A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel/Prednisolone in Patients with Hormone-Refractory Prostate Cancer

Vandetanib (ZACTIMA(TM)) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection signaling. This randomized (1: 1), double-blind study evaluated vandetanib (100mg/day) or placebo in combination with docetaxel (D; 75mg/m(2) every 3 weeks) and prednisolone (P; 2 x 5 mg/day) in 86 patients with metastatic hormone-refractory prostate cancer (mHRPC). The primary assessment was prostate-specific antigen (PSA) response (confirmed reduction of >= 50% from baseline) and a greater number of patients showed a PSA response with placebo + DP (67%) versus vandetanib + DP (40%); hazard ratio = 2.23 (one-sided 80% confidence limit = 2.90; one-sided p = 0.99). More patients experienced progression events (disease progression or death from any cause) with vandetanib + DP (65%) versus placebo + DP (60%); hazard ratio = 1.13 (one-sided 80% confidence limit = 1.44; one-sided p = 0.67). The overall incidence of adverse events was similar in both groups, although more patients experienced adverse events, leading to permanent discontinuation with vandetanib + DP (28%) versus placebo + DP (12%). However, the safety and tolerability profile for vandetanib was similar to that previously reported; adverse events that occurred more frequently in the vandetanib + DP arm were hypertension (14% vs. 2%), erythematous rash (14% vs. 2%), and exfoliative rash (12% vs. 2%). In this study of patients with mHRPC, vandetanib + DP did not demonstrate any efficacy benefit, compared with placebo + DP.

Half-Pringle Maneuver: A Useful Tool in Laparoscopic Liver Resection

Introduction: Laparoscopic liver resections are becoming a common procedure, and bleeding remains the major concern during parenchymal transection. Total vascular inflow occlusion can be performed, but ischemic reperfusion injuries can lead to postoperative morbidity. On the other hand, hemihepatic inflow occlusion, leading to hemiliver ischemia, decreases the amount of liver parenchyma submitted to reperfusion damage and offers the advantage of reduced blood loss. Objective: The aim of this work was to describe our experience with laparoscopic the half-Pringle maneuver for segmentar or nonanatomic liver resctions. Patients and Methods: Eight patients submitted to laparoscopic liver resection in a single tertiary center. Results: There were 5 women and 3 men with a mean age of 40.2 years (range, 26-54). Mean tumor size was 4.1 cm (range, 2.6-6.0), and mean hospital stay was 3.1 days (1-5). There were 3 liver adenomas, 2 hepatocellular carcinomas, 1 metastatic melanoma, 1 metastatic colorectal carcinoma, and 1 peripheral colangiocarcinoma. No postoperative complications or mortalities were observed. Conclusions: Results demonstrate that laparoscopic liver resection with the half-Pringle maneuver is feasible and safe and may be included in the technical armamentarium of laparoscopic liver resections for a selected group of patients.

Expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in medullary thyroid carcinoma: Prognostic implications

Background: Metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) participate in the degeneration of the extracellular matrix and are associated with carcinogenesis. MMP-2 is one of the main metalloproteinases active in neoplasia and is a marker of the malignant phenotype. Since the biological behavior of medullary thyroid carcinoma (MTC) varies widely, the present study was undertaken to determine if there is a correlation between the clinical evolution of MTC and the immunohistochemically detected expression of these enzymes in thyroid surgical specimens containing MTC. If so, their expression would be a novel indicator of the prognosis of MTC. Methods: Thirty-seven patients with MTC who had undergone thyroid surgery were followed for an average of 73 months. Immunohistochemical staining for metalloproteinase-related enzymes was performed in surgical paraffin blocks. The clinical status of the patients after surgery and at the end of the study period was characterized to determine correlations between these and the immunohistochemical markers. A value of p < 0.05 was considered statistically significant. Results: At the end of the study period, 15 patients (40.5%) were alive and without evidence of MTC, 17 (45.9%) had persistent MTC, and 5 (13.5%) had a relapse of their neoplasia. Four patients (10.8%) died during the course of the study. There was a significant correlation (p = 0.0005) between the immunohistochemical staining for MMP-2 and the clinical condition of the patients at the end of the study period, and a correlation between the state of apparent cure compared to persistence of MTC after thyroid surgery (p = 0.0207). No significant correlations were observed between either TIMP-2 expression or immune marking of metastatic lymph nodes and the clinical variables studied. Conclusion: Immunohistochemical expression of MMP-2 in thyroid surgical specimens from patients with MTC is a novel indicator of the prognosis of this cancer.

Novel Primate-Specific Genes, RMEL 1, 2 and 3, with Highly Restricted Expression in Melanoma, Assessed by New Data Mining Tool

Melanoma is a highly aggressive and therapy resistant tumor for which the identification of specific markers and therapeutic targets is highly desirable. We describe here the development and use of a bioinformatic pipeline tool, made publicly available under the name of EST2TSE, for the in silico detection of candidate genes with tissue-specific expression. Using this tool we mined the human EST (Expressed Sequence Tag) database for sequences derived exclusively from melanoma. We found 29 UniGene clusters of multiple ESTs with the potential to predict novel genes with melanoma-specific expression. Using a diverse panel of human tissues and cell lines, we validated the expression of a subset of three previously uncharacterized genes (clusters Hs.295012, Hs.518391, and Hs.559350) to be highly restricted to melanoma/melanocytes and named them RMEL1, 2 and 3, respectively. Expression analysis in nevi, primary melanomas, and metastatic melanomas revealed RMEL1 as a novel melanocytic lineage-specific gene up-regulated during melanoma development. RMEL2 expression was restricted to melanoma tissues and glioblastoma. RMEL3 showed strong up-regulation in nevi and was lost in metastatic tumors. Interestingly, we found correlations of RMEL2 and RMEL3 expression with improved patient outcome, suggesting tumor and/or metastasis suppressor functions for these genes. The three genes are composed of multiple exons and map to 2q12.2, 1q25.3, and 5q11.2, respectively. They are well conserved throughout primates, but not other genomes, and were predicted as having no coding potential, although primate-conserved and human-specific short ORFs could be found. Hairpin RNA secondary structures were also predicted. Concluding, this work offers new melanoma-specific genes for future validation as prognostic markers or as targets for the development of therapeutic strategies to treat melanoma.

Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways

Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.

Neoplasia and paracoccidioidomycosis

Published studies on the association between cancer and paracoccidioidomycosis consist either isolated cases or clinical data based on hospital cohorts of paracoccidioidomycosis. The frequency of neoplasia in series of >= 80 patients with paracoccidioidomycosis ranges from 0.16 to 14.1%, mean of 3.96%. There are only two retrospective controlled studies, one of them showing greater incidence of carcinoma in biopsy and necropsy samples of paracoccidioidomycosis (12 cases in 147 patients with the mycosis: 8.2%) than in the necropsies of the control group (320 cases in 7,302 necropsies: 4.9%). In the other, 22,409 autopsies were reviewed and 4,372 cases of cancer were found; of the 85 patients with paracoccidioidomycosis, 12 were diagnosed with cancer. No differences were observed in the frequency of malignancies between the group of patients with paracoccidioidomycosis (14.1%) and the control group (19.5%). Considering all the reported cases, carcinoma was more frequent than hematological malignancies, and was more often found at the same site or in a neighboring site affected by the mycosis, usually occurring after the diagnosis of the mycosis. Commonly, the basic cause of death was related to secondary infections or neoplasia. Lymphoma was associated with poorly organized rich in fungi granuloma. The clinical course and mortality were related to the cancer evolution or secondary infections and was worse in lymphoid series, metastatic carcinoma or in patients under cytotoxic chemotherapy. Additionally, as in several cases the clinical and histopathological data may mimick neoplasia, the correct diagnosis of both diseases is essential to guarantee an early and safe intervention.

Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis

Perforin (pfp) and interferon-gamma (IFN-gamma) together in C57BL/6 (B6) and BALB/c mouse strains provided optimal protection in 3 separate tumor models controlled by innate immunity. Using experimental (B6, RM-1 prostate carcinoma) and spontaneous (BALB/c, DA3 mammary carcinoma) models of metastatic cancer, mice deficient in both pfp and IFN-gamma were significantly less proficient than pfp- or IFN-gamma -deficient mice in preventing metastasis of tumor cells to the lung. Pfp and IFN-gamma -deficient mice were as susceptible as mice depleted of natural killer (NK) cells in both tumor metastasis models, and IFN-gamma appeared to play an early role in protection from metastasis, Previous experiments in a model of fibrosarcoma induced by the chemical carcinogen methylcholanthrene indicated an important role for NK1.1(+) T cells, Herein, both pfp and IFN-gamma played critical and independent roles in providing the host with protection equivalent to that mediated by NK1.1+ T cells, Further analysis demonstrated that IFN-gamma, but not pfp, controlled the growth rate of sarcomas arising in these mice. Thus, this is the first study to demonstrate that host IFN-gamma, and direct cytotoxicity mediated by cytotoxic lymphocytes expressing pfp independently contribute antitumor effector functions that together control the initiation, growth, and spread of tumors in mice, (C) 2001 by The American Society of Hematology.

Can metal complexes serve as hypoxia activated prodrugs? Investigations of a Co(III) complex of the MMP inhibitor marimastat

For many years proof that the hypoxic nature of malignant tumours can be used to selectively target anticancer drugs has been sought. Several classes of potential redox activated anticancer drugs have been developed to take advantage of the reducing environment resulting from the hypoxia. Drug complexes with redox active metal centres as carriers have been investigated, but have largely been employed with cytotoxic drugs that require release of the drug intracellularly, complicating the design of such complexes. MMP inhibitors, a new class of anticancer drug, conversely act in the extracellular environment and we have investigated inhibitor complexes with several redox active transition metals. Marimastat is an MMP inhibitor with potent in-vitro antimetastatic activity and was recently in Phase III clinical trials for a variety of cancer types. We have synthesised a Co(II1) complex of marimastat incorporating the tetradentate ligand tpa (tris(2-methylpyridyl)amine) as a carrier ligand. The complex was structurally characterised in the solid state by single crystal X-ray diffraction, the first example of a crystal structure containing marimastat. 2D COSY and NOESY NMR spectra showed that the complex exists in two isomeric forms in solution, corresponding to the cis and trans isomers yet only crystallises in one of these forms. Biological testing of the complex in mice with 4T1.2 tumours showed interesting and unexpected outcomes. Initial results of the tumour growth inhibition study showed that a significant inhibition of growth was exhibited by the complex over the free inhibitor and the control. However, the metastatic potential of both free marimastat and the complex were higher than the control indicating likely problems with the experimental protocol. Further experiments are needed to determine the potential of such complexes as hypoxia activated prodrugs but there appears at least to be some promise.

EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer

EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene 'hyperplastic discs' and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.

Efficacy and safety of iodopovidone pleurodesis in malignant pleural effusions

Background and objective: Pleurodesis is one of the best methods of controlling malignant pleural effusions (MPE), a distressing complication of metastatic disease. In recent studies of a wide range of pleural diseases, iodopovidone was used as a sclerosing agent for pleurodesis and demonstrated good results with low morbidity. The aim of this study was to evaluate the efficacy and safety of iodopovidone pleurodesis in MPE. Methods: A retrospective analysis was performed on patients with MPE who underwent pleurodesis at our institution between 2005 and 2008. All patients underwent instillation of 20 mL of 10% iodopovidone, 80 mL of normal saline and 2 mg/kg of lidocaine through a chest tube, which was clamped for 2 h. The tube was removed when the daily output of fluid was < 200 mL. Data on the requirement for additional pleural procedures, adverse events and survival were collected. Results: Sixty-one pleurodesis procedures were performed in 54 patients. No procedure-related mortality was observed. Adverse events occurred after 11 (18%) pleurodesis procedures. The most frequent complication was mild thoracic pain that occurred immediately after 10 (16.4%) procedures, and one patient developed pleural empyema that was treated with drainage and antibiotics. A success rate of 98.4% was observed. Except for the patient who developed pleural empyema, none of the other patients had recurrences of pleural fluid or required additional pleural procedures during the follow-up period (mean of 5.6 months). Conclusions: Iodopovidone pleurodesis was successful and was associated with only a few minor complications. It appears to be a good option for the management of recurrent MPE.

Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with BRAF mutational status and lymph node metastasis

Purpose: To identify papillary thyroid carcinoma (PTC)-associated transcripts, we compared the gene expression profiles of three Serial Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue. Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of 71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic) was investigated. The BRAF(V600E) mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular signal-regulated kinase signaling. Results: We identified and validated new PTC-associated transcripts. Three genes (CST6, CXCL14, and DHRS3) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3, and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14, and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAF(V600E) mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway. Conclusion: CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for FTC therapy.

The interaction between N-category and N-ratio as a new tool to improve lymph node metastasis staging in gastric cancer: Results of a single cancer center in Brazil

Background: Depth of tumor invasion (T-category) and the number of metastatic lymph nodes (N-category) are the most important prognostic factors in patients with gastric cancer. Recently, the ratio between metastatic and dissected lymph nodes (N-ratio) has been established as one. The aim of this study is to evaluate the impact of N-ratio and its interaction with N-category as a prognostic factor in gastric cancer. Methods: This was a retrospective study in which we reviewed clinical and pathological data of 165 patients who had undergone curative surgery at our institution through a 9-year period. The exclusion criteria included metastases, gastric stump tumors and gastrectomy with less than 15 lymph nodes dissected. Results: The median age of the patients was 63 years and most of them were male. Total gastrectomy was the most common procedure and 92.1% of the patients had a D2-lymphadenectomy. Their 5-year overall survival was 57.7%. T-category, N-category, extended gastrectomy, and N-ratio were prognostic factors in overall and disease-free survival in accordance with univariate analysis. In accordance with TNM staging, N1 patients who have had NR1 had 5-year survival in 75.5% whereas in the NR2 group only 33% of the cases had 5-year survival. In the multivariate analysis, the interaction between N-category and N-ratio was an independent prognostic factor. Conclusion: Our findings confirmed the role of N-ratio as prognostic factor of survival in patients with gastric cancer surgically treated with at least 15 lymph nodes dissected. The relationship between N-category and N-ratio is a better predictor than lymph node metastasis staging. (C) 2010 Elsevier Ltd. All rights reserved.

Relationship between the appearance of tongue carcinoma on intraoral ultrasonography and neck metastasis

To evaluate the usefulness of intraoral ultrasonography (IOUS) as a tool for predicting neck metastasis. Squamous cell carcinoma (SCC) of the tongue is aggressive and has a great propensity to metastasize to cervical lymph nodes. SCC of the oral cavity has a worse prognosis when associated with metastatic cervical nodes. Therefore, the metastatic potential of tongue carcinoma should be graded preoperatively to help determine the requirement for neck dissection. Nineteen patients (11 men, 8 women) between 36 and 79 years of age (mean age 60) with T1 to T4a TNM-stage tongue carcinomas were evaluated preoperatively with IOUS. Clinical and pathological TNM classifications were performed. The average tumor thicknesses measured using histological sections were significantly (p < 0.01) lower than those with IOUS (1.3 vs. 1.6 cm, respectively). A significant correlation was observed between the tumor thickness measured using ultrasonography and that measured using histological sections (pathology). Based on this greater accuracy, the cutoff point of tumor thickness based on IOUS evaluation for predicting neck metastasis was determined to be 1.8 cm. Some factors may influence neck metastasis. A knowledge of these would help to avoid unnecessary surgical intervention for N0 patients. The results of this study indicates that there is a significant correlation between neck metastasis and tumor thickness. Intraoral ultrasonography is useful tool for identifying tongue tumors and measuring their thickness, with the thickness measured by IOUS showing a very good correlation with histological measurements. Moreover, IOUS provides prognostic information prior to surgical treatment since tumor thickness can predict the chance of recognizing metastatic cervical nodes.

Surgical treatment of hepatic tumors in children: lessons learned from liver transplantation

Purpose: Hepatectomy remains a complex operation even in experienced hands. The objective of the present study was to describe our experience in liver resections, in the light of liver transplantation, emphasizing the indications for surgery, surgical techniques, complications, and results. Methods: The medical records of 53 children who underwent liver resection for primary or metastatic hepatic tumors were reviewed. Ultrasonography, computed tomographic (CT) scan, and needle biopsy were the initial methods used to diagnose malignant tumors. After neoadjuvant chemotherapy, tumor resectability was evaluated by another CT scan. Surgery was performed by surgeons competent in liver transplantation. As in liver living donor operation, vascular anomalies were investigated. The main arterial anomalies found were the right hepatic artery emerging from the superior mesenteric artery and left hepatic artery from left gastric artery. Hilar structures were dissected very close to liver parenchyma. The hepatic artery and portal vein were dissected and ligated near their entrance to the liver parenchyma to avoid damaging the hilar vessels of the other lobe. During dissection of the suprahepatic veins, the venous infusion was decreased to reduce central venous pressure and potential bleeding from hepatic veins and the vena cava. Results: Fifty-three children with hepatic tumors underwent surgical treatment, 47 patients underwent liver resections, and in 6 cases, liver transplantation was performed because the tumor was considered unresectable. There were 31 cases of hepatoblastoma, with a 9.6% mortality rate. Ten children presented with other malignant tumors-3 undifferentiated sarcomas, 2 hepatocellular carcinomas, 2 fibrolamellar hepatocellular carcinomas, a rhabdomyosarcoma, an immature ovarian teratoma, and a single neuroblastoma. These cases had a 50% mortality rate. Six children had benign tumors-4 mesenchymal hamartoma, 1 focal nodular hyperplasia, and a mucinous cystadenoma. All of these children had a favorable outcome. Hepatic resections included 22 right lobectomies, 9 right trisegmentectomies, 8 left lobectomies, 5 left trisegmentectomies, 2 left segmentectomies, and 1 case of monosegment (segment IV) resection. The overall mortality rate was 14.9%, and all deaths were related to recurrence of malignant disease. The mortality rate of hepatoblastoma patients was less than other malignant tumors (P = .04). Conclusion: The resection of hepatic tumors in children requires expertise in pediatric surgical practice, and many lessons learned from liver transplantation can be applied to hepatectomies. The present series showed no mortality directly related to the surgery and a low complication rate. (C) 2009 Elsevier Inc. All rights reserved.

Breast cancer five-year survival in New South Wales women, 1972 to 1991

This study of breast cancer survival is based on analysis of five-year relative survival of 38 362 cases of invasive breast cancer in New South Wales (NSW) women, incident between 1972 and 1991, with follow-up to 1992, using data from the population-based NSW Central Cancer Registry. Survival was ascertained by matching the registry file of breast cancers against NSW death certificates from 1972 to 1992, mainly by automated probabilistic linkage. Absolute survival of cases was compared with expected survival of age- and period-matched NSW women. Proportional hazard regression analysis was used for examination of the effects on excess mortality of age, period of diagnosis and degree of spread at diagnosis. Relative survival at five years increased from 70 per cent in 1972-1976 to 77 per cent in 1987-1991. Survival improved during the 1970s and in the late 1980s. Regression analysis suggested that part of the improved survival in the late 1980s was due to lesser degree of spread at diagnosis, whereas the improved survival during the 1970s may have been due to treatment. Survival was better for those aged 40-49 years (RR = 0.86) and worse for those aged greater than or equal to 70 years (RR = 1.22) compared with the referent group (60-69 years). Excess mortality was much less for those with invasive localised disease than those with regional spread (RR = 3.1) or metastatic cancer (RR = 15.5) at diagnosis. For the most recent period (1987-1991), relative five-year survival was 90, 70 and 18 per cent, respectively, for the three degree-of-spread categories.