Chronic Sacral Nerve Stimulation as a Novel Treatment for Stress Urinary Incontinence-A Rat Model
NEUROUROLOGY AND URODYNAMICS
2015; 34 (3): 270-273
We propose an animal model to evaluate the effect of chronic sacral nerve stimulation (SNS) on surgically induced intrinsic sphincter deficiency (ISD) secondary to transabdominal urethrolysis (U-Lys).Twenty-five 6-week old virgin female Sprague-Dawley rats were divided into four groups: control (CTRL), U-Lys only, SNS only, and both (U-Lys/SNS). Groups CTRL (N = 5) and U-Lys only (N = 5) were maintained in the animal research facility in standard fashion for 2 weeks. Groups SNS only (N = 5) and U-Lys/SNS (N = 10) underwent chronic SNS for 6 continuous hours daily for 2 weeks. Retrograde leak point pressure (RLPP) was measured at baseline and at 2 weeks following observation or treatment. Five consecutive RLPP measurements were averaged per measurement cycle. SAS 9.3 was used to evaluate means and standard deviation.Baseline mean RLPP was 65 mmHg. The U-Lys only group mean RLPP at initial urethrolysis (58 mmHg) decreased (31 mmHg, P < 0.0001) after 2 weeks of observation. In the SNS only group, mean RLPP significantly increased from baseline (73 mmHg) after 2 weeks of chronic SNS stimulation (80 mmHg, P < 0.01). In rats that underwent both U-Lys and SNS stimulation mean RLPP was initially low (46 mmHg) after U-Lys and then significantly increased after 2 weeks of SNS (65 mmHg, P < 0.0001).Chronic SNS mediates an improvement in urethral sphincteric function at stimulation parameters similar to those used in humans for treating voiding dysfunction. SNS increased urethral resistance in rats with and without surgically induced ISD. Neurourol. Urodynam. 2014 © 2013 Wiley Periodicals, Inc.
View details for DOI 10.1002/nau.22550
View details for Web of Science ID 000352152900012
In-Hospital Arrhythmia Development and Outcomes in Pediatric Patients With Acute Myocarditis
AMERICAN JOURNAL OF CARDIOLOGY
2014; 113 (3): 535-540
Cardiac arrhythmias are a complication of myocarditis. There are no large studies of in-hospital arrhythmia development and outcomes in pediatric patients with acute myocarditis. This was a retrospective 2-center review of patients ≤21 years hospitalized with acute myocarditis from 1996 to 2012. Fulminant myocarditis was defined as the need for inotropic support within 24 hours of presentation. Acute arrhythmias occurred at presentation and subacute after admission. Eighty-five patients (59% men) presented at a median age of 10 years (1 day to 18 years). Arrhythmias occurred in 38 patients (45%): 16 acute, 12 subacute, and 9 acute and subacute (1 onset unknown). Arrhythmias were associated with low voltages on the electrocardiogram (14 of 34, 41% vs 6 of 47, 13%; odds ratio [OR] 4.78, 95% confidence interval [CI] 1.60 to 14.31) and worse outcome (mechanical support, orthotopic heart transplant, or death; OR 7.59, 95% CI 2.61 to 22.07) but were not statistically significantly associated with a fulminant course, ST changes, initial myocardial function, lactate, creatinine level, C-reactive protein and/or erythrocyte sedimentation rate, or troponin I level, after adjusting for multiple comparisons. Subacute arrhythmias were associated with preceding ST changes (10 of 15, 67% vs 15 of 59, 25%, OR 5.87, 95% CI 1.73 to 19.93). All patients surviving to discharge had arrhythmia resolution or control before discharge (10 on antiarrhythmic), with 1 exception (patient with complete heart block requiring a pacemaker). At 1-year follow-up, there were 3 recurrences of ventricular arrhythmias, but no arrhythmia-related mortality. In conclusion, arrhythmias are common in pediatric patients with myocarditis, occurring in nearly 1/2 of all hospitalized children and are associated with a worse outcome. Early identification of subacute arrhythmias using electrocardiographic changes may help management. A majority of patients do not require continued postdischarge arrhythmia treatment.
View details for DOI 10.1016/j.amjcard.2013.10.021
View details for Web of Science ID 000331161700022
Cochlea Radiation Dose Correlates with Hearing Loss After Stereotactic Radiosurgery of Vestibular Schwannoma
2013; 80 (3-4): 359-363
OBJECTIVE: For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. METHODS: Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwanoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. RESULTS: GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4-8.9) and to last MRI was 3.6 years (range 0.5-9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm(3) of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6-10.1 Gy3) significantly increased the odds of hearing loss by approximately 5%. CONCLUSIONS: Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma.
View details for DOI 10.1016/j.wneu.2012.04.001
View details for Web of Science ID 000326653900061
Markedly improved overall survival in 10 consecutive patients with metastatic basal cell carcinoma.
British journal of dermatology
2013; 169 (3): 673-676
BACKGROUND: Metastatic basal cell carcinoma (BCC) is a rare but life-threatening condition. Prior estimates of overall survival (OS) from time of diagnosis of distant metastasis to death are approximately 8-14 months. However, these estimates are based on analyses of case reports published prior to 1984. OBJECTIVES: To assess a more updated OS in metastatic BCC patients at a single academic institution. METHODS: Using patients from 1997 to 2011, a retrospective chart review was performed on biopsy-confirmed cases of distant metastatic BCC at Stanford University School of Medicine. Kaplan-Meier analysis was used to determine OS and progression free survival (PFS). RESULTS: Ten consecutive cases of distant metastatic BCC were identified. Median OS was 7.3 (95% confidence interval, CI; 1.6, ∞) years; median PFS was 3.4 (95% CI; 1.1, 5.2) years. CONCLUSION: Our findings suggest that OS in patients with distant metastaticBCC may be more favorable than previously reported.
View details for DOI 10.1111/bjd.12333
View details for PubMedID 23521172
FOCUSED CARDIAC ULTRASOUND TRAINING: HOW MUCH IS ENOUGH?
JOURNAL OF EMERGENCY MEDICINE
2013; 44 (4): 818-822
Focused transthoracic echocardiography (F-TTE) is an important tool to assess hemodynamically unstable patients in the Emergency Department. Although its scope has been defined by the American College of Emergency Physicians, more research is needed to define an optimal F-TTE training program, including assessment of proficiency.The goal of this study was to determine the effectiveness of current standards in post-residency training to reach proficiency in F-TTE.Fourteen staff Emergency Physicians were enrolled in a standardized teaching curriculum specifically designed to meet the 2008 American College of Emergency Physicians' guidelines for general ultrasound training applied to echocardiography. This training program consisted of 6 h of didactics and 6 h of scanning training, followed by independent scanning over a 5-month period. Acquisition of echocardiographic knowledge was assessed by an online pre- and post-test. At the conclusion of the study, a hands-on skills test assessed the trainees' ability to perform and interpret F-TTE.Ninety percent of trainees passed the written post-test. Two views, the parasternal long and short axis, were easily obtainable, regardless of the level of training or the number of ultrasounds completed. Other views were more difficult to master, but strong trends toward increased competency were evident after 10 h of mixed didactic and scanning training and > 45 ultrasounds.A short, 12-h didactic training in F-TTE provided proficiency in image interpretation and in obtaining adequate images from the parasternal window. More extensive training is needed to master the apical and subcostal windows in a timely manner.
View details for DOI 10.1016/j.jemermed.2012.07.092
View details for Web of Science ID 000317282000024
Risk of Therapy-Related Secondary Leukemia in Hodgkin Lymphoma: The Stanford University Experience Over Three Generations of Clinical Trials
JOURNAL OF CLINICAL ONCOLOGY
2013; 31 (5): 592-598
To assess therapy-related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) risk in patients treated for Hodgkin lymphoma (HL) on successive generations of Stanford clinical trials.Patients with HL treated at Stanford with at least 5 years of follow-up after completing therapy were identified from our database. Records were reviewed for outcome and development of t-AML/MDS.Seven hundred fifty-four patients treated from 1974 to 2003 were identified. Therapy varied across studies. Radiotherapy evolved from extended fields (S and C studies) to involved fields (G studies). Primary chemotherapy was mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or procarbazine, mechlorethamine, and vinblastine (PAVe) in S studies; MOPP, PAVe, vinblastine, bleomycin, and methotrexate (VBM), or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in C studies; and VbM (reduced dose of bleomycin compared with VBM) or mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) in G studies. Cumulative exposure to alkylating agent (AA) was notably lower in the G studies compared with the S and C studies, with a 75% to 83% lower dose of nitrogen mustard in addition to omission of procarbazine and melphalan. Twenty-four (3.2%) of 754 patients developed t-AML/MDS, 15 after primary chemotherapy and nine after salvage chemotherapy for relapsed HL. The incidence of t-AML/MDS was significantly lower in the G studies (0.3%) compared with the S (5.7%) or C (5.2%) studies (P < .001). Additionally, in the G studies, no t-AML/MDS was noted after primary therapy, and the only patient who developed t-AML/MDS did so after second-line therapy.Our data demonstrate the relationship between the cumulative AA dose and t-AML/MDS. Limiting the dose of AA and decreased need for secondary treatments have significantly reduced the incidence of t-AML/MDS, which was extremely rare in the G studies (Stanford V era).
View details for DOI 10.1200/JCO.2012.44.5791
View details for Web of Science ID 000314820400017
View details for PubMedID 23295809
Test-Retest Reliability of Thermal Temporal Summation Using an Individualized Protocol
JOURNAL OF PAIN
2013; 14 (1): 79-88
Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. It is a behavioral correlate of wind-up, the spinal facilitation of recurring C-fiber stimulation. In order to utilize TS in clinical pain research, it is important to characterize TS in a wide range of individuals and to establish its test-retest reliability. Building on a fixed-parameter protocol, we developed an individually adjusted protocol to broadly capture thermally generated TS. We then examined the test-retest reliability of TS within-day (intertrial intervals ranging from 2 to 30 minutes) and between-days (intersession interval of 7 days). We generated TS-like effects in 19 of the 21 participants. Strong correlations were observed across all trials over both days (intraclass correlation [ICC] [A, 10] = .97, 95% confidence level [CL] = .94-.99) and across the initial trials between days (ICC [A, 1] = .83, 95% CL = .58-.93). Repeated measures mixed-effects modeling demonstrated no significant within-day variation and only a small (5 out of 100 points) between-day variation. Finally, a Bland-Altman analysis suggested that TS is reliable across the range of observed scores. Without intervention, thermally-generated TS is generally stable within day and between days.Our study introduces a new strategy to generate thermal TS in a high proportion of individuals. This study confirms the test-retest reliability of thermal TS, supporting its use as a consistent behavioral correlate of central nociceptive facilitation.
View details for DOI 10.1016/j.jpain.2012.10.010
View details for Web of Science ID 000314081100009
View details for PubMedID 23273835
Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers
JOURNAL OF MEDICAL VIROLOGY
2012; 84 (12): 1967-1974
Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG ? 1:320, EBV viral capsid antigen (VCA) IgG ? 1:640, and EBV early antigen (EA) IgG ? 1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response.
View details for DOI 10.1002/jmv.23411
View details for Web of Science ID 000310339300020
View details for PubMedID 23080504
A feasibility study to evaluate breast cancer patients' knowledge of their diagnosis and treatment
PATIENT EDUCATION AND COUNSELING
2012; 89 (2): 321-329
To evaluate the feasibility of an electronic survey to assess patients' knowledge of their breast cancer and treatment, and interest in receiving a medical summary.Women undergoing breast cancer treatment completed an interviewer-administered electronic survey in person or by telephone. Medical records were abstracted to evaluate knowledge accuracy.Among 38 eligible patients approached for the study, 35 (92%) participated and 33 (94%) completed the survey. Participants' perceived knowledge tended to be greater than their actual knowledge. Reporting of clinicopathologic features was most accurate for stage (91%) and lymph node status (88%), and least accurate for tumor size (61%), type (61%), and grade (33%). Accurate reporting of tumor receptor over-expression varied from 76% (estrogen receptor) to 39% (progesterone receptor). Many patients correctly recalled general treatment modalities and details of surgery; fewer recalled details of radiation and chemotherapy. Importantly, nearly all (32/33) were interested in receiving a breast cancer medical summary.An electronic survey is feasible to assess breast cancer patients' knowledge. This data suggest that patients have gaps in knowledge and would like a personalized medical summary.Larger studies are needed to validate and characterize knowledge gaps, and test interventions to improve physician-patient information sharing.
View details for DOI 10.1016/j.pec.2012.08.015
View details for Web of Science ID 000311766700016
View details for PubMedID 23031612
Early Outcomes After Extracardiac Conduit Fontan Operation Without Cardiopulmonary Bypass
2012; 33 (7): 1078-1085
Cardiopulmonary bypass is associated with a systemic inflammatory response. The authors hypothesized that avoiding cardiopulmonary bypass would lead to improved postoperative outcomes for patients undergoing the extracardiac Fontan operation, the final stage in surgical palliation of univentricular congenital heart defects. A review of the Children's Heart Center Database showed a total of 73 patients who underwent an initial Fontan operation at Lucile Packard Children's Hospital at Stanford between 1 November 2001 and 1 November 2006. These patients were divided into two groups: those who underwent cardiopulmonary bypass (n = 26) and those who avoided cardiopulmonary bypass (n = 47). Preoperative demographics, hemodynamics, and early postoperative outcomes were analyzed. The two groups had comparable preoperative demographic characteristics and hemodynamics except that the average weight of the off-bypass group was greater (17.9 ± 9.1 vs 14.2 ± 2.7 kg; P = 0.01). Intraoperatively, the off-bypass group trended toward a lower rate of Fontan fenestration (4.3 vs 19.2%; P = 0.09), had lower common atrial pressures (4.6 ± 1.4 vs 5.5 ± 1.5 mmHg; P = 0.05), and Fontan pressures (11.9 ± 2.1 vs 14.2 ± 2.4 mmHg; P ? 0.01), and required less blood product (59.1 ± 37.6 vs 91.9 ± 49.4 ml/kg; P ? 0.01). Postoperatively, there were no significant differences in hemodynamic parameters, postoperative colloid requirements, duration of mechanical ventilation, volume or duration of pleural drainage, or duration of cardiovascular intensive care unit or hospital stay. Avoiding cardiopulmonary bypass influenced intraoperative hemodynamics and the incidence of fenestration but did not have a significant impact on the early postoperative outcomes of children undergoing the Fontan procedure.
View details for DOI 10.1007/s00246-012-0228-5
View details for Web of Science ID 000308828200011
View details for PubMedID 22349678
Variations in Normal Serum Alpha-Fetoprotein (AFP) Levels in Patients with Testicular Cancer on Surveillance
2012; 35 (10): 588-591
The aim of this study was to assess fluctuations in normal serum alpha-fetoprotein (AFP) levels in patients with germ cell cancer. Marked variations occur after serum AFP levels normalize, creating anxiety among patients and physicians during surveillance.We conducted a retrospective review of patients with germ cell tumors in clinical remission, who had normal AFP levels and were followed at our center from 1991 to 2009. 72 patients, with a median follow-up of 50 months, were identified.Of the 72 patients, 57 (79%) had a non-seminomatous germ cell histology, and 15 (21%) had seminomas. Seminomas were included as controls as serum AFP levels do not increase in this group. 68 patients underwent orchiectomy, and 50 patients received systemic chemotherapy. The majority of patients (93%) demonstrated fluctuations in serum AFP. There was no difference in the mean AFP values between patients with seminona (2.95 ng/ml) and those with non-seminomatous germ cell tumors (3.3 ng/ml) (standard deviation 1.01 ng/ml).Marked variations occur after serum AFP levels normalize in patients undergoing surveillance. Fluctuating AFP levels within normal limits did not result in relapse in our cohort of patients with extended follow-up.
View details for DOI 10.1159/000342695
View details for Web of Science ID 000309666500007
View details for PubMedID 23038230
Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors
2012; 131 (7): 1115-1122
Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ? 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ? 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.
View details for DOI 10.1007/s00439-011-1126-2
View details for Web of Science ID 000305195400010
View details for PubMedID 22203219
BRAF-mutated, Microsatellite-stable Adenocarcinoma of the Proximal Colon: An Aggressive Adenocarcinoma With Poor Survival, Mucinous Differentiation, and Adverse Morphologic Features
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
2012; 36 (5): 744-752
The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.
View details for DOI 10.1097/PAS.0b013e31824430d7
View details for Web of Science ID 000302814000013
View details for PubMedID 22314188
HER2 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma in a US Population: Clinicopathologic Analysis With Proposed Approach to HER2 Assessment
APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY
2012; 20 (1): 13-24
Recent evidence suggests that trastuzumab, a monoclonal antibody which targets HER2, in combination with chemotherapy is a therapeutic option in patients with HER2-positive gastric or gastroesophageal junction cancer. Widely accepted guidelines for HER2 testing in gastric and gastroesophageal junction cancer have not been established. The purpose of this study was to analyze the incidence and patterns of HER2 expression in gastric and gastroesophageal junction cancer using a tissue microarray approach, which closely simulates small biopsies routinely tested for HER2. One hundred sixty-nine patients, including 99 primary gastric adenocarcinomas and 70 primary gastroesophageal junction carcinomas were analyzed for HER2 overexpression by immunohistochemistry and HER2 gene amplification by fluorescence in situ hybridization using scoring schemes proposed by both American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) and the results of the recently published Trastuzumab for Gastric Cancer (ToGA) trial. In our analysis, 19 adenocarcinomas were HER2 positive, defined as either a HER2/CEP17 ratio >2.2 and/or a 3+ HER2 immunohistochemistry score with either the ASCO/CAP or ToGA scoring schemes. Of the 19 HER2-positive adenocarcinomas, 8 (42%) exhibited a characteristic strongly intense basolateral membranous staining pattern which would be interpreted as negative (1+) using the accepted ASCO/CAP scoring scheme for HER2 assessment in breast carcinoma, but were correctly labeled as 3+ positive using the proposed ToGA scoring scheme. Of the 19 HER2-positive adenocarcinomas, 8 (42%) demonstrated heterogeneous HER2 protein expression by immunohistochemistry. Twelve of 99 (12%) gastric carcinomas were positive for HER2. Of these, HER2 was more often identified in intestinal-type adenocarcinomas (10 of 52, 19%) compared with diffuse (2 of 34, 6%) adenocarcinoma. Seven of 70 (10%) gastroesophageal junction carcinomas were positive for HER2 of which all were intestinal type (7 of 58, 12%). HER2 status or primary tumor site did not correlate with patient survival. Gastric and gastroesophageal junction adenocarcinomas typically display a characteristic basolateral membranous pattern of HER2 expression which is often heterogeneous rendering routine evaluation of HER2 status on small tissue samples challenging.
View details for DOI 10.1097/PAI.0b013e31821c821c
View details for Web of Science ID 000298846500003
View details for PubMedID 21617522
QTc prolongation in children following congenital cardiac disease surgery
CARDIOLOGY IN THE YOUNG
2011; 21 (4): 400-410
IntroductionQTc prolongation has been reported in adults following cardiopulmonary bypass; however, this phenomenon has not been studied in children with congenital cardiac disease. This study's aim was to formally assess QTc in children undergoing cardiac surgery.Pre-operative and post-operative electrocardiograms during hospital stays were prospectively analysed on 107 consecutive patients under 18 years of age undergoing cardiac surgery. QTc was measured manually in leads II, V4, and V5. Measurements of 440 and 480 milliseconds were used to categorise patients. Peri-procedural data included bypass and cross-clamp time, medications, and electrolyte measurements. Outcome data included arrhythmias, length of mechanical ventilation, and hospital stay. Patients with post-operative new bundle branch block or ventricularly paced rhythm were excluded.In all, 59 children were included, out of which 26 had new QTc over 440 milliseconds and 6 of 59 had new QTc over 480 milliseconds post-operatively. The mean increase in post-operative QTc was 25 milliseconds, p=0.0001. QTc over 480 was associated with longer cross-clamp time, p=0.003. Other risk factors were not associated with post-operative QTc prolongation. This phenomenon was transient with normalisation occurring in 67% of patients over 60 hours on average. One patient with post-operative QTc over 440 milliseconds developed ventricular tachycardia. There was no correlation between prolonged QTc and duration of mechanical ventilation, or hospital stay.ConclusionA significant number of children undergoing cardiac surgery showed transient QTc prolongation. The precise aetiology of QT prolongation was not discerned, though new QTc over 480 milliseconds was associated with longer cross-clamp time. In this cohort, transient QTc prolongation was not associated with adverse sequela.
View details for DOI 10.1017/S1047951111000175
View details for Web of Science ID 000293593800005
View details for PubMedID 21362209
Correlation of Subjective Questionnaires With Cardiac Function as Determined by Exercise Testing in a Pediatric Population
2010; 31 (7): 1043-1048
Although exercise testing is an important objective method used to assess cardiopulmonary function, subjective assessment often is used as a proxy in the clinical setting. This study aimed to determine whether responses to a subjective functional capacity questionnaire administered to parents and patients in a pediatric exercise laboratory correlate with objective assessment of functional capacity, measured by peak oxygen consumption during maximal voluntary exercise testing.Subjective questionnaire responses and exercise test results collected over 10 years were retrospectively analyzed. Symptoms and physical capabilities were assessed using a 6-point Likert scale regarding the ability to attend school/work, walk, climb stairs, and run, as well as the frequency of fatigue, palpitations, and chest pain. Values of 0 to 3 were considered abnormal, whereas values of 4-5 were regarded as normal. Exercise testing was performed on a stationary cycle ergometer with a continuous ramping protocol. Heart rate and oxygen saturation were continuously monitored. Blood pressures and electrocardiograms (ECGs) were obtained at 2-min intervals. Metabolic gas analysis was performed using a breath-by-breath method. The results of the exercise testing were normalized for body size and expressed as a percentage of predicted peak oxygen consumption (%pVO(2)).Very weak but statistically significant correlations (? < 0.25; P < 0.05) between the scores of the school/work, walking, stair climbing, running, and fatigue items and %pVO(2) were found using Kendall's rank correlations.The subjective Likert scales used to assess basic physical capacity and cardiac-associated symptoms have limited ability to predict actual functional capacity as measured by %pVO(2) achieved. The very weak rank-order correlation between %pVO(2) achieved and the subjective reporting of the ability to attend school/work, walk, climb stairs, and run has low clinical significance and will not be useful in predicting functional capacity within the clinic setting.
View details for DOI 10.1007/s00246-010-9761-2
View details for Web of Science ID 000282424800015
View details for PubMedID 20811883
Variable expression of soluble fms-like tyrosine kinase 1 in patients at high risk for preeclampsia
JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE
2010; 23 (7): 705-711
To explore angiogenic factor differences in preeclamptic patients according to the absence or presence of underlying vascular disease.We prospectively compared serum soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin, and placental growth factor (PlGF) from 41 normal-risk and 32 high-risk (preexisting conditions) subjects at serial gestational ages.Median sFlt1 was lower at delivery in preeclamptic patients with underlying chronic hypertension and/or chronic proteinuria (5115 pg/ml) compared with normal risk preeclamptic patients (16375 pg/ml). PlGF was consistently low in patients who developed preeclampsia.Effects of sFlt1 may be contextual, varying according to the health or disease state of vascular endothelium.
View details for DOI 10.3109/14767050903258753
View details for Web of Science ID 000279865300024
View details for PubMedID 19895348
Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy
JOURNAL OF CLINICAL ONCOLOGY
2010; 28 (7): 1232-1239
Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.
View details for DOI 10.1200/JCO.2009.24.8062
View details for Web of Science ID 000274892500025
View details for PubMedID 20124178
Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys
2010; 14 (1): 126-131
Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant. A total of 205 measurements were performed. The smallest recipients (BSA
or= 1.5 m(2) (p < 0.0001). Resistive indices increased during the first six months in the smallest recipients (p = 0.02), but not in the two larger recipient groups (BSA 0.75-1.5 m(2) and >or=1.5 m(2)). All three BSA groups showed a reduction in renal volume after transplantation, with the greatest reduction occurring in the smallest recipients. In conclusion, renal transplant resistive indices reflect pediatric recipient BSA dependency. The higher resistance to intra-renal vascular flow and significant decrease in renal volume in the smallest group likely reflect accommodation of the size discrepant transplanted adult-sized kidney to the smaller pediatric recipient vasculature with associated lower renal artery flow.
View details for DOI 10.1111/j.1399-3046.2009.01180.x
View details for Web of Science ID 000273478100024
View details for PubMedID 19413712
Longer Relative Telomere Length in Blood from Women with Sporadic and Familial Breast Cancer Compared with Healthy Controls
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2010; 19 (2): 605-613
Telomeres cap the ends of chromosomes and are composed of a series of noncoding hexamer repeats. Telomeres protect the integrity of DNA coding sequences and are integral to the maintenance of genomic stability. Previous studies have shown an association between shortened lymphocyte telomeres and increased risk for specific cancers. However, the association between telomere length and breast cancer risk is less clear. We examined the relative telomere length (RTL) in blood from women with no personal or family history of cancer (controls) compared with different populations of women with breast cancer and women at high genetic risk for developing breast cancer. RTL was determined as the telomere to single gene copy number ratio assessed by quantitative PCR. Breast cancer cases (low risk, n = 40; high risk, n = 62) had significantly longer RTL compared with unaffected controls (n = 50; mean RTL = 1.11 versus 0.84; P < 0.0001). The assessment of risk by RTL quartile showed an increased risk for breast cancer with each longer quartile, with the most significant risk observed in the longest quartile (odds ratio, 23.3; confidence interval, 4.4-122.3; P < 0.0003). Women without breast cancer but at high risk due to family history (n = 30) also showed longer telomeres than controls (mean RTL = 1.09 versus 0.84; P < 0.0001). Our analysis supports previous findings of longer RTL in breast cancer cases compared with controls, and is the first to observe longer RTL in women without breast cancer identified as high risk based on family history.
View details for DOI 10.1158/1055-9965.EPI-09-0896
View details for Web of Science ID 000278403900035
View details for PubMedID 20142254
Metabolic syndrome: do clinical criteria identify similar individuals among overweight premenopausal women?
METABOLISM-CLINICAL AND EXPERIMENTAL
2008; 57 (1): 49-56
The purpose of this analysis was to determine to what extent the clinical criteria for metabolic syndrome (MetSyn) proposed by the World Health Organization (WHO), the European Group for Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Adult Treatment Panel III (ATP III), and the International Diabetes Foundation (IDF); triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio >/=3.0; and enlarged waist circumference (>/=88 cm) and elevated TG (>/=129 mg/dL) (EWET) identified similar or different overweight women and, secondarily, to examine the effect of 7% weight reduction on MetSyn status. Metabolic syndrome was determined among 256 premenopausal women (age = 41 +/- 6 years, body mass index [BMI] = 32 +/- 4 kg/m(2)) participating in a dietary weight loss clinical trial based on the clinical criteria proposed by WHO, EGIR, ATP III, and IDF. The prevalence of TG/HDL-C ratio >/=3.0 and EWET was determined and compared with MetSyn status. Based on the clinical criteria, 16.1% (EGIR), 20.7% (WHO), 31.0% (ATP III), and 31.8% (IDF) of participants met the criteria for MetSyn; 30.3% and 31.8% had TG/HDL-C >/=3.0 and EWET, respectively. Between 77% and 99% of participants were similarly classified across the clinical criteria. The highest and lowest agreements were between ATP III and IDF (kappa = 0.98; 95% confidence interval, 0.96-1.0) and WHO and IDF (kappa = 0.39; 95% confidence interval, 0.26-0.51), respectively. The TG/HDL-C ratio >/=3.0 and EWET moderately agreed with all 4 clinical criteria for MetSyn (kappa range, 0.36-0.59). Among those diagnosed with MetSyn at baseline, 64.0% to 75.0% of the participants who lost >/=7% and 25.8% to 55.6% of participants who lost <7% of their baseline body weight in 6 months no longer met the various clinical criteria for MetSyn, TG/HDL-C >/=3.0, or EWET. Our findings indicate that MetSyn varies substantially between clinical criteria, which raise questions about the clinical utility of these criteria. Regardless of MetSyn clinical criteria, >/=7% reduction in body weight has a beneficial impact on variables used to define MetSyn.
View details for DOI 10.1016/j.metabol.2007.08.006
View details for Web of Science ID 000251929400006
View details for PubMedID 18078858
Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2007; 297 (9): 969-977
Popular diets, particularly those low in carbohydrates, have challenged current recommendations advising a low-fat, high-carbohydrate diet for weight loss. Potential benefits and risks have not been tested adequately.To compare 4 weight-loss diets representing a spectrum of low to high carbohydrate intake for effects on weight loss and related metabolic variables.Twelve-month randomized trial conducted in the United States from February 2003 to October 2005 among 311 free-living, overweight/obese (body mass index, 27-40) nondiabetic, premenopausal women.Participants were randomly assigned to follow the Atkins (n = 77), Zone (n = 79), LEARN (n = 79), or Ornish (n = 76) diets and received weekly instruction for 2 months, then an additional 10-month follow-up.Weight loss at 12 months was the primary outcome. Secondary outcomes included lipid profile (low-density lipoprotein, high-density lipoprotein, and non-high-density lipoprotein cholesterol, and triglyceride levels), percentage of body fat, waist-hip ratio, fasting insulin and glucose levels, and blood pressure. Outcomes were assessed at months 0, 2, 6, and 12. The Tukey studentized range test was used to adjust for multiple testing.Weight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12-month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, -4.7 kg (95% confidence interval [CI], -6.3 to -3.1 kg), Zone, -1.6 kg (95% CI, -2.8 to -0.4 kg), LEARN, -2.6 kg (-3.8 to -1.3 kg), and Ornish, -2.2 kg (-3.6 to -0.8 kg). Weight loss was not statistically different among the Zone, LEARN, and Ornish groups. At 12 months, secondary outcomes for the Atkins group were comparable with or more favorable than the other diet groups.In this study, premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight at 12 months than women assigned to follow the Zone diet, and had experienced comparable or more favorable metabolic effects than those assigned to the Zone, Ornish, or LEARN diets [corrected] While questions remain about long-term effects and mechanisms, a low-carbohydrate, high-protein, high-fat diet may be considered a feasible alternative recommendation for weight loss.clinicaltrials.gov Identifier: NCT00079573.
View details for Web of Science ID 000244697900026
View details for PubMedID 17341711
Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia - A randomized clinical trial
ARCHIVES OF INTERNAL MEDICINE
2007; 167 (4): 346-353
Garlic is widely promoted as a cholesterol-lowering agent, but efficacy studies have produced conflicting results. Garlic supplements differ in bioavailability of key phytochemicals. We evaluated the effect of raw garlic and 2 commonly used garlic supplements on cholesterol concentrations in adults with moderate hypercholesterolemia.In this parallel-design trial, 192 adults with low-density lipoprotein cholesterol (LDL-C) concentrations of 130 to 190 mg/dL (3.36-4.91 mmol/L) were randomly assigned to 1 of the following 4 treatment arms: raw garlic, powdered garlic supplement, aged garlic extract supplement, or placebo. Garlic product doses equivalent to an average-sized garlic clove were consumed 6 d/wk for 6 months. The primary study outcome was LDL-C concentration. Fasting plasma lipid concentrations were assessed monthly. Extensive chemical characterization of study materials was conducted throughout the trial.Retention was 87% to 90% in all 4 treatment arms, and chemical stability of study materials was high throughout the trial. There were no statistically significant effects of the 3 forms of garlic on LDL-C concentrations. The 6-month mean (SD) changes in LDL-C concentrations were +0.4 (19.3) mg/dL (+0.01 [0.50] mmol/L), +3.2 (17.2) mg/dL (+0.08 [0.44] mmol/L), +0.2 (17.8) mg/dL (+0.005 [0.46] mmol/L), and -3.9 (16.5) mg/dL (-0.10 [0.43] mmol/L) for raw garlic, powdered supplement, aged extract supplement, and placebo, respectively. There were no statistically significant effects on high-density lipoprotein cholesterol, triglyceride levels, or total cholesterol-high-density lipoprotein cholesterol ratio.None of the forms of garlic used in this study, including raw garlic, when given at an approximate dose of a 4-g clove per day, 6 d/wk for 6 months, had statistically or clinically significant effects on LDL-C or other plasma lipid concentrations in adults with moderate hypercholesterolemia.
View details for Web of Science ID 000244467000009
View details for PubMedID 17325296
Imputation of missing ages in pedigree data
2007; 63 (3-4): 168-174
In human pedigree data age at disease occurrence frequently is missing and is imputed using various methods. However, little is known about the performance of these methods when applied to families. In particular, there is little information about the level of agreement between imputed and actual values of temporal data and their effects on inferences.We performed two evaluations of five imputation methods used to generate complete data for repositories to be shared by many investigators. Two of the methods are mean substitution methods, two are regression methods and one is a multiple imputation method based on one of the regression methods. To evaluate the methods, we randomly deleted the years of disease diagnosis of some men in a sample of pedigrees ascertained as part of a prostate cancer study. In the first evaluation, we used the five methods to impute the missing diagnosis years and evaluated agreement between imputed and actual values. In the second evaluation, we compared agreement between regression coefficients estimated using imputed diagnosis years with those estimated using the actual years.For both evaluations, we found optimal or near-optimal performance from a regression method that imputes a man's diagnosis year based on the year of birth and year of last observation of all affected men with complete data. The multiple imputation analogue of this method also performed well.
View details for DOI 10.1159/000099829
View details for Web of Science ID 000244952500003
View details for PubMedID 17310126
Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics
2006; 120 (4): 471-485
While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.
View details for DOI 10.1007/s00439-006-0219-9
View details for Web of Science ID 000241791900003
View details for PubMedID 16932970
Improving alertness and performance in emergency department physicians and nurses: The use of planned naps
ANNALS OF EMERGENCY MEDICINE
2006; 48 (5): 596-604
We examine whether a 40-minute nap opportunity at 3 AM can improve cognitive and psychomotor performance in physicians and nurses working 12-hour night shifts.This is a randomized controlled trial of 49 physicians and nurses working 3 consecutive night shifts in an academic emergency department. Subjects were randomized to a control group (no-nap condition=NONE) or nap intervention group (40-minute nap opportunity at 3 AM=NAP). The main outcome measures were Psychomotor Vigilance Task, Probe Recall Memory Task, CathSim intravenous insertion virtual reality simulation, and Profile of Mood States, which were administered before (6:30 PM), during (4 AM), and after (7:30 AM) night shifts. A 40-minute driving simulation was administered at 8 AM and videotaped for behavioral signs of sleepiness and driving accuracy. During the nap period, standard polysomnographic data were recorded.Polysomnographic data revealed that 90% of nap subjects were able to sleep for an average of 24.8 minutes (SD 11.1). At 7:30 AM, the nap group had fewer performance lapses (NAP 3.13, NONE 4.12; p<0.03; mean difference 0.99; 95% CI: -0.1-2.08), reported more vigor (NAP 4.44, NONE 2.39; p<0.03; mean difference 2.05; 95% CI: 0.63-3.47), less fatigue (NAP 7.4, NONE 10.43; p<0.05; mean difference 3.03; 95% CI: 1.11-4.95), and less sleepiness (NAP 5.36, NONE 6.48; p<0.03; mean difference 1.12; 95% CI: 0.41-1.83). They tended to more quickly complete the intravenous insertion (NAP 66.40 sec, NONE 86.48 sec; p=0.10; mean difference 20.08; 95% CI: 4.64-35.52), exhibit less dangerous driving and display fewer behavioral signs of sleepiness during the driving simulation. Immediately after the nap (4 AM), the subjects scored more poorly on Probed Recall Memory (NAP 2.76, NONE 3.7; p<0.05; mean difference 0.94; 95% CI: 0.20-1.68).A nap at 3 AM improved performance and subjective report in physicians and nurses at 7:30 AM compared to a no-nap condition. Immediately after the nap, memory temporarily worsened. The nap group did not perform any better than the no-nap group during a simulated drive home after the night shift.
View details for DOI 10.1016/j.annemergmed.2006.02.005
View details for Web of Science ID 000241749400017
View details for PubMedID 17052562
A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics
AMERICAN JOURNAL OF HUMAN GENETICS
2005; 77 (2): 219-229
Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.
View details for Web of Science ID 000230387200004
View details for PubMedID 15988677
Histologic types of epithelial ovarian cancer: have they different risk factors?
2005; 96 (2): 520-530
The histologic types of epithelial ovarian cancer differ in clinical behavior, descriptive epidemiology, and genetic origins. The goals of the current study were to characterize further the relation of histologic-specific ovarian cancer risks to reproductive and lifestyle attributes.The authors conducted a pooled analysis of 10 case-control studies of ovarian cancer in US White women, involving 1834 patients with invasive epithelial ovarian cancer (1067 serous, 254 mucinous, 373 endometrioid, and 140 clear cell) and 7484 control women.Risks of all four histological types were inversely associated with parity and oral contraceptive use, but the histologic types showed different associations with nonreproductive factors. Unique associations include an inverse relation of serous cancer risk to body mass index, a positive relation of mucinous cancer risk to cigarette smoking, and a weakly positive relation of endometrioid cancer risk to body mass index. Risk of all histologic types was unassociated with age at menarche, age at menopause, a history of infertility, noncontraceptive estrogen use, and alcohol consumption.The most important modifiers of ovarian cancer risk (parity and oral contraceptive use) showed similar associations across the histologies. Nevertheless, the unique associations seen for other modifiers support the conjecture that the histologic types of epithelial ovarian cancer have different etiologies, which should be addressed in future investigations of the molecular basis of ovarian cancers and their responses to therapies.
View details for DOI 10.1016/j.gygno.2004.10.037
View details for Web of Science ID 000226636600041
View details for PubMedID 15661246
Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations
BRITISH JOURNAL OF CANCER
2004; 91 (11): 1911-1915
Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2.
View details for DOI 10.1038/sj.bjc.6602239
View details for Web of Science ID 000225301700010
View details for PubMedID 15545966
Risk of early-onset prostate cancer in relation to germ line polymorphisms of the vitamin D receptor
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2004; 13 (8): 1325-1330
Vitamin D inhibits prostate cancer cell growth, angiogenesis, and metastasis. These actions are mediated by the vitamin D receptor. We examined associations between prostate cancer risk and five polymorphisms in the VDR gene: four single nucleotide polymorphisms (FokI, BsmI, ApaI, and TaqI restriction sites) and the polyadenylic acid microsatellite. Specifically, we genotyped population-based samples of young African Americans (113 cases and 121 controls) and Whites (232 cases and 171 controls) and members of 98 predominantly White families with multiple cases of prostate cancer. Among Whites, there was no evidence for association between prostate cancer risk and alleles at any of the five polymorphic sites regardless of how the men were ascertained. Moreover, estimated five-locus haplotype frequencies were similar in White cases and controls. Among African Americans, prostate cancer risk was associated with homozygosity for the F allele at the FokI site (odds ratio 1.9, 95% confidence interval 1.0-3.3). In addition, estimated haplotype frequencies differed significantly (P < 0.01) between African American cases and controls. These findings need replication in other studies of African Americans. Homozygosity for the F allele at the FokI site is more prevalent in the African American population than in U.S. Whites. If the FokI association noted here were causal, this difference could account for some of the disease burden among African Americans and some of the excess risk in African Americans compared with Whites.
View details for Web of Science ID 000223155500010
View details for PubMedID 15298953
A longitudinal analysis of maternal serum insulin-like growth factor I (IGF-I) and total and nonphosphorylated IGF-binding protein-1 in human pregnancies complicated by intrauterine growth restriction
ENDOCRINE SOC. 2002: 1864-1870
In cord blood and late gestation maternal serum, IGF-I is positively correlated with birth weight, whereas IGF-binding protein-1 (IGFBP-1) is inversely correlated with birth weight. Our goal was to determine whether maternal serum or amniotic fluid concentrations of IGF-I, IGFBP-1, or nonphosphorylated IGFBP-1 (npIGFBP-1) in early gestation predict later fetal growth abnormalities. Maternal serum was collected prospectively across gestation (5-40 wk) from 749 pregnant subjects. Amniotic fluid was collected after amniocentesis during wk 15-26 from 207 subjects. We compared median serum concentrations of IGF-I, IGFBP-1, and npIGFBP-1 in 38 subjects who delivered growth-restricted infants with the control group of 236 subjects with normal weight infants for each gestational age grouping, wk 5-12, 13-23, and 24-34. In the control group median IGF-I concentrations were 14.8, 11, and 15.6 nmol/liter for wk 5-12, 13-23, and 24-34, respectively, compared with 13.7, 14.3, and 10.6 nmol/liter in the intrauterine growth restriction (IUGR) group. Median IGFBP-1 concentrations were 8.5, 30.4, and 24.4 nmol/liter, respectively, in controls, compared with 11.4, 28.6, and 25.5 nmol/liter in the IUGR group. Median npIGFBP-1 concentrations were 6.9, 22, and 17.4 nmol/liter, respectively, in controls, compared with 5.0, 32.1, and 24.2 nmol/liter in the IUGR group. In the control group the median amniotic fluid IGFBP-1 level was 13,160 nmol/liter, and the median npIGFBP-1 level was 15,970 nmol/liter; in the IUGR group these levels were 13,440 and 18,440 nmol/liter, respectively. No clinically useful differences were found between the IUGR and control groups. Our results do not support the use of maternal serum IGF-I or IGFBP-1 or amniotic fluid IGFBP-1 or npIGFBP-1 early in gestation to predict later fetal growth restriction.
View details for Web of Science ID 000174963100066
View details for PubMedID 11932331
A genome screen of families with multiple cases of prostate cancer: Evidence of genetic heterogeneity
AMERICAN JOURNAL OF HUMAN GENETICS
2001; 69 (1): 148-158
We conducted a genomewide screen for prostate cancer-susceptibility genes on the basis of data from 98 families from the United States and Canada that had three or more verified diagnoses of prostate cancer among first- and second-degree relatives. We found a statistically significant excess of markers for which affected relatives exhibited modest amounts of excess allele-sharing; however, no single chromosomal region contained markers with excess allele-sharing of sufficient magnitude to indicate unequivocal evidence of linkage. Positive linkage signals of nominal statistical significance were found in two regions (5p-q and 12p) that have been identified as weakly positive in other data sets and in region 19p, which has not been identified previously. All these signals were considerably stronger for analyses restricted to families with mean age at onset below the median than for analyses of families with mean age at onset above the median. The data provided little support for any of the putative prostate cancer-susceptibility genes identified in other linkage studies.
View details for Web of Science ID 000170108100015
View details for PubMedID 11404817
Detection of disease genes by use of family data. II. Application to nuclear families
AMERICAN JOURNAL OF HUMAN GENETICS
2000; 66 (4): 1341-1350
Two likelihood-based score statistics are used to detect association between a disease and a single diallelic polymorphism, on the basis of data from arbitrary types of nuclear families. The first statistic, the nonfounder statistic, extends the transmission/disequilibrium test to accommodate affected and unaffected offspring and missing parental genotypes. The second statistic, the founder statistic, compares observed or inferred parental genotypes with those of some reference population. In this comparison, the genotypes of affected parents or of those with many affected offspring are weighted more heavily than are the genotypes of unaffected parents or of those with few affected offspring. Genotypes of single unrelated cases and controls can be included in this analysis. We illustrate the two statistics by applying them to data on a polymorphism of the SDR5A2 gene in nuclear families with multiple cases of prostate cancer. We also use simulations to compare the power of the nonfounder statistic with that of the score statistic, on the basis of the conditional logistic regression of offspring genotypes.
View details for Web of Science ID 000088373400016
View details for PubMedID 10739759
Stability of arithmetic disability subtypes
JOURNAL OF LEARNING DISABILITIES
1999; 32 (2): 108-119
Cross-sectional research has identified subtypes of children with learning disabilities who may have distinctive cognitive ability patterns. This study examined the stability over 19 months of academic subtyping classifications for 80 children ages 9 to 13 representing four subtypes of arithmetic disabilities (AD), using three criteria for learning disability identification. Approximately half of the sample retained AD regardless of identification method. Children with pervasive deficits in arithmetic, reading, and spelling displayed the greatest subtype stability. Only one third of the children with the other subtypes, including those with isolated arithmetic deficits, retained their original subtypes. Thus, drawing conclusions and making recommendations based on academic subtyping at a single point in time may be unwise.
View details for Web of Science ID 000079056700002
View details for PubMedID 15499712
An evaluation of the dyslexia training program: A multisensory method for promoting reading in students with reading disabilities
JOURNAL OF LEARNING DISABILITIES
1998; 31 (2): 140-147
The development of reading and spelling skills in students with dyslexia, by definition, is delayed and often remains delayed despite years of instruction. Three qualities are thought to facilitate reading development in these children: the provision of a highly structured phonetic-instruction training program with heavy emphasis on the alphabetic system, drill and repetition to compensate for short-term verbal memory deficits, and multisensory methods to promote nonlanguage mental representations. The Dyslexia Training Program, a remedial reading program derived from Orton-Gillingham methods, embodies these qualities. Following their 2-year program, students displaying dyslexia demonstrated significantly higher reading recognition and comprehension compared with a control group. The two groups did not differ in spelling. In addition, the degree of improvement in reading demonstrated by students who received the Dyslexia Training Program by videotape and by those who received it live from instructors did not differ.
View details for Web of Science ID 000072406800004
View details for PubMedID 9529784
SOME DISTRIBUTIONAL FACTS ABOUT FRICATIVES AND A PERCEPTUAL EXPLANATION
1994; 51 (1-3): 99-110
Across and within languages voiced sibilants tend to be disfavored relative to voiceless ones. This paper explores the claim that voicing more adversely affects the distinctive acoustic properties of sibilants than those of nonsibilants. One prediction associated with this claim is that voicing differentially lowers the amplitude of frication noise for sibilants and non-sibilants so that amplitude differences between the two classes are reduced. Acoustic measurements confirm this prediction. A second prediction is that voicing has a greater negative effect on the identification of sibilants than nonsibilants. Perceptual results from this and previous studies are somewhat variable, but averaged data support this prediction. The findings suggest that voiced sibilants are disfavored in part for perceptual reasons.
View details for Web of Science ID A1994NU53900010
View details for PubMedID 8052677