Mandala M.,Unit of Medical Oncology |
Clerici M.,Clinical Operations Unit |
Corradino I.,Clinical Operations Unit |
Vitalini C.,Clinical Operations Unit |
And 4 more authors.
Annals of Oncology | Year: 2012
Background: To investigate the incidence, risk factors and clinical implications of venous thromboembolism (VTE) in advanced cancer patients treated in phase I studies. Patients and methods: Patients enrolled and treated in phase I studies conducted by SENDO (Southern Europe New Drugs Organization) Foundation between 2000 and 2010 in 15 experimental centers were considered for the study. Clinical data, including adverse events, were prospectively collected during the studies and retrospectively pooled for VTE analysis. Results: Data of 1415 patients were considered for analysis. Five hundred and twenty-six (37.2%) patients were males, and median age was 57.3 years (range: 13-85). Eighty-five percent of patients had metastatic disease, while the remaining had locally advanced irresectable disease. For 706 (49.9%) of the patients, the study treatment was with cytotoxic agent(s) only, for 314 with target therapy(ies) only, while the remaining patients received a target therapy in combination with a cytotoxic drug. Fifty-six (3.96%) patients who developed a VTE, almost all (89.3%) during the course of treatment, the remaining during the follow-up. At univariate analysis, the Khorana score, the combination of an antiangiogenic agent with a cytotoxic drug, and the time from first cancer diagnosis to study entry (as continuous variable) were associated with a statistically significant increase of VTE occurrence. The multivariate analysis confirmed only a statistically significant association for the Khorana score. The hazard ratio of VTE occurrence was 7.88 [95% confidence interval (CI) 2.86-21.70) and 2.74 (95% CI 1.27-5.92) times higher for the highest (≥3) and intermediate (1-2) scores as compared with score = 0. Conclusions: VTE is a relatively common complication among patients treated in the context of phase I studies. The Khorana score predicts VTE development and can be used to identify patients at high of VTE.
Roth A.D.,University of Geneva |
Delorenzi M.,University of Lausanne |
Delorenzi M.,Swiss Institute of Bioinformatics |
Tejpar S.,University Hospital Gasthuisberg |
And 12 more authors.
Journal of the National Cancer Institute | Year: 2012
BackgroundThe prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.MethodsTumors from patients (N 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.Results MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence 0.54, 95% CI 0.37 to 0.81, P . 003) and OS (HR of death 0.43, 95% CI 0.27 to 0.70, P . 001) for MSI-high status and worse RFS (HR 1.47, 95% CI 1.19 to 1.81, P <. 001) and OS (HR 1.58, 95% CI 1.23 to 2.01, P <. 001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.ConclusionsConcomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone. © 2012 The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: firstname.lastname@example.org.
Vecchio S.,IRCCS San Martino IST Instituto Nazionale per la Ricerca sul Cancro |
Spagnolo F.,IRCCS San Martino IST Instituto Nazionale per la Ricerca sul Cancro |
Merlo D.F.,University of Genoa |
Signori A.,University of Genoa |
And 3 more authors.
Melanoma Research | Year: 2014
The management of melanoma brain metastases (MBM) includes different therapeutic modalities, such as surgery, radiotherapy and chemotherapy. Despite the choice of treatments, survival remains poor, exceeding 1 year only in patients with solitary metastases and absence of extracranial disease. A total of 115 consecutive MBM patients observed between 1994 and 2010 were included in an historical cohort study. Demographic, clinical data and tumour characteristics were collected and survival status was ascertained across the follow-up window. The statistical associations between individual and tumour data and overall survival were investigated using Kaplan-Meier survival function and Cox's multiple regression analysis. The median survival was 4.3 months (95% confidence interval 2.6-6.1). Patients who underwent surgery or stereotactic radiosurgery showed a significantly (P<0.001) better prognosis than those who received chemotherapy and/or radiotherapy or supportive therapies. Patients without clinical symptoms experienced a statistically significant better survival (P=0.02) than patients with clinical symptoms; analogue difference was observed to be in favour of patients whose symptoms improved after the first treatment of MBM (P<0.001). The presence of symptoms, clinical outcome and first treatment received were the only independent variables to predict survival. Patients who cannot receive surgery or stereotactic radiosurgery have the worst overall survival. © 2014 Wolters Kluwer Health | Lippincott Williams Wilkins.
Dragoni S.,University of Pavia |
Laforenza U.,University of Pavia |
Bonetti E.,Unit of Clinical Epidemiology |
Lodola F.,University of Pavia |
And 9 more authors.
Stem Cells | Year: 2011
Endothelial progenitor cells (EPCs) home from the bone marrow to the site of tissue regeneration and sustain neovascularization after acute vascular injury and upon the angiogenic switch in solid tumors. Therefore, they represent a suitable tool for cell-based therapy (CBT) in regenerative medicine and provide a novel promising target in the fight against cancer. Intracellular Ca 2+ signals regulate numerous endothelial functions, such as proliferation and tubulogenesis. The growth of endothelial colony forming cells (ECFCs), which are EPCs capable of acquiring a mature endothelial phenotype, is governed by storedependent Ca 2+ entry (SOCE). This study aimed at investigating the nature and the role of VEGF-elicited Ca 2+ signals in ECFCs. VEGF induced asynchronous Ca 2+ oscillations, whose latency, amplitude, and frequency were correlated to the growth factor dose. Removal of external Ca 2+ (0Ca 2+) and SOCE inhibition with N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2, 3-thiadiazole-5-carboxamide (BTP-2) reduced the duration of the oscillatory signal. Blockade of phospholipase C-γ with U73122, emptying the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca 2+ pools with cyclopiazonic acid (CPA), and inhibition of InsP 3 receptors with 2-APB prevented the Ca 2+ response to VEGF. VEGF-induced ECFC proliferation and tubulogenesis were inhibited by the Ca 2+-chelant, BAPTA, and BTP-2. NF-κB activation by VEGF was impaired by BAPTA, BTP-2, and its selective blocker, thymoquinone. Thymoquinone, in turn, suppressed VEGF-dependent ECFC proliferation and tubulogenesis. These data indicate that VEGF-induced Ca 2+oscillations require the interplay between InsP3-dependent Ca 2+ release and SOCE, and promote ECFC growth and tubulogenesis by engaging NF-κB. This novel signaling pathway might be exploited to enhance the outcome of CBT and chemotherapy. © AlphaMed Press.
Palumbo R.,Unit of Medical Oncology |
Sottotetti F.,Unit of Medical Oncology |
Riccardi A.,University of Pavia |
Teragni C.,Unit of Medical Oncology |
And 4 more authors.
Therapeutic Advances in Medical Oncology | Year: 2013
The outcome of patients with metastatic breast cancer (MBC) has clearly improved over the past decades and the proportion of women living with their disease for several years is increasing. However, the usefulness of multiple lines of treatment is still debated and under evaluation. The available data from both randomized trials and large retrospective series are reviewed and discussed in order to analyze management practices, with emphasis on potential prognostic and predictive factors for clinical outcome. At present, evidence-based medicine provides some support for the use of second-line and to a lesser degree and in selected cases, third-line chemotherapy in human epidermal growth factor receptor 2 (HER2) negative MBC. Beyond third-line treatment, messages from recently reported retrospective studies also suggest a clear potential gain for women receiving further therapies after disease progression, since each line can contribute to a longer survival. In HER2-positive disease, the data from observational and retrospective studies support a clinical benefit from the use of trastuzumab beyond disease progression and emerging evidences from randomized controlled trials are leading to the introduction of newer HER2-targeted therapies in multiple lines. The question 'How many lines of treatment should we give patients?' clearly needs further research through prospective, high-quality clinical trials, aiming for a better definition of factors with prognostic and predictive role. In the meantime, the 'optimal' treatment strategy should probably be to use as many therapeutic options as possible, either in sequence or combination, to keep the best efficacy/toxicity balance, considering MBC as a chronic disease. © The Author(s), 2013.
Labianca R.,Unit of Medical Oncology |
Merelli B.,Unit of Medical Oncology
Tumori | Year: 2010
Aims and background. Colon cancer is the thirdmost common cause of cancer diagnosed in the United States, and the second leading cause of cancer death. Although rates of the disease have been going down in recent years, results can be further improved. About 90% of people whose colon cancer is caught before it has spread to nearby lymph nodes or organs survive more than 5 years after diagnosis. However, only 10% of patients whose cancer has spread to distant parts of the body survive 5 years. Diagnosis at an early stage aims to reduce the incidence of tumors in an advanced stage and hence mortality. Methods and study design.We analyzed the literature to understand what new tests to use and new directions to take. Results. There is evidence to support the screening of average-risk individuals over the age of 50 years to detect and prevent colon cancer. Screening of these people can only reduce mortality rates, not incidence, identifying cancer at an early stage and through the removal of clinically significant adenomas. Patient preferences and availability of resources play an important role in the selection of screening tests, because each test presents specific risks and specific benefits. Conclusions. The American Cancer Society has added two new screening methods, CT colonography, also known as virtual colonoscopy, and stool DNA tests to the list of options. A small revolution in screening for colon cancer is in the making. The availability of these less invasive tests should increase the number of people who undergo regular screening. Free full text available at www.tumorionline.it.
Mandala M.,Unit of Medical Oncology |
Tondini C.,Unit of Medical Oncology
Expert Review of Anticancer Therapy | Year: 2011
Pancreatic cancer is still a clinical challenge due to its predominantly late diagnosis and the chemoresistance to cytotoxic and target drugs. One of the major complications of pancreatic cancer is venous thromboembolism (VTE). Both ambulatory and hospitalized pancreatic cancer patients are at higher risk of developing VTE. Among patients with unresectable pancreatic cancer, the occurrence of VTE may be associated with a poor prognosis. Furthermore, emerging clinical data strongly suggest that anticoagulant treatment may improve patient survival by decreasing thromboembolic complications as well as by anticancer activity. Given the clinical relevance for both physicians and basic scientists, this article focuses on the experimental and clinical evidence supporting the relation between the coagulation cascade and the invasive and metastatic potential of pancreatic cancer, and suggests that anticoagulant therapy may represent a useful strategy to improve the prognosis of pancreatic cancer patients. © 2011 Expert Reviews Ltd.
Mandala M.,Unit of Medical Oncology |
Tondini C.,Unit of Medical Oncology
Thrombosis Research | Year: 2012
Breast cancer patients are considered to be at relatively low risk of developing a TEE. The highest incidence of VTE events occurs in metastatic breast cancer patients likely due to extension of disease, immobility for pathologic bone fractures, cancer cachexia and venous compression by the tumour mass. Although thrombosis is less common in patients with early stage cancer compared to those with more advanced disease, it does occur and is clinically challenging. The adjuvant setting is of particular interest in order to assess the specific thrombogenic potential of systemic chemotherapy, because of the low tumor burden with only microscopic tumor foci at the time of treatment administration. This review summarizes risk factors, incidence and strategies to avoid VTE in breast cancer patients receiving adjuvant therapy. © 2012 Elsevier Ltd.
Bregni M.,Unit of Medical Oncology
Journal of Medicine and the Person | Year: 2010
Quality of life (QoL) in medicine and in oncology is an accepted parameter for the evaluation of the benefit of treatments. Scientific methods exist to assess QoL measures in clinical trials. However, many components of the person that are properly humane and determine the patient's attitude towards the disease are not measured by current criteria. Based on clinical experience, the author considers that a shift in knowledge and in doctors' attitudes is required to also include non-measurable parameters in the doctor-patient relationship. © Springer-Verlag 2010.
Cremolini C.,Unit of Medical Oncology |
Schirripa M.,Unit of Medical Oncology |
Antoniotti C.,Unit of Medical Oncology |
Moretto R.,Unit of Medical Oncology |
And 4 more authors.
Nature Reviews Clinical Oncology | Year: 2015
The response to first-line therapy is a primary determinant of outcome in patients with metastatic colorectal cancer (mCRC), for three main reasons: effective upfront therapy provides a unique opportunity to cure some patients; can be crucial in delaying disease progression and achieving symptom relief; and can improve patient eligibility for, and the effectiveness of, further treatments. In the past decade, decision-making regarding the choice of first-line therapy for mCRC has been complicated by the availability of many different options without a definitive consensus on a specific standard of care (despite major advances in categorizing predictive molecular disease subtypes). Most of the efforts of the scientific community have been directed at establishing the best biologic agent to be combined with a chemotherapy doublet, although a different branch of research has produced new data that underscore the importance of defining the optimal chemotherapy backbone. Herein, we review the key clinical trials completed in the past 10 years that have investigated and compared the use of chemotherapy doublets, triplets, and monotherapies, with or without molecularly targeted biologic agents, in the first-line treatment of patients with mCRC. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for mCRC.