range 0.03-90.4). There was no survival difference according to age, nuclear grade, hormonal and HER-2 status, CSF features, sites of metastasis, systemic and IT chemotherapy, or radiotherapy. However, histological grade and performance status had a significant impact on survival in the multivariate analysis. Only four papers have addressed prognostic factors in breast cancer patients with MC in the last two decades. The results of those reports are discussed here. High histological grade and poor performance status seem to impact survival of breast cancer patients with MC. Prospective studies are necessary to clarify the role of IT and systemic treatment in the treatment of those patients.

Pathologic complete response with neoadjuvant imatinib for locally advanced pelvic GIST.

There are few data that show pathologic complete response (pCR) to imatinib treatment in gastrointestinal stromal tumors (GISTs). We describe a case of a patient with pCR of a pelvic, locally advanced, high-risk GIST who was treated with neoadjuvant imatinib and ultimately underwent a conservative procedure. A 48-year-old male presented with a pelvic mass 10 cm in diameter. Biopsy revealed a gastrointestinal stromal tumor of rectal origin. Although it was considered initially resectable, an extensive procedure would have been necessary for complete resection. Treatment with imatinib was initiated, resulting in partial response. The patient remained on imatinib for over 15 months, maintaining stable disease. Radical prostatectomy with anal sphincter preservation was performed. Pathological report revealed no viable neoplastic cells. The use of imatinib was held for 6 months after the surgery. At a follow-up 15 months after surgery, the patient had no evidence of disease. Our report may help to guide future studies of neoadjuvant imatinib for large pelvic or rectum GISTs that are initially considered unresectable.

Synchronous thyroid and colon metastases from epidermoid carcinoma of the lung: case report / Metástases sincrônicas de carcinoma epidermoide de pulmão em tireoide e cólon: relato de caso

CONTEXT: Non-small cell lung cancer (NSCLC) progresses to distant metastases in most cases. The most frequent sites for distant metastases are the bones, central nervous system, adrenal glands and liver. Dissemination to the skin, myocardium, thyroid gland and intestine may occur, but is rare. CASE REPORT: We describe a case of squamous cell carcinoma in the lungs, with metastases in the colon and thyroid, in a 66-year-old female patient. The lesion was unresectable and chemotherapy was started. The patient evolved with intestinal subocclusion, and colonoscopy showed the presence of a polyp. Biopsy and immunohistochemical analysis on the polyp showed that it was compatible with squamous cell carcinoma of pulmonary origin. At a follow-up consultation, the patient presented a thyroid nodule. A aspiration biopsy and cellblock immunohistochemistry confirmed the squamous cell carcinoma of pulmonary origin. After third-line chemotherapy, the patient progressed with acute obstructive abdomen due to a retroperitoneal mass. She underwent exploratory laparotomy and died due to surgical complications. Metastases to the thyroid and colon are rarely reported in cases of epidermoid carcinoma of the lungs. Gastrointestinal involvement in pulmonary metastases may affect the stomach, small intestine and colon, and cases of bleeding and perforation have already been reported. Although richly vascularized, the thyroid is an infrequent site for metastases. Such sites reflect poor prognoses for the clinical evolution. We did not find any previous reports in the literature, on lung cancer with metastases concomitantly in the colon and thyroid, in a single patient.

CONTEXTO: O câncer de pulmão de células não pequenas evolui, na maioria dos casos, com metástases a distância. Ossos, sistema nervoso central, glândula adrenal e fígado são os sítios mais frequentes de metástases. Disseminação para pele, miocárdio, tireoide e intestino pode ocorrer, entretanto é rara. RELATO DE CASO: Descrevemos um caso de carcinoma espinocelular (CEC) de pulmão com metástase em cólon e tireoide, em mulher de 66 anos. A lesão era irressecável, e foi iniciada quimioterapia. A paciente evoluiu com suboclusão intestinal e a colonoscopia evidenciou pólipo colônico cuja biópsia e imunoistoquímica (IHQ) foram compatíveis com CEC de origem pulmonar. Em consulta de acompanhamento, detectou-se nódulo tireoidiano cuja punção aspirativa e IHQ de cellblock confirmaram CEC de origem pulmonar. Após quimioterapia de terceira linha, a paciente evoluiu com abdome agudo obstrutivo por massa retroperitoneal, sendo submetida a laparotomia exploradora, vindo a falecer por complicações da cirurgia. Metástases para tireoide e cólon são raramente reportadas em carcinomas epidermoides de pulmão. O envolvimento gastrointestinal por metástases de pulmão pode acometer estômago, intestino delgado e cólon, e casos de sangramento e perfuração já foram reportados. Embora ricamente vascularizada, a tireoide é sítio infrequente de metástases. Os sítios refletem prognósticos reservados na evolução clínica. Não encontramos, na literatura, relato prévio de câncer de pulmão com metástases em cólon e tireoide concomitantes em um único paciente.