Barriers to Clinical Trial Participation: Comparative Study Between Rural and Urban Participants.

BACKGROUND: The National Clinical Trials Network program conducts phase 2 or phase 3 treatment trials across all National Cancer Institute's designated cancer centers. Participant accrual across these clinical trials is a critical factor in deciding their success. Cancer centers that cater to rural populations, such as The University of Kansas Cancer Center, have an additional responsibility to ensure rural residents have access and are well represented across these studies. OBJECTIVE: There are scant data available regarding the factors that act as barriers to the accrual of rural residents in these clinical trials. This study aims to use electronic screening logs that were used to gather patient data at several participating sites in The Kansas University of Cancer Center's Catchment area. METHODS: Screening log data were used to assess what clinical trial participation barriers are faced by these patients. Additionally, the differences in clinical trial participation barriers were compared between rural and urban participating sites. RESULTS: Analysis revealed that the hospital location rural urban category, defined as whether the hospital was in an urban or rural setting, had a medium effect on enrolment of patients in breast cancer and lung cancer trials (Cohen d=0.7). Additionally, the hospital location category had a medium effect on the proportion of recurrent lung cancer cases at the time of screening (d=0.6). CONCLUSIONS: In consideration of the financially hostile nature of cancer treatment as well as geographical and transportation barriers, clinical trials extended to rural communities are uniquely positioned to alleviate the burden of nonmedical costs in trial participation. However, these options can be far less feasible for patients in rural settings. Since the number of patients with cancer who are eligible for a clinical trial is already limited by the stringent eligibility criteria required of such a complex disease, improving accessibility for rural patients should be a greater focus in health policy.

Homozygous Germline APC p.I1307K Variants: A Case Series.

Approximately 10% of all colorectal cancer is estimated to be due to an inherited predisposition. Identification of a germline pathogenic variant can aid in treatment, screening, and surveillance and help stratify familial cancer risks based on gene-specific cancer associations. The APC gene contributes to a small percentage of hereditary colon cancer, with most pathogenic APC variants causing familial adenomatous polyposis syndrome. However, one specific variant in APC called p.I1307K, found in approximately 10% of Ashkenazi Jewish individuals, is associated with a moderate risk for colon cancer, but not polyposis. Heterozygous carriers of one p.I1307K variant are well documented in the literature, and guidelines recommend earlier and more frequent colonoscopies. Conversely, reports of homozygous carriers of 2 p.I1307K variants are limited, and guidelines for medical management are lacking. This case series describes 4 homozygous p.I1307K patients of Ashkenazi Jewish ancestry identified in cancer genetics clinics. Case 1 is a 73-year-old pancreatic cancer patient with a family history of melanoma and colon cancer. Case 2 is a 62-year-old patient with a personal history of 4 adenomatous colorectal polyps and a family history of breast, pancreatic, colon, and prostate cancers. Case 3 is a 52-year-old patient with a personal history of early-onset breast cancer and uveal melanoma and a family history of breast, prostate, and stomach cancers. Case 4 is a 70-year-old patient with a personal history of gallbladder adenocarcinoma and a family history of breast cancer. These cases exhibit wide phenotypic variability and contribute to the limited reports of homozygous p.I1307K variant carriers.

High prevalence of array comparative genomic hybridization abnormalities in adults with unexplained intellectual disability.

PURPOSE: Array comparative genomic hybridization is now a widely used clinical tool for the evaluation of intellectual disability. The current 10% yield of positive findings is based largely on pediatric data. Adults with unexplained intellectual disability have not been systematically studied with array comparative genomic hybridization. Here, we report our initial experience with array comparative genomic hybridization testing on 45 adults with unexplained intellectual disability referred to an adult genetics clinic. METHODS: Beginning in 2006, we applied clinically available array comparative genomic hybridization testing to adults referred with an intellectual disability phenotype. The initial platform used was an early generation targeted or constitutional array, which was replaced by our current platform using more than 5000 bacterial artificial chromosome clones with an average resolution of 500 Kb and targeting 114 disease loci. All patients also underwent high-resolution karyotype analysis and molecular testing for Fragile X syndrome. RESULTS: Our population comprised 45 patients with unexplained intellectual disability (18 men and 27 women) with an average age of 35.1 years. Most patients had not been evaluated by genetics clinics since childhood or had never undergone a genetic evaluation; only two had documentation of prior normal karyotype studies. Three subjects had abnormal high-resolution chromosome studies, which were also confirmed by array comparative genomic hybridization. Seven of the remaining 42 patients (17%) had novel genomic losses identified only by array comparative genomic hybridization. CONCLUSION: Abnormal genomic losses detected by array comparative genomic hybridization are prevalent in adults with unexplained intellectual disability. Our data showing abnormalities in 22% and 17% of overall patients and of cases with normal karyotypes, respectively, suggest that the yield of array comparative genomic hybridization in adults with unexplained intellectual disability may be higher than in pediatric populations.

Male with mosaicism for supernumerary ring X chromosome: analysis of phenotype and characterization of genotype using array comparative genome hybridization.

Supernumerary, derivative, and ring X chromosomes are relatively common in Turner syndrome females but have been reported rarely in males. To date, less than 10 cases have been published, of which only 2 have been partially characterized in defining the breakpoints and genetic content of the derivative X chromosome. We describe a male with mosaicism for a supernumerary X chromosome (46,XY/47,XY, r(X)) who has multiple congenital anomalies, including features of craniofrontonasal dysplasia (Mendelian Inheritance in Man 304110) and the presence of ectopic female reproductive organs. Using comparative genomic hybridization array mapping, we determined that the derivative X is composed of a 24-Mb fragment that contains the regions Xp11.3 through Xq13.1 and lacks the XIST gene. This is the first report to describe a detailed molecular characterization of a ring X chromosome in a male by comparative genomic hybridization array analysis. We compare the clinical and molecular findings in this patient to other 46,XY, r(X) patients reported in the literature and discuss the potential role of disomy for known genes contained on the ring X chromosome.

Increased calcium supplementation is associated with morbidity and mortality in the infant postoperative cardiac patient.

OBJECTIVE: The purpose of this study was to assess the association of calcium replacement therapy with morbidity and mortality in infants after cardiac surgery involving cardiopulmonary bypass. DESIGN: Retrospective chart review. SETTING: The cardiac intensive care unit at a tertiary care children's hospital. PATIENTS: Infants undergoing cardiac surgery involving cardiopulmonary bypass between October 2002 and August 2004. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Total calcium replacement (mg/kg calcium chloride given) for the first 72 postoperative hours was measured. Morbidity and mortality data were collected. The total volume of blood products given during the first 72 hrs was recorded. Infants with confirmed chromosomal deletions at the 22q11 locus were noted. Correlation and logistic regression analyses were used to generate odds ratios and 95% confidence intervals, with p < .05 being significant. One hundred seventy-one infants met inclusion criteria. Age was 4 +/- 3 months and weight was 4.9 +/- 1.7 kg at surgery. Six infants had deletions of chromosome 22q11. Infants who weighed less required more calcium replacement (r = -.28, p < .001). Greater calcium replacement correlated with a longer intensive care unit length of stay (r = .27, p < .001) and a longer total hospital length of stay (r = .23, p = .002). Greater calcium replacement was significantly associated with morbidity (liver dysfunction [odds ratio, 3.9; confidence interval, 2.1-7.3; p < .001], central nervous system complication [odds ratio, 1.8; confidence interval, 1.1-3.0; p = .02], infection [odds ratio, 1.5; confidence interval, 1.0-2.2; p < .04], extracorporeal membrane oxygenation [odds ratio, 5.0; confidence interval, 2.3-10.6; p < .001]) and mortality (odds ratio, 5.8; confidence interval, 5.8-5.9; p < .001). Greater calcium replacement was not associated with renal insufficiency (odds ratio, 1.5; confidence interval, 0.9-2.3; p = .07). Infants with >1 sd above the mean of total calcium replacement received on average fewer blood products than the total study population. CONCLUSIONS: Greater calcium replacement is associated with increasing morbidity and mortality. Further investigation of the etiology and therapy of hypocalcemia in this population is warranted.

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

PURPOSE: The aim of the study was to determine the actual GJB2 and GJB6 mutation frequencies in North America after several years of generalized testing for autosomal recessive nonsyndromic sensorineural hearing loss to help guide diagnostic testing algorithms, especially in light of molecular diagnostic follow-up to universal newborn hearing screening. METHODS: Mutation types, frequencies, ethnic distributions, and genotype-phenotype correlations for GJB2 and GJB6 were assessed in a very large North American cohort. RESULTS: GJB2 variants were identified in 1796 (24.3%) of the 7401 individuals examined, with 399 (5.4%) homozygous and 429 (5.8%) compound heterozygous. GJB6 deletion testing was performed in 12.0% (888/7401) of all cases. The >300-kb deletion was identified in only nine individuals (1.0%), all of whom were compound heterozygous for mutations in GJB2 and GJB6. Among a total of 139 GJB2 variants identified, 53 (38.1%) were previously unreported, presumably representing novel pathogenic or benign variants. CONCLUSIONS: The frequency and distribution of sequence changes in GJB2 and GJB6 in North America differ from those previously reported, suggesting a considerable role for loci other than GJB2 and GJB6 in the etiology of autosomal recessive nonsyndromic sensorineural hearing loss, with minimal prevalence of the GJB6 deletion.