Cancer risk due to occupational exposure to polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs) demonstrate carcinogenic activity in animal models. Although some epidemiologic studies have implicated PAHs as risk factors for human cancer, the evidence reported to date has not been consistent. The purpose of this report is to describe the associations between occupational exposure to PAHs in the workplace and each of 14 types of cancer. A population-based, case-control study was carried out in Montreal to investigate associations between a large variety of environmental and occupational exposures on the one hand, and several types of cancer on the other. A detailed job history was obtained from each subject along with information on a number of potential confounders. Each job history was reviewed by a team of experts, who used this information to construct a corresponding history of occupational exposures. Among the PAH exposures considered were benzo(a)pyrene (B(a)P) and five categories of PAHs defined on the basis of the source material, namely, wood, petroleum, coal, other sources, and any source. Altogether, 3,730 cancer patients and 533 population controls were interviewed and their job exposure histories coded. For each of 14 types of cancer analyzed, three control groups were available: other cancer patients, population controls, and the pooled set of cancer and population controls. The associations between 14 cancer types and 6 PAH exposures were analyzed using logistic regression methods. For most types of cancer evaluated, there was no evidence of excess risk due to PAHs at the levels encountered in the occupations in which PAH exposure has been prevalent in the Montreal area. For a few cancer sites–the esophagus, the pancreas, and the prostate gland–there were suggestions of excess risk; these observations are noteworthy hypotheses for further investigation. For lung cancer, there appeared to be an increased risk due to PAHs among nonsmokers and light smokers, but not among heavy smokers.     

New insights on P2X purinoceptors

Significant advances in understanding of P_2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P_2X receptor heterogeneity, from data with agonists, has recently been reported.A number of new antagonists at P_2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P_2X purinoceptor.Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P_2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P_2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P_2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P_2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P_2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.     

Urination Frequency and Cystic Pressure Resistance After Fractionated whole or Partial Irradiation of the Rabbit Urinary Bladder

Urination frequency and cystic pressure resistance have been used as end-points to assess x-ray-induced changes of bladder function. Whole or half bladders of adult male rabbits were irradiated, caudally or cranially. The absorbed dose was 33 Gy, 36 Gy or 39 Gy, given in 5 daily fractions. Animals which received a whole bladder dose of 39 Gy or 36 Gy showed increased urination frequency and enhanced bladder pressure resistance during the whole follow-up time of 100 weeks, compared with the sham-irradiated controls. At half bladder irradiation, only the highest doses (39 Gy to the cranial part of the bladder and 39 Gy or 36 Gy to the caudal part) gave rise to a slight increase in frequency at about 20 weeks after exposure.     

Initial experience with dynamic MR imaging in evaluation of normal bone marrow versus malignant bone marrow infiltrations in humans

The purpose of this study was (a) evaluation of dynamic contrast-enhanced MR imaging of normal bone marrow versus malignant bone marrow infiltrations in patients with proven B-cell-type chronic lymphocytic leukemia (B-CLL) and (b) correlation with the clinical stage according to Binet (stages A, B, C) and response to therapy. Bone marrow imaging of the lumbar spine, pelvis, and proximal femurs was performed at 1.5 T in 45 patients without known malignancy and in 30 patients with B-CLL. The differences between opposed-phase and in-phase dynamic gradient-echo sequences before and up to 10 minutes after intravenous application of .1 mmol/kg body weight of gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) were evaluated in normal bone marrow. The contrast-enhancement patterns of normal and malignant bone marrow were compared using the opposed-phase dynamic gradient-echo sequence. Ten of the patients with bone marrow infiltrations (Binet stage C) additionally underwent MR imaging follow-up during therapy. Opposed-phase gradient echo sequences demonstrated a signal decrease of normal bone marrow, and in-phase gradient echo sequences demonstrated a signal increase of normal bone marrow after administration of Gd-DTPA. The dynamic signal intensity time courses differed significantly (P < .05) between Binet stages B and C and controls as well as among the three Binet stages of B-CLL. In the 10 patients followed during therapy, MR imaging sensitively demonstrated response (n = 6), nonresponse (n = 2), or relapse after initial response (n = 2). In out-of-phase imaging, both normal bone marrow and initial bone marrow infiltration in CLL stage Binet A show signal decrease after administration of contrast agent, whereas there is increase in signal intensity in higher-grade bone marrow infiltration in Binet stage B or C disease. The signal loss of normal bone marrow in out-of-phase imaging is a phase effect rather than a T2* effect. The differentiation of initial from higher-grade bone marrow infiltration on out-of-phase images relies solely on a shift in the fat/water ratio.     

Complications of intravesical bacillus Calmette-Guerin: a case report.

Bacillus Calmette-Guerin (BCG) is the most effective agent currently available to treat superficial bladder cancer. However, this form of therapy is not without potential serious or fatal complications. In addition to the potentially toxic systemic side effects attributed to hematogenous absorption of the bacillus, direct upper tract seeding may occur in patients with vesicoureteral reflux. We report on a patient treated with intravesical BCG for bladder cancer in whom unilateral necrotizing granulomatous pyelonephritis developed. Although severe, this complication is rare and we conclude that reflux is not a contraindication for intravesical BCG therapy.     

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain.

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.     

Kupffer cell modulation of the systemic immune response

The effects of global hepatic injury and of Kupffer cell activation on systemic immunity were studied in an in vivo rat model, using the diameters of the delayed-type hypersensitivity (DTH) response to keyhole limpet hemocyanin and of a subcutaneous Staphylococcus aureus abscess as measures of systemic immunoresponsiveness. Hepatic injury with carbon tetrachloride resulted in significant suppression of the DTH score (5.5 +/- 0.7 vs 8.8 +/- 0.8 mm). Kupffer cell activation with intraportal Escherichia coli was likewise suppressive (DTH score, 4.4 +/- 0.5 vs 6.1 +/- 0.4 mm for animals receiving systemic E coli); the magnitude of this suppression correlated with the numbers of organisms extracted by the liver. Conversely, Kupffer cell ablation with carrageenan lessened the immunosuppressive effects of anesthesia and surgery (DTH score, 8.5 +/- 0.9 vs 6.8 +/- 0.6 mm for controls; S aureus abscess, 4.1 +/- 0.4 vs 5.7 +/- 0.4 mm for controls). These results indicate that Kupffer cells can modulate the systemic immune response and suggest that gram-negative portal bacteremia with resultant Kupffer cell activation may contribute to the immunologic derangements characteristic of trauma and critical surgical illness.