Molecular genetic analysis of 30 families with Joubert syndrome.

Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.

A prospective clinical utility and pharmacoeconomic study of the impact of the 21-gene Recurrence Score® assay in oestrogen receptor positive node negative breast cancer.

PURPOSE: The primary purpose of this study was to measure the impact of the 21-gene Recurrence Score® result on systemic treatment recommendations and to perform a prospective health economic analysis in stage I-II, node-negative, oestrogen receptor positive (ER+) breast cancer. METHODS: Consenting patients with ER+ node negative invasive breast cancer and their treating medial oncologists were asked to complete questionnaires about treatment preferences, level of confidence in those preferences and a decisional conflict scale (patients only) after a discussion of their diagnosis and risk without knowledge of the Recurrence Score. At a subsequent visit, the assay result and final treatment recommendations were discussed prior to both parties completing a second set of questionnaires. A Markov health state transition model was constructed, simulating the costs and outcomes experienced by a hypothetical 'assay naïve' population and an 'assay informed' population. RESULTS: One hundred and fifty-six patients across two cancer centres were enrolled. Of the 150 for whom successful assay results were obtained, physicians changed their chemotherapy recommendations in 45 cases (30%; 95% confidence interval (CI) 22.8-38.0%); either to add (10%; 95% CI 5.7-16.0%) or omit (20%; 95% CI 13.9-27.3%) adjuvant chemotherapy. There was an overall significant improvement in physician confidence post-assay (p<0.001). Patient decisional conflict also significantly decreased following the assay (p<0.001). The simulation model found an incremental cost-effectiveness ratio of Canadian Dollars (CAD) $6630/quality-adjusted life years (QALY). CONCLUSION: Within the context of a publicly funded health care system, the Recurrence Score assay significantly affects adjuvant treatment recommendations and is cost effective in ER+ node negative breast cancer.

Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease.

BACKGROUND: We report the effects of the administration of recombinant fibroblast growth factor-2 (rFGF-2) protein on myocardial perfusion using single photon emission computed tomography imaging in humans with advanced coronary disease. METHODS AND RESULTS: A total of 59 patients with coronary disease that was not amenable to mechanical revascularization underwent intracoronary (n=45) or intravenous (n=14) administration of rFGF-2 in ascending doses. Changes in perfusion were evaluated at baseline and again at 29, 57, and 180 days after rFGF-2 administration. In this uncontrolled study, perfusion scans were analyzed by 2 observers who were blinded to patient identity and test sequence; scans were displayed in random order, with scans from nonstudy patients randomly interspersed to enhance blinding. Combining all dose groups, a reduction occurred in the per-segment reversibility score (reflecting the magnitude of inducible ischemia) from 1.7+/-0.4 at baseline to 1.1+/-0.6 at day 29 (P:<0.001), 1.2+/-0.7 at day 57 (P:<0.001), and 1.1+/-0.7 at day 180 (P:<0.001). The 37 patients with evidence of resting hypoperfusion had evidence of improved resting perfusion: their per-segment rest perfusion score of 1.5+/-0. 5 at baseline decreased to 1.0+/-0.8 at day 29 (P:<0.001), 1.0+/-0.8 at day 57 (P:=0.003), and 1.1+/-0.9 at day 180 (P:=0.11). CONCLUSIONS: These preliminary data suggest that the administration of rFGF-2 to patients with advanced coronary disease resulted in an attenuation of stress-induced ischemia and an improvement in resting myocardial perfusion; these findings are consistent with a favorable effect of therapeutic angiogenesis.

Relationship of serum uric acid to cancer occurrence in a prospective male cohort.

Uric acid is a potent antioxidant and thus might protect against cancer. To test this hypothesis, we examined the relationship of serum uric acid to subsequent cancer incidence in a cohort of Japanese men in Hawaii. The study population consisted of 7889 men identified in the years 1965-1968 and followed by active hospital surveillance through November 1991. Cancer risk by serum uric acid level was analyzed using Cox proportional hazards regression with adjustment for age and, where indicated, smoking, alcohol use, and body mass index. No significant associations were seen for total cancer (1544 cases), or for cancers of the stomach (214), colon (272), rectum (105), lung (223), bladder (89), or hematopoietic system (77). For prostate cancer (293 cases), a positive association was found (relative risk for highest versus lowest quartile of serum uric acid = 1.5; 95% confidence interval 1.1-2.1; p for trend = 0.04). When the interval from examination to diagnosis was considered, this association was strongest for cases diagnosed in the first 10 years, was attenuated after 15 years, and disappeared completely after 20 years. The findings from this study do not support the hypothesis that uric acid protects against cancer occurrence.

Pharmacokinetics of recombinant human interferon-beta ser in healthy volunteers and its effect on serum neopterin.

The pharmacokinetics of and biologic response modification by recombinant human interferon-beta ser (rIFN-beta ser) were evaluated in 12 healthy male volunteers. Subjects received a single intravenous (iv) injection of 90 x 10(6) IU of rIFN-beta ser followed by a single or eight consecutive daily 90 x 10(6) IU subcutaneous (sc) doses. Blood samples collected after the iv, first sc, and last sc doses and prior to each sc dose were assayed for interferon antiviral activity and the interferon-inducible marker neopterin. Following iv administration, serum interferon concentrations generally declined biexponentially, with a mean serum clearance of 0.76 +/- 0.28 L/hr-kg, a mean steady-state volume of distribution of 2.88 +/- 1.81 L/kg, and a mean terminal half-life of 4.29 +/- 2.29 hr as determined by noncompartmental analysis. Following sc administration, absorption of rIFN-beta ser was prolonged, with serum concentrations generally below 100 IU/mL. No accumulation of rIFN-beta ser in serum was noted after eight daily sc injections. In contrast, serum neopterin levels did not increase above baseline levels until 12 hr after iv dosing and 24 hr after sc dosing. The mean increase in serum neopterin at 24 hr post iv injection was significantly greater than that at 24 hr post sc dosing.

Comparison of long-term dietary recall between cancer cases and noncases.

A quantitative history of current dietary intake based on 83 food items was administered by interview to a representative sample of 4,809 subjects in Hawaii in 1977-1979. In 1983-1987, this history was readministered to the 131 original respondents who had subsequently developed cancer, as well as 413 randomly selected subjects who remained cancer free. A surrogate was interviewed when the original subject was unavailable. The repeat interview elicited information about diet at the time of the original interview. The authors found that recall values for macronutrients were consistently higher than original levels for both cases and noncases, which may be due in part to a modification in the administration of the repeat questionnaire. Although there were no marked differences overall between cases and noncases in the ability to recall past diet, differences between the two groups were seen in certain subsets of the sample. In the subgroup with the longest recall interval (8-10 years), cases were not able to recall their diets as well as noncases. Also, the difference between original and recall values was larger for cases with colorectal cancer and all cases diagnosed with distant stage disease, compared with noncases. This was not true for cases of breast and prostate cancer and those with localized or regional disease. The following variables were found to have no significant effect on recall for cases or noncases: sex, age, education, and type of respondent (surrogate or subject). Of the five major ethnic groups included in the study, Japanese had the best recall of their past diets, while respondents reporting a diet change between the interviews had poorer recall than did those who reported no change. These results suggest that differential misclassification in dietary case-control studies may pose a significant problem in certain instances, but that these studies can yield meaningful results with certain constraints on the study population.

Prospective serial analysis of interleukin-2 and soluble interleukin-2 receptor in relapsing-remitting multiple sclerosis.

We performed a longitudinal analysis of serum interleukin-2 (IL-2) and soluble IL-2 (sIL-2R) concentrations in 60 patients with relapsing-remitting (R-R) multiple sclerosis (MS) as well as in 33 age- and sex-matched normal controls. Overall, we found that serum IL-2 levels remained low (less than 10 U/ml) and did not change appreciably over time; however, marked fluctuations in sIL-2R levels were observed in both the patient and control groups. Using patients as their own controls, we calculated an interrelapse (disease stable) mean sIL-2R concentration as a baseline for comparison with relapse values; sIL-2R levels greater than the 90th percentile of the Student's t distribution of stable values were defined as "peaks." There were a total of 27 sIL-2R peaks, eight (30%) of which correlated with clinical relapses but were potentially predictive of only 18% (8/45) of all the recorded clinical relapses. There was no difference in disease severity (Expanded Disability Status Scale) score between peak-correlated and noncorrelated relapses. Our data suggest that despite reports of elevated levels of IL-2 and sIL-2R in MS, neither may be a useful marker for predicting clinical disease activity in R-R MS.

Covariance adjustment of survival curves based on Cox's proportional hazards regression model.

Cox's proportional hazards regression model is a useful statistical tool for the analysis of 'survival data' from longitudinal studies. This multivariate method compares the 'survival experience' between two or more exposure groups while allowing for simultaneous adjustment of confounding due to one or more covariates. In addition to the summary regression statistics, further insight on the exposure--response relationship can be gained by visually examining the covariates-adjusted survival curves in the respective comparison groups. Covariates-adjusted survival curves are usually computed by the 'average covariate method'. This method is, however, subject to potential drawbacks. A method that avoids these drawbacks is to estimate adjusted survival curves by the corrected group prognostic curves approach. We have written a computer program to construct survival curves by the latter method. The program is coded in the Interactive Matrix Language of SAS.

Dietary factors in lung cancer prognosis.

A hypothesis-generating analysis of the role of diet on survival was conducted among a sample of 463 men and 212 women with histologically-confirmed lung cancer. Interview information was obtained from two population-based case-control studies of lung cancer conducted on the Island of Oahu, Hawaii, between 1979 and 1985. The interview consisted of a quantitative dietary history to assess the usual intake of foods 1 year prior to diagnosis, a complete tobacco history, and other demographic and lifestyle information. Records from the Hawaii Tumor Registry were reviewed for data on stage, histology, and follow-up status of these patients. A food group analysis showed a significant reduction in the risk of death with increasing consumption of all vegetables combined among women (P for trend = 0.03), but not among men. The covariate-adjusted median survival times for women from the highest to the lowest quartiles of vegetable intake were 33, 21, 15, and 18 months, respectively. The results also suggested an association of fruit intake and survival among women (P for trend = 0.02), although a similar effect was not found among men. Increased consumption of certain foods, such as tomatoes and oranges among men, and broccoli and, perhaps, tomatoes among women, appeared to improve survival. This exploratory analysis provides mixed indications that certain components of vegetables and fruits may prolong survival in lung cancer patients.

Dietary factors in cancer of the lower urinary tract.

This dietary study was based on 195 male and 66 female cases of lower urinary tract cancer, identified in Hawaii between 1977 and 1986. Each case was matched for sex, age, and ethnic group (Caucasian or Japanese) to 2 population-based controls. There was a decrease in risk with increasing levels of consumption of vitamin C in women (p = 0.03) and dark green vegetables in men (p = 0.02). When examined by quartile, the odds ratios for the highest quartile of intake compared to the lowest quartile were 0.4 for women and 0.6 for men, respectively. Although dark green vegetables are a source of carotenoids, the intake of total carotenoids, retinol and total vitamin A was weakly and inconsistently related to risk in both sexes. Among women only, there was also an inverse association with the consumption of regular ground coffee (p = 0.02) but not with other types of coffee. Finally, there were no statistically significant or consistent differences between cases and controls in the intake of artificial sweeteners and tea.

Validation of a quantitative diet history method in Hawaii.

The validity of a quantitative diet history method was evaluated among 262 men and women from the five major ethnic groups of Hawaii (Japanese, Caucasian, Chinese, Filipino, and Hawaiian) in 1984-1987. The reference data included four 1-week food records obtained at approximately 3-month intervals. The diet history was administered 6 months after the fourth week of food records and included 47 foods that were major sources of protein, fat, cholesterol, vitamins A and C, and beta-carotene. Photographs showing three portion sizes were utilized for quantifying intakes in the food records and the diet history. Generally, among all ethnic-sex groups, intakes from the diet history were greater than those from the record sets, particularly for the vitamins. Agreement was measured by the intraclass correlation coefficient (rl) and the weighted kappa statistic (kappa w), and consistency was measured by Spearman's rank correlation (rho). For the total group, the rl's ranged from 0.48 for vitamin A to 0.61 for cholesterol. The kappa w's were generally lower than the rl's, whereas the rho's were higher, ranging from 0.52 for vitamin C to 0.64 for cholesterol. Agreement among the ethnic-sex groups varied, with the Chinese females and the Japanese males having the higher rl's, and the Hawaiian males and females having the lowest values. The results provide evidence that the quantitative diet history gives reasonably accurate estimates of the usual dietary intakes among the major ethnic groups of Hawaii.

Lifetime occupational physical activity and prostate cancer risk.

The authors compared the lifetime occupational physical activity of 452 prostate cancer cases identified through the population-based Hawaii Tumor Registry and 899 population controls interviewed from 1981 to 1983. Each job reported was classified into one of five levels of physical activity using published sources. Among men aged 70 years or older, a negative association was found between prostate cancer risk and proportion of life spent in jobs involving only sedentary or light work. Compared with men never employed in such jobs, men who spent more than 54% of their life in these jobs had an odds ratio of 0.5 (95% confidence interval 0.3-0.9). This negative association was dose-dependent, consistent across ethnic groups, and unrelated to socioeconomic status, dietary risk factors, or job-related chemical exposures. The findings for younger men were less clear, but not inconsistent with those for older men. Surprisingly, no association was found with years spent in moderately active or very active jobs in either age group. Although inconclusive, these results suggest that physical activity may be positively associated with the risk of prostate cancer, but this association is likely to be weak and indirect.

Prospective study of alcohol intake and large bowel cancer.

The alcohol intake of a cohort of Japanese men in Hawaii is directly and significantly related to the risk of developing rectal cancer, whether assessed on the basis of amount consumed or as a percent of total calories. Wine and whiskey are directly related to rectal cancer, but beer is the only alcoholic beverage that displays a statistically significant dose-response (P = 0.008). Colon cancer risk also is related directly to alcohol intake, but the association is statistically significant only when measured as a percent of energy intake. This suggests that alcohol might displace cancer inhibitors from the diet. Calcium, vitamin C, and dietary fiber are inversely related to colon cancer risk in this cohort, and each of these micronutrients displays statistically significant negative correlation with alcohol intake. A possible positive association between alcohol and lung cancer was ruled out after adjusting for cigarette smoking. Cancers of the prostate and stomach were unrelated to alcohol intake, but the risk of acquiring cancer at all other sites combined was strongly related to alcohol intake.

Smoking history and survival among lung cancer patients.

Two population-based case-control studies of lung cancer were conducted on the Island of Oahu, Hawaii, between 1979 and 1985. Interview information concerning smoking habits and other characteristics was obtained from a total of 463 men and 212 women with histologically confirmed lung cancer. Records from the Hawaii Tumor Registry were reviewed for information on the stage, histology, and follow-up status of these patients. Cigarette smoking was found to be positively related to the age-adjusted risk of death among women (relative risk (RR) = 1.6; 95 percent confidence interval (CI) = 1.0-2.4), but not among men (RR = 0.8; 95 percent CI = 0.5-1.2). Among women, the age-adjusted median survival time for never smokers was 33 months (n = 53) compared with a median survival of 18 months (n = 159) for smokers. Both past and current female smokers were at greater risk of death than never-smokers, and there was a significant trend in the risk of death by the number of cigarettes smoked per day (P = 0.04), and the age at which the subjects started smoking (P = 0.01). The effects of tumor stage and histology upon the association between tobacco smoking and survival were also explored.

Urothelial cancer in white and Japanese patients in Hawaii: pathology.

The sites, growth patterns, histological grades and degrees of invasion of urothelial tumors were assessed among white and Japanese patients in Hawaii. Tissues were available from 225 white and 164 Japanese patients, representing virtually all of the urothelial tumors from these races entered into the Hawaii Tumor Registry for Oahu island between 1977 and 1986. No statistically significant interracial differences emerged from the analysis. Grade 1 papillary tumors were the most numerous types encountered, consisting of 43% of the urothelial tumors in men of both races, and 37.5% in white and 31% in Japanese women. Recently, observed increasing incidence trends of urothelial tumors among white men in the United States are associated with a synchronous decrease in mortality trends. Our analysis indicates that these diverging trends cannot be accounted for by increased numbers of noninvasive papillary tumors.

Reproducibility of a diet history in older men in Hawaii.

A diet history method was tested for reproducibility among 106 older men from the five major ethnic groups (Japanese, Caucasian, Hawaiian, Filipino, and Chinese) of Hawaii. The questionnaire, administered by trained interviewers, was designed to estimate the dietary intakes of total and saturated fat, cholesterol, vitamin A, beta-carotene, vitamin C, and zinc. Subjects were asked to recall their usual frequencies and amounts of consumption during a usual month of more than 100 food items, along with the intake of seasonal foods with a high vitamin A content. A second interview was conducted 1-14 months later to obtain a diet history covering the same time period as the first interview. The same questionnaire was utilized in both interviews. The effects of ethnicity, age, and recall interval (period between the diet reference date and initial interview) on the reproducibility of nutrient intakes were examined. The intraclass correlation coefficient (rI) and the weighted kappa statistic (Kw) were used to assess agreement. The overall levels of reproducibility were relatively good. Neither ethnicity, age, nor length of recall period had a major effect on reproducibility. The data suggested that this diet history method is an appropriate instrument for estimating the usual dietary intakes of a healthy heterogeneous group of older men in Hawaii.

Smoking, alcohol, occupation, and hair dye use in cancer of the lower urinary tract.

This case-control study was based on 137 Caucasian and 124 Japanese cases of urinary tract cancer identified in Hawaii between 1977 and 1986. Each case was matched on sex, age, and race to two population-based controls. Heavy cigarette smokers (41 or more pack-years for men; 21 or more pack-years for women) had a significantly elevated risk compared with nonsmokers (odds ratio (OR) = 6.2, 95% confidence interval (CI) 3.4-11.1 for the men; OR = 2.8, 95% CI 1.2-6.3 for the women). When the men and women were combined, employment in high-risk industries (includes machinery, automotive, and textiles, among others) was significantly associated with cancer risk (OR = 1.6, 95% CI 1.1-2.3). Alcohol intake and hair dye use showed weaker positive associations with risk that were not statistically significant.

Ethnic patterns of childhood cancer in Hawaii between 1960 and 1984.

Cases of childhood cancer (less than 15 years of age at diagnosis), diagnosed between 1960 and 1984, were obtained from the Hawaii Tumor Registry, a population-based Surveillance, Epidemiology, and End Results (SEER) participant covering the entire State of Hawaii. During the 25 years of data collection, cancer was diagnosed in 398 males and 302 females, with overall age-adjusted incidence rates of 140.5 and 112.2 per million, respectively. Leukemia was the leading cause of childhood cancer, accounting for over 1/3 of diagnoses during the study period. Standardized incidence ratios (SIR) were calculated for each ethnic-sex group separately based on US white age-specific incidence rates for 1973 to 1982 from the SEER program. Overall, incidence rates for childhood cancer in Hawaii were generally similar to those found in all SEER areas.