Summary Background Appropriate timing of androgen deprivation treatment (ADT) for prostate cancer is controversial. Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed. Methods Eligible patients from 36 institutes in the USA were randomly assigned in 1988–93 to receive immediate ADT (n=47) or to be observed (n=51), with ADT to be given on detection of distant metastases or symptomatic recurrences. Patients were followed up every 3 months for the first year and every 6 months thereafter. The primary endpoint was progression-free survival; secondary endpoints were overall and disease-specific survival. Analysis was by intention to treat. To ensure that the treatment groups were comparable, we did a retrospective central pathology review of slides and regraded the Gleason scores for available samples. This trial predates the requirement for clinical trial registration. Findings At median follow-up of 11·9 years (range 9·7–14·5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1·84 [95% CI 1·01–3·35], p=0·04), prostate-cancer-specific survival (4·09 [1·76–9·49], p=0·0004), and progression-free survival (3·42 [1·96–5·98], p Interpretation Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment. The beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes between treatments.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(06)70700-8.pdf

Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy

Bacteria in nature appear as diverse communities, which may comprise of hundreds of different species. The shared capacity of the bacterial communities to adapt in any imaginable set of conditions is remarkable. Many bacteria have growth requirements, as yet undiscovered, which are fulfilled by their natural habitats. Indeed, bacterial communities have members specialized on different functions and providing vital elements to other bacteria living in the same community. Therefore, most bacteria cannot easily be isolated from their habitats by the routine culturing methods used in most laboratories today. To overcome the difficulties in culturing of individual microbes, modern approaches analyse the structure of bacterial communities by determining the characteristic features of the microbial DNA extracted from the community samples. Using such techniques we have found that 90% of the bacteria in the chicken gastrointestinal tract represent previously unknown species. Furthermore, more than half of the 640 different species found represent previously unknown bacterial genera. Bacteria in the gastrointestinal tract derive most of their carbon and energy from dietary compounds which are either resistant to attack by digestive fluids or absorbed so slowly by the host that bacteria can successfully compete for them. The performance improvements on use of a growth promoting feed antibiotic is due to factors such as reduced competition for nutrients in the small intestine, reduced local inflammation due to control of pathogens, and reduced size of intestine. Since bacterial species differ in their substrate preferences and growth requirements, the chemical composition and structure of the digesta largely determines the species distribution of the bacterial community in the gastrointestinal tract. Consequently, it should be possible to shift the microbial community from harmful to non-harmful bacteria by changing the diet.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0043933904000200

Characteristics of the gastrointestinal microbial communities, with special reference to the chicken

Development of prognostic models enables identification of variables that are influential in predicting patient outcome and the use of these multiple risk factors in a systematic, reproducible way according to evidence based methods. The reliability of models depends on informed use of statistical methods, in combination with prior knowledge of disease. We reviewed published articles to assess reporting and methods used to develop new prognostic models in cancer. We developed a systematic search string and identified articles from PubMed. Forty-seven articles were included that satisfied the following inclusion criteria: published in 2005; aiming to predict patient outcome; presenting new prognostic models in cancer with outcome time to an event and including a combination of at least two separate variables; and analysing data using multivariable analysis suitable for time to event data. In 47 studies, prospective cohort or randomised controlled trial data were used for model development in only 33% (15) of studies. In 30% (14) of the studies insufficient data were available, having fewer than 10 events per variable (EPV) used in model development. EPV could not be calculated in a further 40% (19) of the studies. The coding of candidate variables was only reported in 68% (32) of the studies. Although use of continuous variables was reported in all studies, only one article reported using recommended methods of retaining all these variables as continuous without categorisation. Statistical methods for selection of variables in the multivariate modelling were often flawed. A method that is not recommended, namely, using statistical significance in univariate analysis as a pre-screening test to select variables for inclusion in the multivariate model, was applied in 48% (21) of the studies. We found that published prognostic models are often characterised by both use of inappropriate methods for development of multivariable models and poor reporting. In addition, models are limited by the lack of studies based on prospective data of sufficient sample size to avoid overfitting. The use of poor methods compromises the reliability of prognostic models developed to provide objective probability estimates to complement clinical intuition of the physician and guidelines.

/pdf/reporting-methods-in-studies-developing-prognostic-models-in-2hiuununjd.pdf

Reporting methods in studies developing prognostic models in cancer: a review.

Broiler chickens from eight commercial farms in Southern Finland were analyzed for the structure of their gastrointestinal microbial community by a nonselective DNA-based method, percent G+C-based profiling. The bacteriological impact of the feed source and in-farm whole-wheat amendment of the diet was assessed by percent G+C profiling. Also, a phylogenetic 16S rRNA gene (rDNA)-based study was carried out to aid in interpretation of the percent G+C profiles. This survey showed that most of the 16S rDNA sequences found could not be assigned to any previously known bacterial genus or they represented an unknown species of one of the taxonomically heterogeneous genera, such as Ruminococcus or Clostridium. The data from bacterial community profiling were analyzed by t-test, multiple linear regression, and principal-component statistical approaches. The percent G+C profiling method with appropriate statistical analyses detected microbial community differences smaller than 10% within each 5% increment of the percent G+C profiles. Diet turned out to be the strongest determinant of the cecal bacterial community structure. Both the source of feed and local feed amendment changed the bacteriological profile significantly, whereas profiles of individual farms with identical feed regimens hardly differed from each other. This suggests that the management of typical Finnish farms is relatively uniform or that hygiene on the farm, in fact, has little impact on the structure of the cecal bacterial community. Therefore, feed compounders should have a significant role in the modulation of gut microflora and consequently in prevention of gastrointestinal disorders in farm animals.

/pdf/percent-g-c-profiling-accurately-reveals-diet-related-6h75x664b5.pdf

Percent G+C profiling accurately reveals diet-related differences in the gastrointestinal microbial community of broiler chickens

Objectives

Omeprazole is used for the treatment of infection caused by Helicobacter pylori, and it is metabolized by the polymorphic cytochrome P4502C19 (CYP2C19). We have found that the anti–H pylori efficacy by the combination of omeprazole and antibiotics is related to the CYP2C19 genotype.



Methods

One hundred eight patients with cultured H pylori –positive gastritis or peptic ulcer were treated with three regimens: quadruple treatment without proton pump inhibitors (n = 25), dual treatment with omeprazole and amoxicillin (INN, amoxicilline) (n = 26), and triple treatment with omeprazole, amoxicillin, and clarithromycin (n = 57). The CYP2C19 genotype was determined by the polymerase chain reaction– restriction fragment length polymorphism (PCR-RFLP) method and the assessment of the eradication of H pylori was based on all negative examinations, including culture, histology, and 13C-urea breath test.



Results

The eradication rates for the extensive metabolizers were 50% and 86% for the dual and triple treatments, respectively. In contrast, all of the poor metabolizers treated with omeprazole and antibiotics (n = 15) showed an eradication of H pylori.



Conclusion

The anti–H pylori effect of dual treatment is highly efficient for CYP2C19 poor metabolizers, which suggests that clarithromycin is not necessary as a first line of therapy for this type of patients. Genotyping can provide a choice for the optimal regimen based on individual CYP2C19 genotype.



Clinical Pharmacology & Therapeutics (1999) 66, 528–534; doi:

CYP2C19 genotype–related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori

An investigation was carried out to determine whether variations of dietary carbohydrates could modify the colonic flora in rats. Sprague-Dawley rats were fed with two equicaloric diets based on the AIN-76 diet (American Institute of Nutrition 1977) but differing from that diet in content of carbohydrates, i.e. high sucrose (64%) of high corn starch (64%). Feeding was continued for 9 months ad libitum and no variation in weight gain was recorded among the different diets. A prevalence of aerobes, and a significant reduction in the ratio anaerobes/aerobes in the faeces of rats on the high starch diet compared with the high sucrose diet, was observed. The anaerobe genera identified included Actinomyces, Bacteroides, Bifidobacterium, Clostridium, Eubacterium, Lactobacillus and Propionibacterium. Bacteroides was the most prevalent genus in both dietary groups (51.2 and 29.5% in the faeces of rats fed the sucrose and starch diets, respectively). In contrast, clostridia were prevalent in the starch-fed group (23.8%) and less so in the sucrose diet (11.5%), as propionibacteria were prevalent in faeces of rats fed the starch diet (15.5%), and low in the sucrose diet (3.9%). The remaining genera were scarce in faeces from rats on either diet. Total short-chain fatty acids (SCFA) were significantly higher in the faeces of animals fed the starch diet compared with those fed the sucrose diet. The relative concentrations of acetic, propionic and butyric acids were not significantly different between the two dietary groups. In conclusion, high starch diet can markedly modify the composition of faecal flora and alter considerably the faecal concentration of SCFAs, compound which might have a health-promoting effect.

The effect of sucrose or starch-based diet on short-chain fatty acids and faecal microflora in rats.

Morphological, physiological, and biochemical characteristics and the DNA base compositions of 133 thermophilic Bacillus strains were determined. A total of 54 of these strains were received as identified species (mainly Bacillus stearothermophilus, Bacillus coagulans, Bacillus brevis, and Bacillus licheniformis) from international culture collections, and 79 newly isolated strains, which were isolated mainly from sugar diffusion juices of Italian plants, were also examined. Numerical taxonomy techniques (simple matching coefficient and unweight pair grouping using the mathematical average) and DNA G+C values showed that the strains aggregated into nine clusters. Both B. licheniformis and B. brevis were well separated from the other organisms. B. stearothermophilus and B. coagulans were confirmed as separate clusters and exhibited greater heterogeneity than previously shown. The B. stearothermophilus strains clustered into four groups, three of which have been recognized previously by other authors; the members of the fourth group had distinctive characteristics, including considerable biochemical inertness, an inability to grow at temperatures greater than 60°C, and a high G+C content. Within the B. coagulans cluster the strains with characteristics very similar to those of the new species Bacillus smithii clustered together. However, the remaining strains were still clearly separated into two groups; one of these groups was considered B. coagulans sensu stricto, and the other was distinguished by morphological and biochemical criteria, such as spores which do not swell the sporangia, utilization of citrate, a higher proteolytic activity, and acidification of some carbohydrates. Our results were confirmed by comparing them with distinctive characteristics of recently described thermophilic Bacillus species.

Numerical analysis and DNA base compositions of some thermophilic Bacillus species.

Epidemiology of prostate cancer in the Umbria region of Italy: evidence of opportunistic screening effects.

Amoxicillin was administered at doses of 500 mg and 1000 mg, intravenously and intramuscularly to normal volunteers in a parallel study. Intramuscular amoxicillin was 100% bioavailable at both dose levels. Mean peak serum levels observed for the 500 mg and 1000 mg doses, respectively, were: i.v. (5 min after dosing) 46 and 74 micrograms/ml; i.m. (30 min after dosing) 14 and 21 micrograms/ml. Six hour trough levels ranged between 0.5 and 0.9 micrograms/ml. Between 50% and 60% of the doses were excreted in urine as intact amoxicillin in the 24 h after dosing. Almost 90% of this excretion occurred in the first 3 h after dosing. There was a statistically significant increase in mean clearance, after i.v. dosing, from the 500 mg level (14.8 l/h) to the 1000 mg level (20.7 l/h) implying that amoxicillin pharmacokinetics are non-linear over this range. Since there was very little difference between mean renal clearances at these dose levels (9.2 and 11.7 l/h, respectively) this clearance change might be due to enhancement of non-renal clearance. It would not be expected that this non-linearity would have any therapeutic influence.

Human intravenous and intramuscular pharmacokinetics of amoxicillin.

We analyzed the 10-year survival of 1,512 women with breast cancer in relation to age at diagnosis. The incident cases were from an ad hoc investigation in Umbria, a region of central Italy, for the period 1978-1982. The follow-up was carried out by an automatic link with the RENCAM (Nominative register of causes of death) and verified at the Register's Offices of the various towns of the region. Observed survival at 1 year was 0.89, at 3 years 0.75, at 5 years 0.64 and at 10 years 0.47. Median survival was 9.0 years. Relative survival at 1, 3, 5, 10 years was respectively 0.91, 0.79, 0.71 and 0.59. Women < 35 years of age had a better prognosis both at 5 (0.83) and 10 years (0.69) from diagnosis. Thereafter, survival decreased with increasing age. The exception to this trend was women in the 45-49 and 60-64 year age ranges, for which survival was greater than the previous age range classes by 6% and 13%, respectively, at 5 years from diagnosis and 6% and 14% at 10 years. Comparison of data from Umbria and Italian and European Registries shows that the prognosis for Umbrian women with breast cancer is quite good.

V. Mastrandrea

Papers

The effect of sucrose or starch-based diet on short-chain fatty acids and faecal microflora in rats.

Numerical analysis and DNA base compositions of some thermophilic Bacillus species.

Epidemiology of prostate cancer in the Umbria region of Italy: evidence of opportunistic screening effects.

Human intravenous and intramuscular pharmacokinetics of amoxicillin.

Ten-year survival and age at diagnosis of women with breast cancer from a population-based study in Umbria, Italy.