Comparative In Vitro Activity of Sparfloxacin (AT 4140, RP 64206 - SPFX) Against 275 Multiresistant Clinical Isolates

The in-vitto activity of sparfloxacin was compared with that of pefloxacin, ofloxacin, ciprofloxacin, imipenem, ceftazidime, gentamicin and amikacin against 275 multiresistant nosocomial clinical isolates. They consisted of Pseudomonas aetuginosa (37), Entetobacter cloacae (42), Acinetobactet anitratus (60), Klebsiella pneumoniae (37) and Staphylococcus sp (99). Minimum inhibitory concentrations (MIC₉₀) and geometric mean MICs for sparfloxacin were as follows (mg/1): P. aeruginosa 128 - 23.7, E. cloacae 1 - 0.13, A. anitratus 2 - 0.14, K. pneumoniae 1 - 0.08, MRSA 16 - 0.98, MSSA 0.12 - 0.03, MRSE 0.25 - 0.12 and MSSE 0.12 - 0.05. It is concluded that sparfloxacin was the most potent agent against staphylococci and A. anitratus including strains resistant to the other quinolones while ciprofloxacin was the most potent agent against P. aeruginosa, E. cloacae and K. pneumoniae.     

Serum C-reactive protein at admission predicts in-hospital mortality in medical patients

BACKGROUND: Previous studies have examined the role of inflammatory markers in patients with coronary heart disease, stroke, chronic renal failure and other selected patient populations. The aim of this study was to assess the clinical utility of serum C-reactive protein (CRP) at admission in predicting outcome in hospitalized medical patients. METHODS: All patients admitted to our medical department were eligible to be included in the study. At the time of admission, demographic and clinical information was obtained. CPR was measured within 12 h of hospitalization. The results were analyzed using Cox proportional hazards multiple regression model. RESULTS: Three hundred eighty-two patients were included in the study (186 males and 196 females). Age (mean+/-standard deviation) was 70.8+/-15.7 years. Serum CRP [median (interquartile range) at admission was 29.7 mg/l (6.6-114.3). Serum CRP at admission was independently associated with in-hospital death. Levels above 120 mg/l increased the probability of fatal outcome three fold (hazard ratio=2.98, 95% confidence interval: 1.35-6.58). In patients older than 80 years, CRP at admission was a stronger predictor of in-hospital death (hazard ratio=5.41, 95% confidence interval: 1.38-21.26). CONCLUSIONS: Serum CRP at admission is an independent predictor of mortality in hospitalized patients, particularly in the elderly. Admission CRP higher than 120 mg/l was associated with increased probability of in-hospital death (three fold in the overall population and five fold in the elderly subgroup) compared with lower levels.     

Lack of Fas (APO-1/CD95) gene structural alterations or transcript variant ratio changes in breast cancer

Fas (APO-1/CD95) is a transmembrane receptor protein involved in cell death signaling. Fas receptor and ligand are both expressed in breast cancer cells, however these cells are resistant to apoptosis. Fas gene mutations were detected in hematological and solid tumors, while overexpression of a soluble Fas isoform in serum was related to cancer stage and prognosis. In this work, direct sequencing of exons 6 and 9 of the Fas gene from 90 patients did not reveal any structural alterations. Moreover, no decrease was found in the ratio of the corresponding mRNA species of transmembrane versus soluble Fas isoforms in 31 breast cancer samples compared to 14 controls. Therefore, inhibition of Fas-mediated apoptosis may not be due to structural alterations in the critical exons 6 and 9 of the Fas gene or a shift of expression towards the soluble Fas isoform, but to other mechanisms operating in breast cancer cells.     

Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma: mutational and functional analysis

CONTEXT: The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small-cell lung carcinomas harboring activating EGFR TK domain somatic mutations. OBJECTIVE AND METHODS: Because the EGFR pathway has been reported to be important for the pathophysiology of thyroid carcinoma, we investigated the expression and mutational status of EGFR in 14 thyroid carcinoma cell lines as well as its functional role by evaluating their in vitro sensitivity to AEE788, a new dual-family EGFR/ErbB2 and vascular endothelial growth factor receptor TK inhibitor. We also evaluated the mutational status, mRNA and protein expression, as well as phosphorylation status of EGFR in a panel of thyroid carcinoma specimens. RESULTS: EGFR expression and phosphorylation in the thyroid carcinoma cell lines and tissue specimens were present but not stronger than in noncancerous thyroid tissue. EGFR TK domain mutations were detected in two of 62 histological specimens (3.2%) but not in cell lines. All thyroid carcinoma cell lines were significantly less sensitive (IC(50) at least 25-fold higher) in vitro to AEE788 than a primary culture of EGFR-mutant lung carcinoma cells. CONCLUSIONS: Thyroid carcinoma cells overall are poorly responsive to clinically relevant concentrations of AEE788 in vitro. The presence of EGFR-activating TK domain mutations may identify a small minority of thyroid cancer patients that may benefit from EGFR inhibitors, but additional preclinical evidence of efficacy is needed.     

Ibrutinib Monotherapy in Relapsed or Refractory,Transformed Diffuse Large B-cell Lymphoma

BackgroundHistologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment.Patients and MethodsWe prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate.ResultsTwenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib.ConclusionsIbrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.     

Anthropometric, behavioral, and female reproductive factors and risk of multiple myeloma: a pooled analysis

Background

Risk of developing multiple myeloma (MM) rises with age and is greater among men and blacks than among women and whites, respectively, and possibly increased among obese persons. Other risk factors remain poorly understood. By pooling data from two complementary epidemiologic studies, we assessed whether obesity, smoking, or alcohol consumption alters MM risk and whether female reproductive history might explain the lower occurrence of MM in females than in males.

Methods

The Los Angeles County MM Case–Control Study (1985–1992) included 278 incident cases and 278 controls, matched on age, sex, race, and neighborhood of residence at case’s diagnosis. We estimated MM risk using conditional logistic regression to calculate odds ratios (ORs) and 95 % confidence intervals (CIs). In the prospective California Teachers Study (CTS), 152 women were diagnosed with incident MM between 1995 and 2009; we calculated hazard ratios using Cox proportional hazards analysis. Data from the two studies were pooled using a stratified, nested case–control sampling scheme (10:1 match) for the CTS; conditional logistic regression among 430 cases and 1,798 matched controls was conducted.

Results

Obesity and smoking were not associated with MM risk in the individual or combined studies. Alcohol consumption was associated with decreased MM risk among whites only (pooled OR = 0.66, 95 % CI = 0.49–0.90) for ever versus never drinking. Higher gravidity and parity were associated with increased MM risk, with pooled ORs of 1.38 (95 % CI = 1.01–1.90) for ≥3 versus 1–2 pregnancies and 1.50 (95 % CI = 1.09–2.06) for ≥3 versus 1–2 live births.

Conclusions

Female reproductive history may modestly alter MM risk, but appears unlikely to explain the sex disparity in incidence. Further investigation in consortial efforts is warranted.     

Thymidylate synthase inhibition induces p53-dependent and p53-independent apoptotic responses in human urinary bladder cancer cells

Purpose  

In search for more effective clinical protocols, the antimetabolite drug 5-fluorouracil (5-FU) has been successfully included in new regimens of bladder cancer combination chemotherapy. In the present study, we have investigated the effects of 5-FU treatment on apoptosis induction in wild-type and mutant p53 urinary bladder cancer cells.