Hashish smoking and T-lymphocytes

To investigate the effect of long term hashish use on T-lymphocytes we have measured the incorporation of¹⁴C-thymidine by peripheral blood lymphocytes, unstimulated and stimulated by phytohemagglutinin, as well as the proportion and number of E-rosettes in 12 healthy male chronic users of the drug before and after a smoking session, and in 15 control subjects.The results show that hashish smoking does not impair the response of lymphocytes to PHA, at least at the concentration of PHA used. Furthermore there is a possibility that among chronic users a hashish smoking session may have a slight stimulatory effect.

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Zusammenfassung Zur Untersuchung des Langzeiteffekts von Haschischgebrauch auf T-Lymphozyten haben wir den Einbau von¹⁴C-Thymidin in Lymphozyten des strömenden Blutes ohne und mit Stimulierung durch Phythämagglutinine (PHA) gemessen. Zugleich wurde das Zahlenverhältnis von E-Rosetten bei zwölf gesunden männlichen chronischen Haschischkonsumenten vor und nach einer Rauchperiode bestimmt sowie mit 15 Kontrollpersonen verglichen. Haschischrauchen ergab keine Schädigung der Lymphozytenrekation auf PHA, wenigstens bei der verwendeten PHA-Konzentration. Es ist nicht ausgeschlossen, daß nach chronischem Haschischrauchen eine leichte Stimulierung eintritt.

     

Bayesian Analysis of Genetic Interactions in Case–control Studies,with Application to Adiponectin Genes and Colorectal Cancer Risk

Complex diseases such as cancers are influenced by interacting networks of genetic and environmental factors. However, a joint analysis of multiple genes and environmental factors is challenging, owing to potentially large numbers of correlated and complex variables. We describe Bayesian generalized linear models for simultaneously analyzing covariates, main effects of numerous loci, gene–gene and gene–environment interactions in population case–control studies. Our Bayesian models use Student‐t prior distributions with different shrinkage parameters for different types of effects, allowing reliable estimates of main effects and interactions and hence increasing the power for detection of real signals. We implement a fast and stable algorithm for fitting models by extending available tools for classical generalized linear models to the Bayesian case. We propose a novel method to interpret and visualize models with multiple interactions by computing the average predictive probability. Simulations show that the method has the potential to dissect interacting networks of complex diseases. Application of the method to a large case–control study of adiponectin genes and colorectal cancer risk highlights the previous results and detects new epistatic interactions and sex‐specific effects that warrant follow‐up in independent studies.     

Hepatitis B virus, tobacco smoking and ethanol consumption in the etiology of hepatocellular carcinoma

Tobacco smoking and alcohol drinking histories were obtained from 194 patients with hepatocellular carcinoma (HCC) and 456 hospital controls, and the results were analysed in conjunction with the results of serological determinations of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) in all subjects, as well as the presence or absence of cirrhosis in HCC patients. The relative risk (RR) of HCC (and 95% confidence interval) among HBsAg-positive subjects was 13.7 (8.0-23.5), whereas the excess risk among antibody-positive subjects was small and statistically non-significant. In the presence of cirrhosis the RR for HBsAg-positive subjects was considerably higher (30.7 vs. 7.1 among HBsAg-positive subjects without cirrhosis) indicating that HBV may affect the development of HCC through at least two different and potentially multiplicative mechanisms (DNA integration and liver regeneration). Moderate ethanol consumption does not affect the risk of HCC, but there is a statistically significant and dose-dependent association between tobacco smoking and HBsAg-negative HCC. In most of the developed countries of Europe and North America, where the prevalence of HBsAg carrier state is very low and tobacco smoking very common, more cases of HCC may be due to tobacco smoking than to HBV, even though the RR for HCC is much higher among HBsAg carriers than among tobacco smokers.     

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Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women’s Health Initiative

Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk. We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women’s Health Initiative SNP Health Association Resource cohort of 3,642 self-identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1, and ADIPOR2. The genome-wide human SNP array 6.0 (909,622 SNPs) (www.affymetrix.com) was used. We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95 % CI 1.059–1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence. This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment.     

A double-blind,randomised, placebo-controlled,phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer

BackgroundWe conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.MethodsPatients were randomised to paclitaxel (90 mg/m², weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ?0.82 (1-sided α = 0.14) after 120 events supporting a treatment effect.FindingsPatients were randomised in India (n = 170), the United States (n = 52) and Brazil (n = 15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR) = 0.788; 95% confidence interval (CI), 0.558–1.112; P = 0.1715 [1-sided P = 0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR = 0.674; 95% CI 0.465–0.975; P = 0.0343) and improved overall response (67% versus 54%; P = 0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR = 1.022; 95% CI 0.715–1.461; P = 0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.InterpretationThe addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.FundingNorthwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.     

Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

Purpose

Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors.

Patients and Methods

We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum.

Results

We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10^-4), TGFBR1*6A (p = 1.6 × 10^-4) and rs11568785 (p = 1.4 × 10^-4).

Conclusion

These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies.     

A pilot study of cabergoline for the treatment of metastatic breast cancer

Purpose

The prolactin (PRL) receptor is over-expressed in breast cancer, and pre-clinical data indicate that it contributes to breast oncogenesis. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary PRL secretion.

Methods

A phase II study of cabergoline in patients with metastatic breast cancer was conducted. The primary end point of the study was to determine the clinical benefit rate (CBR) at 2 months. Eligible patients had tumors of any receptor status with no limit of prior lines of therapy. Measurable and unmeasurable diseases were allowed. Cabergoline 1 mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. PRL receptor immunohistochemical staining was performed on available baseline tumor tissue; serial serum PRL levels were assessed.

Results

Twenty women were enrolled; 18 were evaluable for CBR. Tumor receptor status was distributed as follows: HR?any/HER2+ 2(10%), HR+/HER2? 18 (90%). The CBR was 33% (6/18), median progression free survival was 1.8 months, and median overall survival was 10.4 months. Two patients experienced disease control for over 12 months. Most common treatment-related adverse events were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). Nine patients had baseline tissue for analysis; there was no association between baseline tumor PRL receptor expression and clinical benefit (p = 0.24). Change in serum PRL level and response were not correlated after 2 months of treatment (p = 0.64).

Conclusion

Cabergoline was well tolerated, and while the ORR was low, a small subset of patients experienced extended disease control.