A new scenario in metastatic renal cell carcinoma: a SOG-GU consensus.

BACKGROUND: This article describes and compares approved targeted therapies and the newer immunotherapy agents. MATERIALS AND METHODS: This article especially performs an in-depth review of currently available data for tivozanib, explaining its mechanism of action, its safety profile and its role as an efficacy drug in the management of renal cancer. RESULTS: Despite the fact that the treatment of advanced RCC has been dramatically modified in recent years, durable remissions are scarce and it remains a lethal disease. For first- and second-line therapy, there is now growing evidence to guide the selection of the appropriate treatment. CONCLUSIONS: Several TKIs are standard of care at different settings. Among those approved TKIs, tivozanib has similar efficacy than others with a better safety profile. The use of prognostic factors is critical to the selection of optimal therapy.

Prostate carcinoma and stem cells.

Stem cells, as classically defined, are cells with a capacity to self-renew and to generate daughter cells that can differentiate down several cell lineages to form all of the cell types that are found in the mature tissue. Stem cells and tumour cells have many similar features, including infinite lifespan, self-renewal, multidrug resistance, telomerase expression and, in the instance of the prostate, androgen independence. Evidence supports a role for stem cells in the etiology of many types of cancer. The evolution of androgen-independent prostate carcinoma may reflect the emergence of stemlike prostate tumour cells. Because cancer may be a disease of stem cell lineages and Shh-Gli signalling controls the behaviour of precursors and of cells with stem cell properties in the mammalian tissues, prostate cancer might derive from inappropriate expansion of prostatic epithelial stem cell lineages caused by abnormal Shh-Gli function. This review attempts to integrate these recent results.

Prostate cancer and Hedgehog signalling pathway.

The Hedgehog (Hh) family of intercellular signalling proteins have come to be recognised as key mediators in many fundamental processes in embryonic development. Their activities are central to the growth, patterning and morphogenesis of many different regions within the bodies of vertebrates. In some contexts, Hh signals act as morphogens in the dose-dependent induction of distinct cell fates within a target field, in others as mitogens in the regulation of cell proliferation or as inducing factors controlling the form of a developing organ. These diverse functions of Hh proteins raise many intriguing questions about their mode of action. Various studies have now demonstrated the function of Hh signalling in the control of cell proliferation, especially for stem cells and stem-like progenitors. Abnormal activation of the Hh pathway has been demonstrated in a variety of human tumours. Hh pathway activity in these tumours is required for cancer cell proliferation and tumour growth. Recent studies have uncovered the role for Hh signalling in advanced prostate cancer and demonstrated that autocrine signalling by tumour cells is required for proliferation, viability and invasive behaviour. Thus, Hh signalling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring.

Choroid plexus carcinoma: a rare condition and its therapeutic management.

Choroid plexus carcinomas are rare tumours, found chiefly during childhood. The commonest pattern of progression is via the neural axis. We present the case of a patient with unusual metastatic dissemination, affecting lungs and bones two years after diagnosis, and the approach adopted towards him.

Cyclooxygenase-2 (COX-2): a molecular target in prostate cancer.

Epidemiological studies provided the first evidence that COX may be involved in the pathogenesis of cancer. In the process of carcinogenesis and in the route of intracellular signalling during carcinogenesis, COX-2 expression may be a universal phenomenon. In general, COX-2 is up-regulated throughout the tumorigenic process, from early hyperplasia to metastatic disease. COX-2 has been reported to be constitutively overexpressed in a variety of malignancies and is frequently constitutively elevated in prostate carcinoma. COX-2 was consistently overexpressed in premalignant lesions such as prostatic intraepithelial neoplasia, and carcinoma. Cases are described with evolution of proliferative inflammatory atrophy of the prostate and prostate carcinoma. The increase of evidence implicating COX-2 in cancer has stimulated clinical trials to investigate the efficacy of selective COX-2 inhibitors in individuals at risk for human cancer. Regarding prostate carcinoma there is much direct or indirect evidence to support the use of COX-2 inhibitors in this disease. Trials using these drugs in familial adenomatous polyposis (FAP) and other patients with a high risk of colorectal carcinoma are ongoing.

Non-seminomatous germ-cell tumour associated with acute megakaryoblastic leukaemia.

The association of mediastinal germ-cell tumours (MGCTs) with haematologic neoplasms is a rare though well known circumstance, and few cases are found in the literature. Most of these refer to non-seminomatous tumours in young males. The diagnosis of the haematological condition is usually either synchronic or metachronic with that of the germ-cell tumour. From those cases that have been published, we know that the prognosis is poor and basically determined by the haematologic neoplasia. The case report we present is that of a young male with an initial diagnosis of both conditions. It was possible to apply specific treatment, initially in the case of the leukaemia, and later in the case of the germ-cell tumour. The approach adopted is a multidisciplinary one.

Intra-arterial and intravenous chemotherapy for the treatment of malignant glioma. Preliminary results.

Twenty-one patients with malignant glioma were treated with cis-diamminedichloroplatinum II (CDDP II) 60-90 mg/m2 intra-arterial (I.A.) bolus on day 1 and Carmustine (BCNU) 100 mg/m2 intravenously (I.V.) on days 1 and 2. Three patients received additional Aziridinylbenzoquinone (AZQ) 7 mg/m2 (I.V.) on days 1 and 2. At the time of this treatment, seven patients had local recurrence after previous surgery and radiotherapy. Nine patients had subtotal tumor resection or biopsy, one patient had macroscopic tumor resection, and four patients had no previous surgery because of medical contraindication. Six patients received five or more courses of I.A. and I.V. chemotherapy. Five of these patients showed complete remission (CR) and one had a partial remission (PR) by brain computerized tomography (CT scan). Another 15 patients treated with two to four courses of I.A., and I.V. chemotherapy showed eight partial responses (PR), and seven showed no changes (NC) by brain CT scan. Five patients died with disease. Patients who achieved CR also received radical radiotherapy for remission consolidation. Sixteen patients are still alive; five patients are off treatment, four of these with no evidence of disease (NED), one alive with disease (AWD); and the remaining 11 patients are still on treatment. Toxicity, symptomatic neurological recovery, disease stabilization, and causes of death will be discussed.

Phase II clinical trial of cis-dichlorodiammineplatinum in gastric cancer.

Eighteen patients with gastric cancer in Stage IV who had failed combination chemotherapy were treated with cis-dichlorodiammineplatinum as a single agent. Objective response was observed in four patients (22%), and another two had stable disease lasting 114 and 234 days, respectively. The median duration of the response was 150 days (range, 92-186). Gastrointestinal toxicity occurred in all the patients, but leukopenia and thrombocytopenia was the major complication in patients who had been heavily pretreated. The response rate found in this study shows that cis-platinum is an active drug in gastric cancer.

[A solitary cerebellar metastasis: a diagnostic exercise]. / Metástasis cerebelosa solitaria: un ejercicio diagnóstico.

Presentation of a solitary cerebellar mass lead us to think about the presence of a primary tumour or the possibility of a pulmonary, mammary or digestive metastasis. However, once discarded these origins, is necessary to search the primary neoplasms in less frequent organs. Approximately, 5% of all intracranial metastasis have it's origin in a renal cancer. These lesions generally appear at the supratentorial area and within a generalized disease. In the other hand, the presentation of a solitary cerebellar metastasis from a renal carcinoma without affectation of other organs is a very unusual fact. We present a case of these characteristics discussing about diagnostic, therapeutic and prognostic aspects of this unpredictable tumor.

[Protein A: an immunomodulator in cancer patients]. / Proteína A: inmunomodulador en pacientes con cáncer.

Protein A defined as one of the components of the wall of Staphylococcus Aureus Cowans 1 has shown its effects as modifier of the immune response: it induce changes in cellular receptors, polyclonal activation of T and B lymphocytes, liberation of lymphokines, increase in the production of gamma-interferon (probably as the result of activation of NK cells). In the present work we have studied NK activity and its modifications by Protein A and gamma-interferon in blood of 50 patients with solid tumours. The method used was the Cr 51 liberation assay. The effectors cells were non-adherent lymphocytes treated with different doses and times of incubation of Protein A and gamma-interferon. As target cells we utilized the cellular line K-562 for NK activity and autologous tumoral cells isolated from surgical specimen for tumour-specific cytotoxicity. The results obtained allow us to state the following conclusions: 1. NK activity against K-562 cells is not always a specific parameter of such activity. 2. Tumour-specific cytotoxicity can vary according to the histological type of tumour. 3. Protein A is a potent inducer of tumour-specific cytotoxicity in a higher degree than gamma-interferon.

[Prognostic value of the expression of ABH isoantigens in tumors of the bladder urothelium]. / Valor pronóstico de la expresión de isoantígenos ABH en tumores de urotelio vesical.

The usefulness of studying ABH isoantigens associated to bladder cancer cells with the specific red blood cells adherence assay, and immunohistochemistry methods in urinary bladder carcinoma biopsies, as well as its application as early predictors of tumor invasiveness and relapse, is reviewed.

Circulating MicroRNAs in blood of patients with prostate cancer.

INTRODUCTION: MicroRNAs (miRNAs) are small regulatory RNAs that do not code for proteins. Detection of circulating tumor cells (CTC) would provide diagnostic and prognostic information in prostate tumors (PT). Thus, miRNAs could constitute a promising new class of biomarkers for CTC detection. OBJECTIVES: To analyze circulating microRNAs in whole blood as non-invasive markers in patients with localized prostate cancer and healthy individuals. MATERIAL AND METHODS: A preliminary study including a population of 40 patients with mean age of 71 years and mean PSA of 18, 9 ng/ml (range). Regarding the risk group (RG): 33.3% had low risk, 30% intermediate risk and 36.7% high risk. A previous in silico study identified 92 candidates and was followed by another in vivo to verify the findings of the former using array technology by real-time PCR. RESULTS: Statistical analysis of the results revealed 10 microRNAs candidates with statistically significant differential expression between the different risk groups and healthy controls: hsa-miR-337-3p, hsa-miR-330-3p, hsa-miR-339-3p, hsa-miR-124, hsa-miR-218, hsa-miR-128, hsa-miR-10a, hsa-miR-199b-5p, hsa-miR-200b and hsa-miR-15b. CONCLUSIONS: Our data suggest that circulating microRNAs can act as biomarkers to identify risk groups in CaP.

Cytokine and endocrine signaling in prostate cancer.

Prostate epithelial and stromal cells develop paracrine interactions, which may be responsible for the occurrence and progression of prostate pathologies. Strikingly, stromal cells exhibit pleiotropic effects on epithelial cell growth, ranging from stimulation to inhibition. Steroid hormone receptors are considered ligand-activated transcriptional factors. Moreover, it has been suggested that the human androgen receptor can also be activated in the absence of surrounding ligands such as growth factors and cytokines. Strong evidence suggests that cytokines may play an important role in ligand-independent activation of androgen receptor in prostate cancer cells. In our view, one of the most striking finding in the prostate cancer development process is the relationship between carcinogenesis and secretion of cytokines.

Searching for Hif1-α interacting proteins in renal cell carcinoma.

INTRODUCTION: Kidney tumours are frequently characterised by hypoxic conditions due to a local imbalance between oxygen (O2) supply and consumption. Hif1-α regulates angiogenesis, tumour growth, tumour progression, metastatic spread, and glucose metabolism by acting as a transcription factor for relevant genes. Here, we describe an immunohistochemical study of Hif1-α, a comprehensive computational study of Hif1-α interacting proteins (HIPs), an analysis correlating expression levels of Hif1-α with upstream and downstream proteins, and an analysis of the utility of Hif1-α for prognosis in a cohort of patients with renal cell carcinoma. MATERIALS AND METHODS: The patient cohort included 80 patients. For immunohistochemistry evaluation, tissue microarrays were constructed. The IntAct, MINT, and BOND databases were used for the HIP approach. The Kruskal-Wallis test was used for comparing protein expression with pathology measurements. Correlation was expressed as the Pearson coefficient. RESULTS: Hif1-α expression correlates significantly with the "clear" histological subtype of renal cell carcinoma (p < 0.01). The samples with the worst prognoses related to the pathological variables analysed showed the highest levels of Hif1-α expression. Significant correlations were found with Bcl-2, CAIX, C-kit, EGFR, TGF-ß, proteins of the VEGF family, proteins related to differentiation (such as Notch1 and Notch3) and certain metabolic enzymes. Bioinformatic analysis suggested 45 evidence-based HIPs and 4 complexes involving protein Hif1-α. CONCLUSIONS: This work summarises the multifaceted role of Hif1-α in the pathology of renal cell carcinomas, and it identifies HIPs that could help provide mechanistic explanations for the different behaviours seen in tumours.

Tissue array analysis for the differentiation of gliosis from gliomas.

The aim of this study was to provide a methodology to make a clear distinction between malignant tumors and morphologically similar benign processes, by examining the expression of EGFR, VEGF, HIF1-α, survivin, Bcl-2 and p53 proteins. Four groups of patient samples were studied: group 1, low-grade astrocytomas (WHO grades I-II) (n=6); group 2, peripheral area of high-grade astrocytomas (WHO grades III-IV) (n=5); group 3, gliomatosis cerebri (n=11); and group 4, reactive gliosis (n=6). Tissue arrays (TAs) were designed to study apoptosis, angiogenesis and invasion-related proteins by immunohistochemistry (IHC). By means of non-parametric analysis (Mann-Whitney U test), EGFR staining was shown to be significantly lower in reactive gliosis than in the low- and high-grade astrocytomas (p=0.015 and p=0.030, respectively); Bcl-2 immunoreactivity was significantly higher in the gliomatosis cerebri samples than in the reactive processes (p=0.005); and finally, Bcl-2 presented significantly lower expression levels in reactive gliosis compared to the peripheral areas of high-grade astrocytomas (p=0.004). The results indicate that Bcl-2 and EGFR may be useful in conducting differential diagnosis between the above groups, while the expression of the remaining antibodies does not appear to aid in distinguishing between the samples analyzed. The use of TAs to identify the protein expression profiles of biological markers related to different pathways was verified, and its potential as a discriminatory technique for everyday pathology procedures was demonstrated.

Fructose transporter GLUT5 expression in clear renal cell carcinoma.

Renal cell carcinomas (RCC) can be subclassified for general purposes into clear cell, papillary cell, chromophobe cell carcinomas and oncocytomas. Other tumours such as collecting duct, medullary, mucinous tubular and spindle cell and associated with Xp 11.2 translocations/TFE 3 gene fusion, are much less common. There is also a residual group of unclassified cases. Previous studies have shown that RCC has high glycolytic rates, and expresses GLUT transporters, but no distinction has been made among the different subtypes of renal cell tumours and their grades of malignancy. In clear renal cell carcinoma (cRCC) glycogen levels increase, glycolysis is activated and gluconeogenesis is reduced. The clear cell subtype of RCC is characterized histologically by a distinctive pale, glassy cytoplasm and this appearance of cRCC is due to abnormalities in carbohydrate and lipid metabolism, and this abnormality results in glycogen and sterol storage. Several isoforms of glucose carriers (GLUTs) have been identified. We show here in a panel of 80 cRCC samples a significant correlation between isoform 5 (GLUT5) and many pathological parameters such as grade of differentiation, pelvis invasion and breaking capsule. GLUT5 expression also appears to associate more strongly with the clear cell RCC subtype. These data suggest a role for the GLUT5 isoform in fructose uptake that takes place in cRCC cells and which subsequently leads to the malignant RCC progression.

Pharmacogenomics in lung cancer: an analysis of DNA repair gene expression in patients treated with platinum-based chemotherapy.

Lung cancer is a worldwide epidemic and despite platinum-based chemotherapy being the cornerstone of non-small cell lung cancer treatment, patient response rates to these regimens remain very low. Although resistance to cisplatin is multifactorial, DNA repair plays a critical role in cisplatin resistance. One of the most important goals in translational research is to investigate the clinical use of DNA repair pathways that may influence cisplatin chemosensitivity. Trying to understand the role of genes involved in DNA repair and response to treatment has become one of the main objectives of individualised chemotherapy. It is well known that chemosensitivity is individually predetermined, and the upregulation of mRNA transcripts has been linked to differential response to cytotoxic drugs. In this article, the authors try to highlight the more relevant aspects regarding these issues, primarily focused on the potential role of ERCC1, RRM1, XPD and BRCA1 expression profiling as predictors of anticancer drug efficacy.