An 8-gene qRT-PCR-based gene expression score that has prognostic value in early breast cancer.

BACKGROUND: Gene expression profiling may improve prognostic accuracy in patients with early breast cancer. Our objective was to demonstrate that it is possible to develop a simple molecular signature to predict distant relapse. METHODS: We included 153 patients with stage I-II hormonal receptor-positive breast cancer. RNA was isolated from formalin-fixed paraffin-embedded samples and qRT-PCR amplification of 83 genes was performed with gene expression assays. The genes we analyzed were those included in the 70-Gene Signature, the Recurrence Score and the Two-Gene Index. The association among gene expression, clinical variables and distant metastasis-free survival was analyzed using Cox regression models. RESULTS: An 8-gene prognostic score was defined. Distant metastasis-free survival at 5 years was 97% for patients defined as low-risk by the prognostic score versus 60% for patients defined as high-risk. The 8-gene score remained a significant factor in multivariate analysis and its performance was similar to that of two validated gene profiles: the 70-Gene Signature and the Recurrence Score. The validity of the signature was verified in independent cohorts obtained from the GEO database. CONCLUSIONS: This study identifies a simple gene expression score that complements histopathological prognostic factors in breast cancer, and can be determined in paraffin-embedded samples.

Palliative care is a key component of daily practice in oncology: descriptive study of hospitalisation events at an oncology treatment centre.

PURPOSE: The impact that palliative care services have had on admission to oncology services has not been well-defined. This retrospective study was undertaken in the oncology service of a general hospital where there is also a palliative care service. METHODS: The medical records of 397 patients (542 events) admitted during a period of 6 months at a single centre were reviewed. RESULTS: The main final diagnoses were tumour progression, infection and chemotherapy administration. Seventeen percent of patients died during hospitalisation. The decision to withdraw active treatment was taken during this time in 11% of patients. CONCLUSION: Key therapeutic decisions are commonly made during hospitalisation events of patients with cancer. Our results suggest that oncologists still take care of patients at the end of life, although this may highly depend on models of health care and admission criteria.

TWIST1 overexpression is associated with nodal invasion and male sex in primary colorectal cancer.

BACKGROUND: TWIST1 is a basic helix-loop-helix (bHLH) transcription factor that has been involved in tumor progression and metastasis in several cancer types, although no evidence has been provided yet on its implication in colorectal carcinogenesis. METHODS: We examined the expression pattern of TWIST1 messenger RNA (mRNA) in 54 colorectal cancer biopsies compared with each respective adjacent normal mucosa by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) methodology. RESULTS: TWIST1 mRNA was found significantly overexpressed in colorectal cancer samples compared to nontumorous colon mucosa (P < 0.0001). Receiver operating characteristic (ROC) curve analysis demonstrated that TWIST1 mRNA levels are significantly increased in patients with nodal invasion and, interestingly, a significant correlation with patient sex was also found. CONCLUSIONS: Evidence for upregulation of TWIST1 mRNA in colorectal cancer is provided, suggesting its implication in the onset of malignant progression of this disease. In addition, significant higher levels of TWIST1 mRNA were found in men than in women, suggesting a possible transcriptional regulation of TWIST1 by sexual hormones. The use of TWIST1 as a new prognostic marker of advanced malignancy, and as a potential therapeutic target in colorectal cancer, is proposed.

HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence.

Downregulation of the catalytic subunit of the mitochondrial H(+)-ATP synthase (beta-F1-ATPase) is a hallmark of many types of cancer. The expression of beta-F1-ATPase is stringently controlled by posttranscriptional mechanisms. Herein, we pursue the identification of beta-F1-ATPase messenger RNA-binding proteins (beta-mRNABPs) that interact and could define the bioenergetic phenotype of the cancer cell in order to establish its relevance as markers of breast cancer progression. RNA immunoprecipitation and RNA affinity chromatography identify HuR as a beta-mRNABP that interacts with the 3'-untranslated region of the transcript. Subcellular fractionation and high-resolution immunoelectron microscopy revealed the cofractionation and presence of HuR in subcellular structures associated to liver mitochondria. Analysis of the expression level of HuR in a cohort of breast carcinomas shows its association with the degree of alteration of the bioenergetic phenotype of the tumor. Moreover, HuR expression is shown to be an independent marker of breast cancer prognosis. A low tumor expression of HuR predicts a higher risk of disease recurrence in early stage breast cancer patients as assessed by clinical and bioenergetic markers of prognosis, strongly supporting the incorporation of HuR as an additional marker for the follow-up of these patients. Mechanistically, overexpression experiments and short hairpin RNA-mediated silencing of HuR in human embryonic kidney and HeLa cells indicate that HuR is not regulating beta-F1-ATPase expression. Overall, the participation of additional RNA-binding proteins in controlling beta-F1-ATPase expression and therefore in defining the bioenergetic signature of the cancer cell is expected.

Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.

Cdc42, a member of Rho GTPases family, is involved in the regulation of several cellular functions, such as rearrangement of actin cytoskeleton, membrane trafficking, cell-cycle progression, and transcriptional regulation. Aberrant expression or activity of Cdc42 has been reported in several tumours. Here, the specific role of Cdc42 in development and progression of colorectal cancer was analyzed through microarrays technology. A comparative analysis of Cdc42 overexpressing cells versus cells with decreased Cdc42 levels through siRNA revealed that Cdc42 overexpression down-regulated the potential tumour suppressor gene ID4. Results were validated by quantitative RT-PCR and the methylation status of the specific promoter, analyzed. Methylation-specific PCR and bisulfite sequencing PCR analysis revealed that Cdc42 induced the methylation of the CpG island of the ID4 promoter. Colorectal adenocarcinoma samples were compared with the corresponding adjacent normal tissue of the same patient in order to determine specific gene expression levels. The downregulation of ID4 by Cdc42 was also found of relevance in colorectal adenocarcinoma biopsies. Cdc42 was found to be overexpressed with high incidence (60%) in colorectal cancer samples, and this expression was associated with silencing of ID4 with statistical significance (p<0.05). Cdc42 may have a role in the development of colon cancer. Furthermore, inhibition of Cdc42 activity may have a direct impact in the management of colorectal cancer.

Meningeal relapse by follicular lymphoma as a single mass.

Follicular lymphoma is the second most common lymphoma throughout the world. Its course is usually indolent. Affection of Central Nervous System by a follicular lymphoma is usually as primary disease, and secondary affection is usually due to high-grade transformation. In this case-report we describe a young patient who presented a follicular lymphoma which secondary affected the central nervous system without high grade transformation.

Primary cardiac osteosarcoma.

Primary cardiac neoplasms are an infrequent disease, as most of the tumors arising in the heart are metastatic. Between the malignant tumors, sarcomas are the most frequent ones, accounting for at least 95% of them. We report the case of a 70-year old woman, diagnosed of primary cardiac osteosarcoma arising in the left atrium. Although complete excision of the tumor was performed, the disease relapsed and subsequently developed metastatic disease. In this paper, we also review briefly the management of this rare disease and the therapeutic options.

Epidermal growth factor receptor and glioblastoma multiforme: molecular basis for a new approach.

High-grade gliomas are the most common primary malignant brain tumours. Surgery, radiotherapy and chemotherapy are the cornerstone of actual treatment. In spite of large therapeutic efforts, overall survival is still poor. New molecular data allow a new molecular classification for high-grade gliomas and open a therapeutic window for targeted therapy. Molecular diagnostic tools may provide a basis for receptor-based therapies and enough information to personalise future treatments. In this regard, epidermal growth factor receptor (EGFR) is a target that will play a critical role in the management of glioma patients. This review summarises basic and preclinical data that support future use of therapies against EGFR.

Molecular biology of pancreatic cancer.

Pancreatic cancer is a leading cause of cancer death. This devastating disease has the horrible honour of close to equal incidence and mortality rates. Late diagnosis and a constitutive resistance to every chemotherapy approach are responsible for this scenario. However, molecular biology tools in cooperation with translational efforts have dissected several secrets that underlie pancreatic cancer. Progressive acquisition of malignant, invasive phenotypes from pre-malignant lesions, recent revelations on core signalling pathways and new targeted designed trials offer a better future for pancreatic cancer patients. This review will summarise recent advances in the molecular biology of pancreatic cancer.

Employment in a cohort of cancer patients in Spain. A predictive model of working outcomes.

INTRODUCTION: Cancer patients can have problems remaining in employment but the importance of this issue has until now received little attention in Spain. PATIENTS AND METHODS: The study included 347 consecutive cancer patients who were employed at diagnosis. Diagnosis had been confirmed at least 6 months before the interview. Participants completed a questionnaire concerning cancer-related symptoms and work-related factors and clinical details were obtained from their medical records. The study was approved by the Ethical Committee of La Paz Hospital. All patients gave consent to participate. RESULTS: Eighty-five percent of patients were unable to work after diagnosis, but 59% returned to work at the end of treatment. Gender, age, type of worker and type of treatment were independently associated with the ability to work after diagnosis. At the end of treatment these factors were age, education, tumour stage, overall response to the therapy, associated co-morbidity and sequelae of the disease or its treatment. Twenty-one percent noticed changes in their relationship with co-workers and managers, usually in the sense that they tried to be helpful. In a multivariate logistic regression analysis, the strongest predictors for remaining in employment were age, overall response and sequelae of the disease or its treatment. CONCLUSIONS: Cancer survivors in this study encountered some problems in returning to work, mainly linked to the sequelae of their disease and its treatment, rather than to discrimination by employers or colleagues. Prediction of working outcomes is possible to recommend interventions.

Idiopathic and recurrent thromboembolic phenomena in cancer patients.

BACKGROUND: Venous thromboembolism (VTE) is one of the most common complications in cancer patients. It is not only associated with both reduced survival and a high number of recurrences, but an idiopathic VTE also increases the likelihood of a cancer diagnosis. METHODS: Between January 2000 and October 2005 we reviewed the medical history of 88 patients who were admitted to a tertiary hospital and presented both a diagnosis of VTE and any type of tumour. The information collected included the type of tumour, the temporal association between tumour diagnosis and VTE, anticoagulation treatment applied and percentage of recurrences. RESULTS: Ten patients (11.4%) presented the VTE prior to the cancer diagnosis; only half of them underwent a posterior tumour screening routine. Fifteen patients (17%) were diagnosed simultaneously and 71% presented the VTE after the tumour was detected. In 47 patients (53.4%) no risk factors for VTEs were detected. Twenty-nine patients (31.7%) presented a recurrent VTE, mainly during chemotherapy treatment (66%). Less than half of the patients (47.57%) were receiving treatment with low-molecular- weight heparins (LMWH). CONCLUSIONS: Idiopathic VTEs may be the first manifestation of an occult neoplasia, but tumour screening is scheduled in only a few patients. Regarding the high incidence of recurrent VTE in cancer populations, a high percentage is attributed to the underuse of LMWH, whose efficacy in preventing recurrent phenomena is superior to oral dicumarinics.

Retroperitoneal Castleman's disease with colon cancer. A rare association.

Castleman's disease (CD) is a rare disorder of uncertain aetiology characterised by massive proliferation of lymphoid tissue usually localised as mediastinal masses, although abdominal involvement has been reported. Localised forms are usually associated with a good prognosis, but several more aggressive multifocal variants have been observed. Two different histologic subtypes have been described: the hyaline vascular type, more common in unicentric CD and usually asymptomatic, and the plasma cell form. Unicentric CD may be associated with an increased risk of lymphoma, but there was no reported increased risk of other malignancies. A patient with plasma cell subtype unicentric CD localised in retroperitoneum associated with an adenocarcinoma of ileocaecal valve and liver metastasis is reported.

Cirrhosis-like radiological pattern in patients with breast cancer.

INTRODUCTION: Hepatic toxicity of breast cancer therapy is well known, usually consisting of elevation in the serum levels of hepatic enzymes or fatty infiltration of the liver. The chemotherapeutic agents most commonly linked to hepatotoxic effects are methotrexate, anthracyclines, taxanes and cyclophosphamide. There are few reports of patients with liver metastasis having radiological findings mimicking cirrhosis, both in the presence or the absence of prior systemic chemotherapy. Hepatotoxicity of antineoplastic drugs and cellular necrosis induced by response of liver metastases to chemotherapy may play a critical role in its physiopathology. MATERIALS AND METHODS: This article reports a series of ten women with breast cancer (nine with liver metastasis) treated with chemotherapy or hormonotherapy. RESULTS: They had low risk factors for hepatic disease, but developed a cirrhosis-like appearance in the computed tomography scan. The patient without liver metastasis is the second of this kind described in the literature. Relatively few reports have documented clinical sequelae of portal hypertension. In our series, three patients had oesophageal bleeding varices needing be hospitalised. To our knowledge, these are the first cases reported in the literature. CONCLUSIONS: This suggests that some manifestations of portal hypertension may develop in association with the cirrhosis- like pattern induced by breast cancer therapy.

[Causes of lung cancer: smoking, environmental tobacco smoke exposure, occupational and environmental exposures and genetic predisposition]. / Factores etiológicos del cáncer de pulmón: fumador activo, fumador pasivo, carcinógenos medioambientales y factores genéticos.

Every year, in Spain 18,000 new cases of lung cancer (LC) are diagnosed. Approximately, 80-90% LC in men and women are directly attributable to tobacco abuse. Cigarette smoke contains over 300 chemicals, 40 of which are known to be potent carcinogens. In the last decade, as in Spain, prevalence of smoking in women has generally increased in the European Union. LC risk can be substantially reduced after smoking cessation, yet never reaches baseline. On the other hand, environmental tobacco smoke exposure (passive smoking) in nonsmokers appears to have a significantly increased risk of LC. An updated of etiology factors of LC, risk related to duration as well as intensity of smoking, relationship between environmental tobacco smoke exposure and LC risk, genetic predisposition and a variety of occupational and environmental exposures implicated as potential risk factors for the development of LC will be reviewed here.

Capecitabine as first-line treatment for patients older than 70 years with metastatic colorectal cancer: an oncopaz cooperative group study.

PURPOSE: To determine the tolerability of capecitabine in elderly patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Fifty-one patients with advanced CRC who were >/= 70 years and considered ineligible for combination chemotherapy received oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 every 3 weeks. Patients with a creatinine clearance of 30 to 50 mL/min received a dose of 950 mg/m(2) twice daily. RESULTS: A total of 248 cycles of capecitabine were administered (median, five cycles; range, one to eight cycles). The overall response rate was 24% (95% CI, 15% to 41%), including two complete responses (CR; 4%) and 10 partial responses (PR; 20%). Disease control (CR + PR + stable disease) was achieved in 67% of patients. The median times to disease progression and overall survival were 7 months (95% CI, 6.4 to 9.5 months) and 11 months (95% CI, 8.6 to 13.3 months), respectively. Of the 35 patients evaluated for clinical benefit response, 14 (40%; 95% CI, 24% to 58%) showed clinical benefit. Capecitabine was well tolerated. Treatment-related grade 3 and 4 adverse events were observed in only six patients (12%), and the most common events were diarrhea, hand-foot syndrome, and thrombocytopenia. One patient (2%) had an episode of angina, but no treatment-related deaths were reported. CONCLUSION: Our findings suggest that capecitabine is effective and well tolerated in elderly patients with advanced CRC who are considered ineligible for combination chemotherapy.

Generation and characterization of monoclonal antibodies against choline kinase alpha and their potential use as diagnostic tools in cancer.

Choline kinase alpha (ChoKalpha) is a metabolic enzyme involved in the synthesis of phosphatidylcholine, recently implicated in cancer onset since it is overexpressed in a variety of human cancers such as mammary, lung, colorectal and prostate adenocarcinomas. Furthermore, overexpression of ChoKalpha in human HEK293T cells confers them oncogenic properties with the induction of tumors after subcutaneous injection in nude mice. ChoKalpha levels in tumor samples have been analyzed using polyclonal antibodies and Western blotting. These techniques have considerable limitations and do not allow for a precise and efficient evaluation of the real significance of ChoK overexpression in human carcinogenesis. We developed a set of monoclonal antibodies with high specificity and sensitivity against ChoKalpha, and characterized their properties. We provide evidence that the newly generated MoAbs against ChoKalpha have potential use in cancer diagnosis by conventional immunohistochemistry techniques.

[The last phase in the progressive neoplasic disease: care at the end-of-life, refractory symptoms and sedation]. / Ultima etapa de la enfermedad neoplásica progresiva: cuidados en la agonía, síntomas refractarios y sedación.

End-of-life is one of the most stressful phases during course of a neoplasic disease. Frequently, death of patients with cancer comes after a continuous and progressive physical impairment. As death approaches, the medical team might redefine outcomes and treat as priority symptoms and relief suffering. That care encompasses the physical, psychological, social, spiritual, and existential needs of patients and their families. However, symptoms are frequently observed that are intolerable for the patient and which do not respond to usual palliative measures. The intolerable nature and being refractory to treatment indicates to the health-care team, on many occasions, the need for sedation of the patient. The medical team can take comfort in the knowledge that they did their best to provide safe passage to all their patients and that, although they did not always cure them, the patients often were healed.

Colony-stimulating factors: clinical evidence for treatment and prophylaxis of chemotherapy-induced febrile neutropenia.

The hematopoietic growth factors (HGFs) are a family of glycoproteins which plays a major role in the proliferation, differentiation, and survival of primitive hematopoietic stem and progenitor cells, and in the functions of some mature cells. More than 20 different molecules of HGF have been identified. Among them, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been demostrated to be effective in reducing the incidence of febrile neutropenia when administered inmediately after chemotherapy and as supportive therapy in patients undergoing bone marrow transplantation. Chemotherapy used for treatment of cancer often causes neutropenia, which may be profound, requiring hospitalization, and leading to potentially fatal infection. The uses of the recombinant human hematopoietic colony-stimulating factors G-CSF and GM-CSF for treatment and prophylaxis of chemotherapy-induced febrile neutropenia will be reviewed here.

Molecular biology of malignant gliomas.

Gliomas are the most common primary brain tumours. In keeping with the degree of aggressiveness, gliomas are divided into four grades, with different biological behaviour. Furthermore, as different gliomas share a predominant histological appearance, the final classification includes both, histological features and degree of malignancy. For example, gliomas of astrocytic origin (astrocytomas) are classified into pilocytic astrocytoma (grade I), astrocytoma (grade II), anaplastic astrocytoma (grade III) and glioblastoma multiforme (GMB) (grade IV). Tumors derived from oligodendrocytes include grade II (oliogodendrogliomas) and grade III neoplasms (oligoastrocytoma). Each subtype has a specific prognosis that dictates the clinical management. In this regard, a patient diagnosed with an oligodendroglioma totally removed has 10-15 years of potential survival. On the opposite site, patients carrying a glioblastoma multiforme usually die within the first year after the diagnosis is made. Therefore, different approaches are needed in each case. Obviously, prognosis and biological behaviour of malignant gliomas are closely related and supported by the different molecular background that possesses each type of glioma. Furthermore, the ability that allows several low-grade gliomas to progress into more aggressive tumors has allowed cancer researchers to elucidate several pathways implicated in molecular biology of these devastating tumors. In this review, we describe classical pathways involved in human malignant gliomas with special focus with recent advances, such as glioma stem-like cells and expression patterns from microarray studies.

Radiofrequency ablation for hepatocellular carcinoma and liver metastases: experience in Hospital La Paz.

INTRODUCTION: Radiofrequency ablation for patients presenting with non-resectable primary or metastatic liver tumours seems to be a valid therapeutic alternative. In the present study, we show a descriptive list of indications, results and complications of Radiofrequency Ablation Technique for treating non-resectable solid hepatic tumours. MATERIALS AND METHODS: Twenty two patients were included in this study; eleven of them (50%) sustained liver metastases from colorectal adenocarcinoma, ten patients (45.5%) had hepatocellular carcinoma and 1 patient had insulinoma. RESULTS: Local recurrence rate of hepatocellular carcinoma was 22.7% and 27.3% for colorectal carcinoma, after a respective median follow-up of 21 and 14 months. Complications rate was 6.9% and technique-associated mortality rate was 0%. CONCLUSIONS: Radiofrequency ablation is an easy to make, safe and useful technique for the treatment of primary and metastatic liver tumours.