Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis.

BACKGROUND: Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients' survival. METHODS: We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. RESULTS: CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients' cohort. CONCLUSIONS: We herein provide novel evidence regarding the possible interactions between the components of AGE-RAGE axis, GLO-I and adiponectin receptors in CRC. AGE and AdipoR1 are possibly involved in colorectal carcinogenesis, whereas AdipoR2 and GLO-I emerged as novel independent prognostic biomarkers of adverse significance for patients with early disease stage. Further studies are warranted to extend our observations and investigate their potential therapeutic significance.

Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer.

The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.

Combined treatment with bevacizumab and standard chemotherapy restores abnormal immune parameters in advanced colorectal cancer patients.

BACKGROUND: Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5-fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL). METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n = 20) and patients (n = 40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb. RESULTS: PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p < 0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p < 0.001 for both IFL and B-IFL groups), IFN-γ (p < 0.001 for IFL and p = 0.001 for B-IFL), IL-12 (p < 0.001 for both IFL and B-IFL) and IL-18 (p < 0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p < 0.001 for both IFL and B-IFL), whereas IL-4 (p < 0.001 for IFL and p = 0.001 for B-IFL) and IL-10 [p < 0.001 for IFL and p = 0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p < 0.001, p < 0.04, p < 0.001, respectively). CONCLUSION: Our study demonstrates that the abnormal immune parameters observed in metastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome.

Identification and characterization of a HER-2/neu epitope as a potential target for cancer immunotherapy.

Our aim is to develop peptide vaccines that stimulate tumor antigen-specific T-lymphocyte responses against frequently detected cancers. We describe herein a novel HLA-A*0201-restricted epitope, encompassing amino acids 828-836 (residues QIAKGMSYL), which is naturally presented by various HER-2/neu (+) tumor cell lines. HER-2/neu(828-836), [HER-2(9(828))], possesses two anchor residues and stabilized HLA-A*0201 on T2 cells in a concentration-dependent Class I binding assay. This peptide was stable for 3.5 h in an off-kinetic assay. HER-2(9(828)) was found to be immunogenic in HLA-A*0201 transgenic (HHD) mice inducing peptide-specific and functionally potent CTL and long-lasting anti-tumor immunity. Most important, using HLA-A*0201 pentamer analysis we could detect increased ex vivo frequencies of CD8(+) T-lymphocytes specifically recognizing HER-2(9(828)) in 8 out of 20 HLA-A*0201(+) HER-2/neu (+) breast cancer patients. Moreover, HER-2(9(828))-specific human CTL recognized the tumor cell line SKOV3.A2 as well as the primary RS.A2.1.DR1 tumor cell line both expressing HER-2/neu and HLA-A*0201. Finally, therapeutic vaccination with HER-2(9(828)) in HHD mice was proven effective against established transplantable ALC.A2.1.HER tumors, inducing complete tumor regression in 50% of mice. Our data encourage further exploitation of HER-2(9(828)) as a promising candidate for peptide-based cancer vaccines.

Correlation between LGR5 stem cells and location of tumor as well as age, sex and metastasis in colon adenocarcinoma.

PURPOSE: G-protein receptors belong to a large family of receptors which includes more than 800 kinds. An interest for these receptors arose upon noticing their expression on skin, intestine and breast stem cells. METHODS: We examined the tissues of 53 patients who had been diagnosed with adenocarcinoma of the colon. There were no exclusion criteria. We measured the expression levels of LGR5 by immunohistochemistry and we correlated those and the location of the colon primary tumor with the age, sex and the metastatic potential. RESULTS: The median values of the two groups- the orthosigmoid and the other colon location- were 1 and 3.5 respectively with no statistical significance and with p=0.132. Spearman Rho indicated no statistical significance between the expression of LGR5 and age with p=0.219. Moreover, the Mann-Whitney U test showed no statistical significance between LGR5 and sex with p=0.778. Fisher's test, however, showed a statistically significant result between metastasis and expression of LGR5 with p=0.025. CONCLUSION: It becomes apparent that patients with increased expression of these two markers are characterized by a more aggressive form of the disease with an increased rate of metastasis. Also, interactions on both paths lead to a simultaneous overexpression, thus proving the diversity of carcinogenic pathways. Racial and other factors are not affected, and ultimately the need to target these indicators in treatment protocols is imperative.

Use of statins and breast cancer: a meta-analysis of seven randomized clinical trials and nine observational studies.

PURPOSE: A growing body of evidence suggests that statins may have chemopreventive potential against breast cancer. Laboratory studies demonstrate that statins induce apoptosis and reduce cell invasiveness in various cell lines, including breast carcinoma cells. However, the clinical relevance of these data remains unclear. The nonconclusive nature of the epidemiologic data prompted us to conduct a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. PATIENTS AND METHODS: A comprehensive search for articles published up until 2005 was performed; reviews of each study were conducted; and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% CIs were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed. RESULTS: Seven large randomized trials and nine observational studies (five case-control and four cohort studies) contributed to the analysis. We found no evidence of publication bias or heterogeneity among the studies. Statin use did not significantly affect breast cancer risk (fixed effects model: RR = 1.03; 95% CI, 0.93 to 1.14; random effects model: RR = 1.02; 95% CI, 0.89 to 1.18). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, the sensitivity analysis confirmed the stability of our results. CONCLUSION: Our meta-analysis findings do not support a protective effect of statins against breast cancer. However, this conclusion is limited by the relatively short follow-up times of the studies analyzed. Further studies are required to investigate the potential decrease in breast cancer risk among long-term statin users.

Gemcitabine in combination with vinorelbine for heavily pretreated advanced breast cancer.

PURPOSE: To evaluate the activity and toxicity of gemcitabine and vinorelbine in patients with metastatic breast cancer (MBC), previously treated with anthracyclines alone or with taxanes. PATIENTS AND METHODS: A total of 86 pretreated patients with MBC (median age 62 years), entered the study. Thirty-six patients had been pretreated with anthracyclines and 8 were resistant. The combination of gemcitabine (1000 mg/m2) and vinorelbine (25 mg/m2) was administered on days 1 and 8 every 3 weeks, for a total of 6 cycles. RESULTS: A total of 344 cycles of chemotherapy were administered (median 4 cycles per patient). Partial responses were observed in 31 patients (36.0%; 95% CI: 23-56). The median duration of response was 7 months (range 3-11 months) and the median overall survival was 14 months (range 6-21). The scheme was well tolerated. CONCLUSION: The combination of vinorelbine and gemcitabine is an active scheme in pretreated MBC, demonstrating an acceptable toxicity profile, and may well represent a valuable therapeutic choice after anthracycline/taxane regimens.

Gemcitabine combined with 5-fluorouracil for the treatment of advanced carcinoma of the pancreas.

BACKGROUND: Gemcitabine is an active agent in pancreatic cancer, showing clinical synergy with 5-fluorouracil (5-FU). The aim of the study was to evaluate the safety and efficacy of the combination of gemcitabine and 5-FU in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-two patients (median age, 62 years), with advanced or metastatic pancreatic adenocarcinoma, were enrolled in the study. The combination of gemcitabine (1000 mg/m2) and 5-FU (600 mg/m2) was administered on days 1, 8 and 15 and repeated every 28 days. RESULTS: A total of 168 cycles (median 4 cycles per patient) were administered. Partial responses were observed in 6 patients (14.2%) and stable disease in 11 (26.2%). The overall clinical benefit was 40.4%. Symptom relief and improvement of performance status were observed in 18 (42.8%) patients. The median time to progression, median duration of response and the median overall survival, were 6, 7 and 13 months, respectively. The most common grade 3 to 4 toxicities were neutropenia, anaemia and diarrhoea. CONCLUSION: The combination of gemcitabine and 5-FU is an active regimen for the treatment of advanced pancreatic cancer with an acceptable toxicity profile.

Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO).

AIMS AND BACKGROUND: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. STUDY DESIGN: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. RESULTS: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). CONCLUSIONS: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

The Prognostic Influence of BRAF Mutation and other Molecular, Clinical and Laboratory Parameters in Stage IV Colorectal Cancer.

Our aim was to evaluate the predictive and prognostic influence of BRAF mutation and other molecular, clinical and laboratory parameters in stage IV colorectal cancer (CRC). 60 patients were included in this retrospective analysis, and 17 variables were examined for their relation with treatment response and survival. KRAS mutation was identified in 40.3 % of cases, BRAF and PIK3CA in 8.8 % and 10.5 % respectively. 29.8 % of patients responded to treatment. Median survival time was 14.3 months. Weight loss, fever, abdominal metastases, blood transfusion, hypoalbuminaimia, BRAF and PIK3CA mutations, CRP and DNA Index were associated with survival. In multivariate analysis, male patients had 3.8 times higher probability of response, increased DNA Index was inversely correlated with response and one unit raise of DNA Index augmented 6 times the probability of death. Our findings potentiate the prognostic role of BRAF, PIK3CA mutations and ploidy in advanced CRC.

Expression of caspase-3 predicts prognosis in advanced noncardia gastric cancer.

There is strong evidence that tumor growth is not only a result of uncontrolled cell proliferation but also of decreased apoptosis. Caspase-3 is a member of interleukin-1 beta-converting enzyme which is involved in the induction of apoptosis. Data on the expression of caspase-3 in patients with gastric cancer and its association with patient outcome are somewhat contradictory. We aimed to investigate the potential relation of the expression of caspase-3 protein with response to therapy and overall survival in patients with advanced noncardia gastric cancer. Tumor tissue samples collected from 359 consecutive patients with gastric cancer stage IV were retrospectively analyzed for the expression of caspase-3 in the primary tumor. The DNA apoptotic index assessed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling method. All patients were followed up until death. Caspase-3 was expressed in 43.5 % of tumors. Caspase-3 expression compared to no expression was related with a higher DNA apoptotic index (p < 0.05). In multivariate analysis, tumor expression of caspase-3 was found to be an independent predictor of poor treatment response and survival (p < 0.05). Expression of caspase-3 in advanced gastric cancer is a predictor of poor response to treatment and survival. Further studies are needed to fully elucidate the prognostic value of caspase-3 expression in these patients.

Multidrug resistance proteins and topoisomerase IIalpha expression in colon cancer: association with metastatic potential.

AIMS: To investigate the role of multidrug resistance proteins and topoisomerase IIalpha in colon cancer. METHODS: Tissue sections from 89 Dukes' stage B-D colon cancer patients were selected. The expression of multidrug resistance proteins and topoisomerase IIalpha in primary tumour cells was assessed by standard immunohistochemistry. The extent of their expression was measured by image analysis and was correlated with clinicopathological features of the patients. RESULTS: P-glycoprotein was associated with the presence of lymph node metastasis (P=0.005), vessel invasion (P=0.0001) and perineural invasion (P=0.020). CONCLUSIONS: P-glycoprotein is probably involved in the processes of local invasion and metastatic dissemination.

Adjuvant systemic therapy protocol for Dukes' B2 and C resectable colon carcinoma.

AIMS AND BACKGROUND: Trials of adjuvant systemic therapy in high risk patients with Dukes' B2 and C colon cancer utilizing 5-fluorouracil-based regimens have been ongoing since the 1960s. The aim of this study was to compare the combination of 5-FU and leucovorin with the combination of 5-FU and alfa-2b interferon (IFN) in patients who had undergone "curative" resection foronocarcinoma. STUDY DESIGN: A total of 322 patients with histologically proven adenocarcinoma of the colon, Dukes' stage B2 and C, were entered in the study. They were randomized to A) leucovorin 20 mg/m2 rapid intravenous injection and 5-FU 425 mg/m2 IV days 1-5 every 28 days for six cycles or B) 5-FU 600 mg/m2 24-hour infusion for five days, then 600 mg/m2 IV once a week and IFN 5 MU subcutaneously three times a week for six months. RESULTS: There was no statistically significant difference in either disease-free survival or overall survival. Toxicity was the same in the two groups with the exception of flu-like syndrome, which was universal in IFN-treated patients. CONCLUSIONS: There was no difference in disease-free survival or overall survival between the two combinations in any patient subset. Toxicity was greater with the 5-FU+IFN combination because of the flu-like syndrome. These data do not support the use of IFN in combination with 5-FU as systemic adjuvant therapy for patients with locally advanced colon carcinoma.

Current concepts in the diagnosis and management of poorly differentiated gastrointestinal neuroendocrine carcinomas.

Poorly differentiated neuroendocrine carcinomas (PDNEC) are rare tumours that can originate from any site of the gastrointestinal tract exhibiting an overall aggressive behaviour that may vary between tumours according to the degree of cellular proliferation. The majority of PDNEC are locally advanced or metastatic at presentation, and are only infrequently associated with secretory hormonal syndromes. PDNEC exhibit aggressive histological features (high mitotic rate, high Ki67 labelling index and presence of necrosis) and are further subdivided into two morphological subgroups, small and large cell variants. As PDNEC express somatostatin receptors less frequently, somatostatin receptor scintigraphy is usually negative, whereas 18F-fluorodeoxyglucose positron emission tomography appears to be the best method of evaluating disease spread and guiding further treatment. PDNEC have traditionally been treated similarly to small cell lung carcinoma, although they show a number of different clinical and histopathologic features. First line systemic chemotherapy with a platinum-based agent and etoposide is used for patients with metastatic disease, leading to variable response rates that are often of relative short duration. Sequential or concurrent chemoradiation is recommended for patients with locoregional disease. In patients with localised disease, complete surgical resection should be offered followed by adjuvant treatment (chemotherapy with or without radiotherapy); the value of neoadjuvant chemotherapy has not been evaluated as yet. The role of second line therapies is evolving, with temozolomide being a promising agent. However, the majority of data regarding PDNEC is hampered by the small number of series and their retrospective nature, making it important that multicentre co-operative studies be performed.

Modulation of peripheral immune responses by paclitaxel-ifosfamide-cisplatin chemotherapy in advanced non-small-cell lung cancer.

PURPOSE: The aim of this study was to assess systemic immunological responses in non-small-cell lung cancer (NSCLC) patients with stage III/IV disease during treatment with paclitaxel-ifosfamide-cisplatin (TIP) chemotherapy. METHODS: Peripheral blood mononuclear cells (PBMCs) collected from healthy donors (HD) (n = 20) and chemotherapy-naive NSCLC patients treated with TIP (n = 32) were tested for production of IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10, IL-12 and IL-2 upon polyclonal stimulation with anti-CD3 mAb. They were further assessed over a treatment period of twelve weeks (i.e., four treatment cycles). RESULTS: PBMCs from NSCLC patients produced higher IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10 and IL-12 levels, whereas IL-2 exhibited lower values compared to HD (p < 0.001 for all parameters). Of interest, patients who responded to treatment had significantly higher increases in IL-2 (p < 0.001) and significantly higher decreases in IL-1 (p < 0.001), TNF-α (p < 0.001), TNF-ß (p < 0.001), IL-6 (p = 0.02), IL-8 (p < 0.001), IL-10 (p < 0.001) and IL-12 (p < 0.001) levels. Non-responders revealed post-therapeutically a significantly higher increase in IL-1, TNF-α, TNF-ß, IL-6, IL-8, IL-10 and IL-12 secretion and a significantly higher decrease in IL-2 levels (p < 0.001 for all parameters). Patients who responded to treatment and had a significantly higher increase in IL-2 showed a significantly longer median survival (p value < 0.001, 26 vs. 7.5 months). CONCLUSION: Our study indicates that monitoring cytokine dynamics in patients with advanced NSCLC and especially those of IL-2 in peripheral blood components in vitro could be used as a predictor of treatment-related outcome and overall survival in NSCLC.

Identification of a novel immunogenic HLA-A*0201-binding epitope of HER-2/neu with potent antitumor properties.

HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85-94 (HER-2(10(85))). HER-2(10(85)) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(10(85)) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu+ HLA-A2.1+ breast cancer patients analyzed had HER-2(10(85))-reactive T cells ranging from 0.35-0.70% of CD8+ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(10(85))pentamer+/CD8+ cells (PENT+/CD8+), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(10(85))-specific human CTL recognized the HER-2/neu+ HLA-A2.1+ tumor cell line SKBR3.A2, as determined by IFN-gamma intracellular staining and in the high sensitivity CD107alpha degranulation assay. Finally, HER-2(10(85)) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(10(85)) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(10(85)) as a possible target for anticancer immunotherapy.

Comparison of two oral regimens for the outpatient treatment of low-risk cancer patients with chemotherapy-induced neutropenia and fever: ciprofloxacin plus cefuroxime axetil versus ciprofloxacin plus amoxicillin/clavulanate.

The objective of this investigation was to assess retrospectively the safety and the efficacy of oral ciprofloxacin plus cefuroxime axetil compared to the combination of oral ciprofloxacin plus amoxicillin/clavulanate, as initial outpatient treatment, in low-risk cancer patients with fever and neutropenia. We analysed retrospectively 120 episodes of febrile neutropenia, treated on an outpatient basis at 2 different oncology units; 63 episodes were treated with the oral regimen of ciprofloxacin plus amoxicillin/clavulanate and 57 were treated with the combination of oral ciprofloxacin plus cefuroxime. 20 treatment failures were recorded-2 of them among patients receiving ciprofloxacin plus amoxicillin/clavulanate and 18 in the ciprofloxacin plus cefuroxime group. Univariate analysis showed that the administration of ciprofloxacin plus cefuroxime was associated with a worse outcome compared to the regimen ciprofloxacin plus amoxicillin/clavulanate (OR 11, CI 2.42-49.9, p =0.002). In the multivariate model, after adjusting for the absolute number of neutrophils and the duration of neutropenia, the effect of the antibiotic regimen on the outcome disappeared, and no significant differences between the 2 regimens were noted, although the regimen of ciprofloxacin plus cefuroxime was associated with a trend to a worse outcome (OR 4.74, CI 0.72-31.1, p =0.10). In conclusion, the 2 regimens appeared equally safe and effective but prospective studies are needed to confirm these results.

Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials.

PURPOSE: A growing body of literature suggests that statins may have chemopreventive potential against cancer. Our aim was to examine the strength of this association through a detailed meta-analysis and meta-regression analysis of randomized controlled trials (RCTs). METHODS: A comprehensive search for trials published up to 2005 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% CIs were calculated using the random- and fixed-effects models. Subgroup, sensitivity, and meta-regression analyses were also conducted. RESULTS: Thirty-five RCTs of statins for cardiovascular outcomes contributed to the analysis (n = 109,143). The degree of variability between trials was consistent with what would be expected to occur by chance alone. Statin use was not associated with a substantially increased or decreased overall risk of cancer (RR = 0.99; 95% CI, 0.94 to 1.04). Similarly, statin use did not significantly affect respiratory cancer risk (RR = 0.95; 95% CI, 0.83 to 1.09). However, the meta-regression analysis indicated that age of study participants modified the association between statin use and cancer risk (P = .003). CONCLUSION: Our findings do not support a protective effect of statins against cancer. However, this conclusion is limited by the relatively short follow-up periods (4.5 years on average) of the studies analyzed. Thus, it is important to continue monitoring the long-term safety profiles of statins. Until then, physicians need to be vigilant in ensuring that statin use remains restricted to the approved indications.

Visceral leishmaniasis masquerading as myelodysplasia.

We report a case of a 61-year-old man with head and neck cancer who presented with pancytopenia two months after the completion of his chemotherapy and was diagnosed with myelodysplasia on the basis of two bone marrow examinations, before the correct diagnosis of visceral leishmaniasis was established with splenectomy.