A historical cohort study on glycemic-control and cancer-risk among patients with diabetes.

AIMS: This population-based historical cohort study examined whether poor glycemic-control (i.e., high glucose and HbA1c blood levels) in patients with diabetes is associated with cancer-risk. METHODS: From a large healthcare database, patients aged 21-89 years, diagnosed with diabetes before January 2002 (prevalent) or during 2002-2010 (incident), were followed for cancer during 2004-2012 (excluding cancers diagnosed within the first 2 years since diabetes diagnosis). Risks of selected cancers (all-sites, colon, breast, lung, prostate, pancreas and liver) were estimated according to glycemic-control in a Cox regression model with time-dependent covariates, adjusted for age, sex, ethnic origin, socioeconomic status, smoking and parity. Missing glucose or HbA1c values were imputed. RESULTS: Among 440,000 patients included in our analysis, cancer was detected more than 2 years after diabetes diagnosis in 26,887 patients (6%) during the follow-up period. Associations of poor glycemic-control with all-sites cancer and most specific cancers were either null or only weak (hazard ratios (HRs) for a 1% HbA1c or a 30 mg/dl glucose increase between 0.94 and 1.09). Exceptions were pancreatic cancer, for which there was a strong positive association (HRs: 1.26-1.51), and prostate cancer, for which there was a moderate negative association (HRs: 0.85-0.96). CONCLUSION: Overall, poor glycemic-control appears to be only weakly associated with cancer-risk, if at all. A substantial part of the positive association with pancreatic cancer is attributable to reverse causation, with the cancer causing poorer glycemic-control prior to its diagnosis. The negative association with prostate cancer may be related to lower PSA levels in those with poor control.

Traumeel S in preventing and treating mucositis in young patients undergoing SCT: a report of the Children's Oncology Group.

Mucositis can be a serious complication of hematopoietic SCT (HSCT). A previous phase II trial in 32 children undergoing HSCT reported a beneficial effect of the homeopathic remedy Traumeel S. The Children's Oncology Group sought to replicate the results in a multi-institutional trial. The study was an international multi-center, double-blind, randomized trial comparing Traumeel with placebo in patients aged 3-25 years undergoing myeloablative HSCT. Traumeel/placebo was started on Day -1 as a five-time daily mouth rinse. Efficacy of the treatment was assessed using the modified Walsh scale for mucositis, scored daily from Day -1 to 20 days after HCST. The main outcome was the sum of Walsh scale scores (area-under-the-curve (AUC)) over this period. Other outcomes included narcotic use, days of total parenteral feeding, days of nasogastric feeding and adverse events. In 181 evaluable patients, there was no statistical difference in mucositis (AUC) in the Traumeel group (76.7) compared with placebo (67.3) (P=0.13). There was a trend towards less narcotic usage in the Traumeel patients. No statistically beneficial effect from Traumeel was demonstrated for mucositis. We could not confirm that Traumeel is an effective treatment for mucositis in children undergoing HSCT.

Factors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries.

A retrospective analysis was conducted to examine factors affecting early mortality after myeloablative, single-unit cord blood transplantation (CBT) for hematological malignancies in adolescents and adults. Data were collected from the three main CBT registries pooling 514 records of unrelated, single, unmanipulated, first myeloablative allogeneic CBTs conducted in North America or Europe from 1995 to 2005, with an HLA match ≥ 4/6 loci, in patients aged 12-55. Overall 100-day, 180-day and 1-year survival (Kaplan-Meier method) were 56, 46 and 37%, respectively, with no significant heterogeneity across registries. Multivariate analysis showed cell dose < 2.5 × 107/kg (odds ratio (OR) 2.76, P < 0.0001), older age (P = 0.002), advanced disease (P = 0.02), positive CMV sero-status (OR 1.37 P = 0.11), female gender (OR 1.43, P = 0.07) and limited CBT center experience (< 10 records contributed, OR 2.08, P = 0.0003) to be associated with higher 100-day mortality. A multivariate model predictive of 1-year mortality included similar prognostic factors except female gender. Transplant year did not appear as a significant independent predictor. This is the first analysis to pool records from three major CBT registries in the United States and Europe. In spite of some differences in practice patterns, survival was remarkably homogeneous. The resulting model may contribute to better understanding factors affecting CBT outcomes.

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin.

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 non-carriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P=0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P=0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wild-type klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

Partial agonist/antagonist properties of androstenedione and 4-androsten-3beta,17beta-diol.

Androgens play important endocrine roles in development and physiology. Here, we characterize activities of two "Andro" prohormones, androstenedione (A-dione) and 4-androsten-3beta,17beta-diol (A-diol) in MDA-MB-453 (MDA) and LNCaP cells. A-dione and A-diol, like cyproterone acetate, were partial agonists of transfected mouse mammary tumor virus (MMTV) and endogenous prostate-specific antigen (PSA) promoters. Different from bicalutamide but similar to CPA, both are inducers of LNCaP cell proliferation with only mild suppression of 5alpha-dihydrotestosterone (DHT)-enhanced cell growth. Like bicalutamide and cyproterone acetate, A-dione and A-diol significantly antagonized DHT/R1881-induced PSA expression by up to 30% in LNCaP cells. Meanwhile, in MDA cells, EC(50)s for the MMTV promoter were between 10 and 100nM. Co-factor studies showed GRIP1 as most active for endogenous androgen receptor (AR), increasing MMTV transcription by up to five-fold, without substantially altering EC(50)s of DHT, A-dione or A-diol. Consistent with their transcriptional activities, A-dione and A-diol bound full-length endogenous AR from MDA or LNCaP cells with affinities of 30-70nM, although binding to expressed ligand-binding domain (LBD) was >20-fold weaker. In contrast, DHT, R1881, and bicalutamide bound similarly to LBD or aporeceptor. Together, these data suggest that A-dione and A-diol are ligands for AR with partial agonist/antagonist activities in cell-based transcription assays. Binding affinities for both are most accurately assessed by AR aporeceptor complex. In addition to being testosterone precursors in vivo, either may impart its own transcriptional regulation of AR.

A comparison of population-based cancer incidence rates in Israel and Jordan.

Reliable information about comparative cancer incidence in the Middle East has been lacking. The Middle East Cancer Consortium (MECC) has formed a network of population-based registries with standardized basic data. Here the age-adjusted cancer incidences are compared for four populations: Israeli Jews, Israeli non-Jews, Jordanians and the US Surveillance Epidemiology and End Results (SEER) population, for the years 1996-1997 (Israel) and 1996-1998 (other populations). The all-sites rate of cancer is approximately twice as high in Israeli Jews and SEER, compared with Israeli non-Jews and Jordanians. Rates of lung cancer are similar among Israeli Jews and non-Jews and about twice as high as in Jordanians. Childhood leukaemia rates in Jordan are higher than in Israeli Jews, but lower than SEER. Hodgkin lymphoma rates in Israeli non-Jews and Jordanians are similar to SEER, but non-Hodgkin lymphoma rates are lower than SEER. The previous suspicion of higher overall leukaemia and lymphoma rates in Jordan is thus not confirmed.

Body mass index at age 18 years and during adult life and ovarian cancer risk.

During the years 1994-1999, a nationwide ovarian cancer case-control study was conducted in Israel. The present analysis addresses the question: Is epithelial ovarian cancer associated with body mass index at age 18 years and/or with weight changes in body mass index between adolescence and adult life? The study is based on 1,269 women with epithelial ovarian cancer and 2,111 matched controls. A significant decrease in risk of ovarian cancer was observed with parity, oral contraceptive use, and postmenopausal status. A significant increase in risk with family history of ovarian/breast cancer was also found. No significant association with age at menarche or infertility was found. For body mass index at age 18 years, the odds ratio of the highest versus lowest body mass index quartile was 1.42 (95% confidence interval: 1.08, 1.85) and after adjusting for confounders was 1.54 (95% confidence interval: 1.17, 2.02). However, no statistically significant risk associated with change in weight from age 18 years to adult life was found. The authors conclude that, in their population, body mass index at age 18 years is an independent risk factor for ovarian cancer.

Circulating leptin levels after cardiopulmonary bypass in children.

OBJECTIVE: To characterize the dynamics of circulating leptin in children after cardiac surgery with cardiopulmonary bypass (CPB), which is known to induce a systemic inflammatory response. DESIGN: Investigative study. SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Eight children (age range, 3 months to 13 years) undergoing CPB to correct congenital heart disease. INTERVENTIONS: The time courses of leptin and cortisol levels were determined. Serial blood samples were collected from the arterial catheter or from the CPB circuit preoperatively; on termination of CPB; and at 2, 4, 8, 12, 18, and 24 hours postoperatively. Plasma was recovered immediately, divided into aliquots, and frozen at -70 degrees C until use. Leptin was measured by a human leptin radioimmunoassay kit. MEASUREMENTS AND MAIN RESULTS: Leptin levels during CPB decreased to 50% of pre-CPB levels (p < 0.01). After termination of CPB, levels increased gradually and peaked at 12 hours postoperatively (10 P.M. to 1 A.M.). Cortisol levels were inversely correlated to leptin levels (p = 0.016). CONCLUSION: CPB is associated with acute changes in circulating leptin levels. These changes parallel those in cortisol, showing an inverse relationship between leptin and cortisol, suggesting a relationship between the neurobiology of these systems that could be important for the neuroendocrine response to CPB. A prognostic role of leptin and its relationship to cortisol after CPB warrant further study.

Design and serendipity in establishing a large cohort with wide dietary intake distributions : the National Institutes of Health-American Association of Retired Persons Diet and Health Study.

In 1995-1996, the authors mailed a food frequency questionnaire to 3.5 million American Association of Retired Persons members who were aged 50-69 years and who resided in one of six states or two metropolitan areas with high-quality cancer registries. In establishing a cohort of 567,169 persons (340,148 men and 227,021 women), the authors were fortunate in that a less-than-anticipated baseline response rate (threatening inadequate numbers of respondents in the intake extremes) was offset by both a shifting and a widening of the intake distributions among those who provided satisfactory data. Reported median intakes for the first and fifth intake quintiles, respectively, were 20.4 and 40.1 (men) and 20.1 and 40.0 (women) percent calories from fat, 10.3 and 32.0 (men) and 8.7 and 28.7 (women) g per day of dietary fiber, 3.1 and 11.6 (men) and 2.8 and 11.3 (women) servings per day of fruits and vegetables, and 20.7 and 156.8 (men) and 10.5 and 97.0 (women) g per day of red meat. After 5 years of follow-up, the cohort is expected to yield nearly 4,000 breast cancers, more than 10,000 prostate cancers, more than 4,000 colorectal cancers, and more than 900 pancreatic cancers. The large size and wide intake range of the cohort will provide ample power for examining a number of important diet and cancer hypotheses.

The acute promyelocytic leukemia-associated protein, promyelocytic leukemia zinc finger, regulates 1,25-dihydroxyvitamin D(3)-induced monocytic differentiation of U937 cells through a physical interaction with vitamin D(3) receptor.

Monocyte differentiation induced by 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is interrupted during the course of acute promyelocytic leukemia (APL). One form of APL is associated with the translocation t(11;17), which joins the promyelocytic leukemia zinc finger (PLZF) and retinoic acid receptor alpha (RARalpha) genes. Because PLZF is coexpressed in the myeloid lineage with the vitamin D(3) receptor (VDR), the interplay between PLZF and VDR was examined. It was found that PLZF interacts directly with VDR. This occurred at least partly through contacts in the DNA-binding domain of VDR and the broad complex, tram-trak, bric-a-brac/pox virus zinc finger (BTB/POZ) domain of PLZF. Moreover, PLZF altered the mobility of VDR derived from nuclear extracts when bound to its cognate binding site, forming a slowly migrating DNA-protein complex. Overexpression of PLZF in a monocytic cell line abrogated 1,25(OH)(2)D(3) activation from both a minimal VDR responsive reporter and the promoter of p21(WAF1/CIP1), a target gene of VDR. Deletion of the BTB/POZ domain significantly relieved PLZF-mediated repression of 1,25(OH)(2)D(3)-dependent activation. In addition, stable, inducible expression of PLZF in U937 cells inhibited the ability of 1,25(OH)(2)D(3) to induce surface expression of the monocytic marker CD14 and morphologic changes associated with differentiation. These results suggest that PLZF may play an important role in regulating the process by which 1,25(OH)(2)D(3) induces monocytic differentiation in hematopoietic cells.

A randomized, controlled clinical trial of the homeopathic medication TRAUMEEL S in the treatment of chemotherapy-induced stomatitis in children undergoing stem cell transplantation.

BACKGROUND: Stomatitis is a common consequence of chemotherapy and a condition for which there is little effective treatment. Although the management of patients with other chemotherapy-related toxicities has improved in recent years, the incidence of stomatitis is increasing because of more intensive treatment and is often a dose limiting factor in chemotherapy. The authors assessed the efficacy of a homeopathic remedy, TRAUMEEL S(R), in the management of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted in 32 patients ages 3-25 years who had undergone allogeneic (16 patients) or autologous (16 patients) stem cell transplantation. Of the 30 evaluable patients, 15 were assigned placebo, and 15 were assigned TRAUMEEL S both as a mouth rinse, administered five times daily from 2 days after transplantation for a minimum of 14 days, or until at least 2 days after all signs of stomatitis were absent. Stomatitis scores were evaluated according to the World Health Organization grading system for mucositis. RESULTS: A total of five patients (33%) in the TRAUMEEL S treatment group did not develop stomatitis compared with only one patient (7%) in the placebo group. Stomatitis worsened in only 7 patients (47%) in the TRAUMEEL S treatment group compared with 14 patients (93%) in the placebo group. The mean area under the curve stomatitis scores were 10.4 in the TRAUMEEL S treatment group and 24.3 in the placebo group. This difference was statistically significant (P < 0.01). CONCLUSIONS: This study indicates that TRAUMEEL S may reduce significantly the severity and duration of chemotherapy-induced stomatitis in children undergoing bone marrow transplantation.

Implementation of a 4-y, high-fiber, high-fruit-and-vegetable, low-fat dietary intervention: results of dietary changes in the Polyp Prevention Trial.

BACKGROUND: The Polyp Prevention Trial (PPT) was a multicenter randomized clinical trial designed to determine the effects of a high-fiber (4.30 g/MJ), high-fruit-and-vegetable (0.84 servings/MJ), low-fat (20% of energy from fat) diet on the recurrence of adenomatous polyps in the large bowel. OBJECTIVE: Our goal was to determine whether the PPT intervention plan could effect change in 3 dietary goals and to examine the intervention's effect on the intake of other food groups and nutrients. DESIGN: Participants with large-bowel adenomatous polyps diagnosed in the past 6 mo were randomly assigned to either the intervention (n = 1037) or the control (n = 1042) group and remained in the trial for 4 y. Three dietary assessment instruments were used to measure dietary change: food-frequency questionnaires (in 100% of the sample), 4-d food records (in a 20% random cohort), and 24-h dietary recalls (in a 10% random sample). RESULTS: Intervention participants made and sustained significant changes in all PPT goals as measured by the dietary assessment instruments; the control participants' intakes remained essentially the same throughout the trial. The absolute differences between the intervention and control groups over the 4-y period were 9.7% of energy from fat (95% CI: 9.0%, 10.3%), 1.65 g dietary fiber/MJ (95% CI: 1.53, 1.74), and 0.27 servings of fruit and vegetables/MJ (95% CI: 0.25, 0.29). Intervention participants also reported significant changes in the intake of other nutrients and food groups. The intervention group also had significantly higher serum carotenoid concentrations and lower body weights than did the control group. CONCLUSION: Motivated, free-living individuals, given appropriate support, can make and sustain major dietary changes over a 4-y period.

Bayesian monitoring of a phase 2 chemoprevention trial in high-risk cohorts for prostate cancer.

The objective of phase 2 cancer chemoprevention trials is to evaluate whether a chemopreventive agent will cause significant modulation of intermediate endpoint biomarkers (IEB) in patients at high risk for the disease. A phase 2 chemoprevention trial of 4-hydroxyphenyl retinamide (4-HPR) versus placebo was conducted in men with a histologic diagnosis of early prostate cancer and scheduled to have radical prostatectomy. A Bayesian monitoring method was used to sequentially monitor this trial for evidence of biological activity or ineffectiveness based on a single IEB variable. Different prior distributions were used and posterior distributions were obtained to calculate the probability that treatment differences are greater than or less than a predetermined clinically significant effect. The interim analysis of transforming growth factor-alpha expression indicated a high probability of insufficient biological activity of 4-HPR on this IEB. This study demonstrates the potential utility of Bayesian methods in the decision-making process in the conduct of phase 2 chemoprevention trials.

Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc.

Upon engagement of the B Cell Receptor (BCR) of WEHI 231 immature B cells, a drop in c-Myc expression is followed by activation of the cyclin-dependent kinase inhibitor (CKI) p27(Kip1), which induces growth arrest and apoptosis. Here, we report inverse patterns of p27 and c-Myc protein expression follow BCR engagement. We present evidence demonstrating, for the first time, that the p27(Kip1) gene is a target of transcriptional repression by c-Myc. Specifically, the changes in p27 protein levels correlated with changes in p27 mRNA levels, and gene transcription. Induction of p27 promoter activity followed BCR engagement of WEHI 231 cells, and this induction could be repressed upon co-transfection of a c-Myc expression vector. Inhibition of the TATA-less p27 promoter by c-Myc was also observed in Jurkat T cells, vascular smooth muscle, and Hs578T breast cancer cells, extending the observation beyond immune cells. Consistent with a putative Inr element CCAGACC (where +1 is underlined) at the start site of transcription in the p27 promoter, deletion of Myc homology box II reduced the extent of repression. Furthermore, enhanced repression was observed upon transfection of the c-Myc 'super-repressor', with mutation of Phe115 to Leu. The sequences mediating transcriptional activity and c-Myc repression were mapped to bp -20 to +20 of the p27 gene. Finally, binding of Max was shown to facilitate c-Myc binding and repression of p27 promoter activity. Overall, these studies identify the p27 CKI gene as a new target whereby c-Myc can control cell proliferation, survival and neoplastic transformation.

Covariate measurement error adjustment for matched case-control studies.

We propose a conditional scores procedure for obtaining bias-corrected estimates of log odds ratios from matched case-control data in which one or more covariates are subject to measurement error. The approach involves conditioning on sufficient statistics for the unobservable true covariates that are treated as fixed unknown parameters. For the case of Gaussian nondifferential measurement error, we derive a set of unbiased score equations that can then be solved to estimate the log odds ratio parameters of interest. The procedure successfully removes the bias in naive estimates, and standard error estimates are obtained by resampling methods. We present an example of the procedure applied to data from a matched case-control study of prostate cancer and serum hormone levels, and we compare its performance to that of regression calibration procedures.

Molecular analysis of the prostate-specific antigen upstream gene enhancer.

BACKGROUND: Our objective was to identify factors other than androgen receptor that bind to and regulate the prostate-specific antigen (PSA) upstream gene enhancer (PSE). METHODS: DNAse I footprinting and electromobility shift assays (EMSA) were performed over the PSE using lysates from PSA-producing cell lines, LNCaP and LAPC4, and nonproducing PSA cell lines, PC-3 cells, U937 monocytes, and Namalwa B cells. Mutational analysis and transient transfection assays were used to determine the contributions made by different elements towards the regulation of the enhancer. RESULTS: Three distinct regions surrounding androgen response elements of the PSE were found to bind unknown ubiquitous and cell type-specific proteins. These regions, when mutated in a PSE reporter construct, were shown to be required for maximal activation in LNCaP cells. CONCLUSIONS: These results correlate unknown sequence-specific DNA binding proteins with androgen-mediated regulation of a prostate-specific gene, thus providing further insight into the mechanism of PSA gene expression.

Cancer registration in the Middle East.

This project signals an advance in cancer registration in the Middle East region. While it is too early to declare a major breakthrough, significant strides have been made toward establishing a basis for reliable information on the cancer burden at a population level and future collaborative efforts in cancer epidemiologic research and prevention.