Phase II study of capecitabine and mitomycin C as first-line treatment in patients with advanced colorectal cancer

This study was designed to assess the safety and efficacy of capecitabine and mitomycin C (MMC) in previously untreated patients with advanced colorectal cancer (CRC). Patients received capecitabine 2500 mg m2 day 1, orally divided in two doses of 1250 mg m-2 in the morning and evening for 14 days every 21 days and MMC 7 mg m-2 (maximum total dose 14 mg) as an intravenous bolus every 6 weeks for a total of four courses. The median age was 70 years (range 24–85) and the majority of patients (86.9%) were of performance status 1/2. The most common metastatic site was liver. In all, 84 patients were assessable for response. The overall response rate was 38% (95% CI: 27.7–49.3) and a further 33.3% of patients achieved stable disease over 12 weeks. There was good symptom resolution ranging from 64 to 86%. Grade 3/4 toxicity was as follows: hand–foot syndrome 19.7%; diarrhoea 10%; neutropenia 2.4%; infection 2.3%. Capecitabine and MMC have shown encouraging activity with a favourable toxicity profile, a convenient administration schedule, and could be considered for patients deemed unsuitable for oxaliplatin and irinotecan combinations.S Rao, D Cunningham, T Price, M E Hill, P J Ross, N Tebbutt, A R Norman, J Oates and P Shellit

Psychologie der Kreativität

Ein kleiner Streifzug durch die psychologische Kreativitätsforschung befasst sich mit den Möglichkeiten der Erfassung kreativer Prozesse, ihrer Manifestation, den Determinanten, der Frage nach der Notwendigkeit zu kreativem Denken und schließlich Erkenntnissen darüber, wie kreatives Denken gefördert werden kann

Regulatory T Cell Expansion in HTLV-1 and Strongyloidiasis Co-infection Is Associated with Reduced IL-5 Responses to Strongyloides stercoralis Antigen

Human strongyloidiasis varies from a mild, controlled infection to a severe frequently fatal disseminated infection depending on the hosts. Patients infected with the retrovirus HTLV-1 have more frequent and more severe forms of strongyloidiasis. It is not clear how human strongyloidiasis is controlled by the immune system and how HTLV-1 infection affects this control. We hypothesize that HTLV-1 leads to dissemination of Strongyloides stercoralis by augmenting regulatory T cell numbers, which in turn down regulate the immune response to the parasite. In our study, patients with HTLV-1 and Strongyloides co-infection had higher parasite burdens than patients with only strongyloidiasis. Eosinophils play an essential role in control of strongyloidiasis in animal models, and eosinophil counts were decreased in the HTLV-1 and Strongyloides stercoralis co-infected subjects compared to patients with only strongyloidiasis. The proportion of T cells with a regulatory cell phenotype was increased in HTLV-1 positive subjects co-infected with strongyloidiasis compared to patients with only strongyloidiasis. IL-5 is a key host molecule in stimulating eosinophil production and activation, and Strongyloides stercoralis antigen-specific IL-5 responses were reduced in strongyloidiasis/HTLV-1 co-infected patients. Reduced IL-5 responses and eosinophil counts were inversely correlated to the number of regulatory T cells. These findings suggest a role for regulatory T cells in susceptibility to Strongyloides hyperinfection

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BACKGROUND: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. METHODS: A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. RESULTS: Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. CONCLUSION: Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity

BluePort: A Platform to Study the Eosinophilic Response of Mice to the Bite of a Vector of Leishmania Parasites, Lutzomyia longipalpis Sand Flies

transmission in residents of endemic areas has been attributed to the acquisition of immunity to sand fly salivary proteins. One theoretical way to accelerate the acquisition of this immunity is to increase the density of antigen-presenting cells at the sand fly bite site. Here we describe a novel tissue platform that can be used for this purpose. sand flies. Results presented indicate that a shift in the inflammatory response, from neutrophilic to eosinophilic, is the main histopathological feature associated with the immunity acquired through repeated exposure to the bite of sand flies, and that the BluePort tissue compartment could be used to accelerate this process. In addition, changes observed inside the BluePort parenchyma indicate that it could be used to study complex immunobiological processes, and to develop ectopic secondary lymphoid structures.Understanding the characteristics of the dermal response to the bite of sand flies is a critical element of strategies to control leishmaniasis using vaccines that target salivary proteins. Finding that dermal eosinophilia is such a prominent component of the anti-salivary immunity induced by repeated exposure to sand fly bites raises one important consideration: how to avoid the immunological conflict derived from a protective Th2-driven immunity directed to sand fly saliva with a protective Th1-driven immunity directed to the parasite. The BluePort platform is an ideal tool to address experimentally this conundrum

NK-like homeodomain proteins activate NOTCH3-signaling in leukemic T-cells

<p>Abstract</p> <p>Background</p> <p>Homeodomain proteins control fundamental cellular processes in development and in cancer if deregulated. Three members of the NK-like subfamily of homeobox genes (NKLs), TLX1, TLX3 and NKX2-5, are implicated in T-cell acute lymphoblastic leukemia (T-ALL). They are activated by particular chromosomal aberrations. However, their precise function in leukemogenesis is still unclear. Here we screened further NKLs in 24 T-ALL cell lines and identified the common expression of MSX2. The subsequent aim of this study was to analyze the role of MSX2 in T-cell differentiation which may be disturbed by oncogenic NKLs.</p> <p>Methods</p> <p>Specific gene activity was examined by quantitative real-time PCR, and globally by expression profiling. Proteins were analyzed by western blot, immuno-cytology and immuno-precipitation. For overexpression studies cell lines were transduced by lentiviruses.</p> <p>Results</p> <p>Quantification of MSX2 mRNA in primary hematopoietic cells demonstrated higher levels in CD34+ stem cells as compared to peripheral blood cells and mature CD3+ T-cells. Furthermore, analysis of MSX2 expression levels in T-cell lines after treatment with core thymic factors confirmed their involvement in regulation. These results indicated that MSX2 represents an hematopoietic NKL family member which is downregulated during T-cell development and may functionally substituted by oncogenic NKLs. For functional analysis JURKAT cells were lentivirally transduced, overexpressing either MSX2 or oncogenic TLX1 and NKX2-5, respectively. These cells displayed transcriptional activation of NOTCH3-signaling, including NOTCH3 and HEY1 as analyzed by gene expression profiling and quantitative RT-PCR, and consistently attenuated sensitivity to gamma-secretase inhibitor as analyzed by MTT-assays. Furthermore, in addition to MSX2, both TLX1 and NKX2-5 proteins interacted with NOTCH-pathway repressors, SPEN/MINT/SHARP and TLE1/GRG1, representing a potential mechanism for (de)regulation. Finally, elevated expression of NOTCH3 and HEY1 was detected in primary TLX1/3 positive T-ALL cells corresponding to the cell line data.</p> <p>Conclusion</p> <p>Identification and analysis of MSX2 in hematopoietic cells implicates a modulatory role via NOTCH3-signaling in early T-cell differentiation. Our data suggest that reduction of NOTCH3-signaling by physiological downregulation of MSX2 expression during T-cell development is abrogated by ectopic expression of oncogenic NKLs, substituting MSX2 function.</p

Epithelial cell polarity: a major gatekeeper against cancer?

The correct establishment and maintenance of cell polarity are crucial for normal cell physiology and tissue homeostasis. Conversely, loss of cell polarity, tissue disorganisation and excessive cell growth are hallmarks of cancer. In this review, we focus on identifying the stages of tumoural development that are affected by the loss or deregulation of epithelial cell polarity. Asymmetric division has recently emerged as a major regulatory mechanism that controls stem cell numbers and differentiation. Links between cell polarity and asymmetric cell division in the context of cancer will be examined. Apical–basal polarity and cell–cell adhesion are tightly interconnected. Hence, how loss of cell polarity in epithelial cells may promote epithelial mesenchymal transition and metastasis will also be discussed. Altogether, we present the argument that loss of epithelial cell polarity may have an important role in both the initiation of tumourigenesis and in later stages of tumour development, favouring the progression of tumours from benign to malignancy

Treatment in advanced colorectal cancer: what, when and how?

Treatment of advanced colorectal cancer (CRC) increasingly requires a multidisciplinary approach and multiple treatment options add to the complexity of clinical decision-making. Recently novel targeted therapy against angiogenesis and epidermal growth factor receptor completed a plethora of phase III studies. The addition of bevacizumab to chemotherapy improved the efficacy over chemotherapy alone in both first and second line settings, although the magnitude of benefit may not be as great when a more optimal chemotherapy platform is used. Studies performed thus far did not address conclusively whether bevacizumab should be continued in subsequent lines of treatment. Anti-angiogenesis tyrosine kinase inhibitors have not shown any additional benefit over chemotherapy alone so far. Although some benefits were seen with cetuximab in all settings of treating advanced CRC, K-ras mutation status provides an important determinant of who would not benefit from such a treatment. Caution should be exercised in combining anti-angiogenesis with anti-EGFR strategy until further randomised data become available. In this review, we have focused on the implications of these trial results on the everyday management decisions of treating advanced CRC