CLL family 'Pedigree 14' revisited: 1947-2004.

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.     

Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.     

Resistive index: an experimental study of the normal range in the pig

OBJECTIVES: To study the normal range and distribution of the resistive index (RI) and the resistive index ratio (RIR) in the non-obstructed non-dilated porcine kidney, and to assess the reliability of the threshold values RI 0.70 and RIR 1.10 as prognosticators of true obstruction in the upper urinary tracts. METHODS AND MATERIALS: Twenty female pigs of Danish land race breed were studied under general anaesthesia. Blood pressure and urine output was monitored throughout the experiment. Doppler evaluations were obtained from an interlobar artery in the lower half of each kidney, and the RI was calculated as the average of 3 x 3 cycles for each side independently. Statistical analysis of the obtained results was performed. RESULTS: Forty renal units were studied. The RI values ranged from 0.48-0.85 (mean 0.63). Nine renal units (22.5%) had RI values > or = 0.70. RIR values ranged from 1.00-1.38 (mean 1.07). Three RIR values (15%) were above 1.10. There was no statistically significant relationship between RI and laterality (p = 0.25), and no overall significant relationship between RI and mean arterial blood pressure (r2 = 0.21) or urine output (r2 = 0.004). CONCLUSIONS: This study shows a wide distribution of the RI normal values in the pig model, and our results do not support the normal ranges for RI and RIR, or the cut-off values used in clinical practice.     

Risk for anogenital cancer and other cancer among women hospitalized with gonorrhea

BACKGROUND: We investigated the relationship between infections with Neisseria gonorrhoeae and anogenital and other cancers. METHODS: Nationwide and population based register linkage study utilizing prospectively notified information. The observed numbers of cancers among the women were compared with those expected on the basis of national incidence rates. RESULTS: In a cohort of 4440 women hospitalized for gonorrhea we observed a total of 227 cases of cervical intraepithelial neoplasia grade III (CIN III), with 103 expected (standardized incidence ratio (SIR), 2.2; 95% confidence interval (CI), 1.9-2.5). No significantly increased risk for other anogenital cancers or cancer at other sites was seen. CONCLUSIONS: These results support the view that the observed association between gonorrheal infection and subsequent cervical preneoplasia is due mainly to surveillance bias. However, our results also indicate that women hospitalized with a N. gonorrhoeae infection will benefit from the compliance with the regular Pap smear screening programs.     

The toxicology of perfluorooctanoate

PFOA is a peroxisome proliferator (PPAR agonist) and exerts morphological and biochemical effects characteristic of PPAR agonists. These effects include increased beta-oxidation of fatty acids, increases in several cytochrome P-450 (CYP450)-mediated reactions, and inhibition of the secretion of very low-density lipoproteins and cholesterol from the liver. These effects on lipid metabolism and transport result in a reduction of cholesterol and triglycerides in serum and an accumulation of lipids in the liver. The triad of tumors observed (liver, Leydig cell, and pancreatic acinar-cell) is typical of many PPAR agonists and is believed to involve nongenotoxic mechanisms. The hepatocellular tumors observed in rats are likely to have been the result of the activation of the peroxisome proliferator activated receptor alpha (PPARalpha). The tumors observed in the testis (Leydig-cell) have been hypothesized to be associated with an increased level of serum estradiol in concert with testicular growth factors. The mechanism responsible for the acinar-cell tumors of the pancreas in rats remains the subject of active investigation. The mechanism resulting in the hepatocellular tumors in rats (PPARalpha activation) is not likely to be relevant to humans. Similarly, the proposed mechanism for Leydig-cell tumor formation is of questionable relevance to humans. Acinar tumors of the pancreas are rare in humans, and the relevance of the these tumors, as found in rats, to humans is uncertain. Epidemiological investigations and medical surveillance of occupationally exposed workers have not found consistent associations between PFOA exposure and adverse health effects.     

Risk of congenital malformations associated with proximity to hazardous waste sites.

Concern about environmental pollutants has increased; however, it remains unclear whether chronic exposures to toxic chemicals in the environment occur at doses sufficient to produce adverse health effects in humans. To date, community studies have not adequately addressed this question. In this study, the authors linked two existing data bases of the New York State Department of Health to evaluate the relation between congenital malformations and residential proximity to hazardous waste sites in New York State. A total of 9,313 newborns with congenital malformations and 17,802 healthy controls living in proximity to 590 hazardous waste sites in 1983 and 1984 were evaluated. After the authors controlled for several possible confounding factors, results indicated that maternal proximity to hazardous waste sites may carry a small additional risk of bearing children with congenital malformations (odds ratio (OR) = 1.12, 95% confidence interval (Cl) 1.06-1.18). Higher malformation rates were associated with both a higher exposure risk (no exposure risk: OR = 1.00; low exposure risk: OR = 1.09, 95% Cl 1.04-1.15; high exposure risk: OR = 1.63, 95% Cl 1.34-1.99) and documentation of off-site chemical leaks (not exposed: OR = 1.00; exposed, but no leaks at site: OR = 1.08, 95% Cl 1.02-1.15; exposed, and leaks found at site: OR = 1.17, 95% Cl 1.08-1.27). The increased rates detected may be important in terms of their public health implications. Further research is necessary to strengthen causal inferences regarding the teratogenicity, of waste site exposure.