Survey of quality of life, phenotypic expression, and response to treatment in Krabbe leukodystrophy.

OBJECTIVES: To develop a quality of life (QOL) survey for Krabbe disease (KD), and to thereby improve understanding of its phenotypic expression and response to treatment. METHODS: The survey, the Leukodystrophy Quality of Life Assessment (LQLA) and the Vineland Adaptive Behavior Scales were co-administered to 33 patients or their caretakers. These included the phenotypes of early infantile KD (EIKD; 0-6 months old at onset), late infantile cases (LIKD; 7-12 months old at onset), and cases that emerged after 12 months old, late onset (LOKD). The sample included cases with and without stem cell transplantation (SCT). Reliability and concurrent validity were assessed for overall and subscale scores. Analysis of variance tested differences in QOL between phenotypes and transplant groups (none, pre-, post-symptom). RESULTS: Good concurrent validity with the Vineland was shown for total, communication, daily activity, social, and motor scales and good reliability was observed. LOKD cases had better communication skills than either EIKD or LIKD and better overall QOL than EIKD. Analyses of individual items showed that communication items, mostly, contributed significantly to phenotype differences. Presymptomatic SCT significantly improved QOL compared to postsymptomatic SCT or no treatment. Presymptomatically treated patients had near-normal total scores. CONCLUSIONS: The LQLA is valid and reliable. Despite small sample size, phenotypic demarcation was determined to be due mainly to differences in communication skills. There was a relative enhancement of QOL in LOKD patients, and in those who had presymptomatic SCT. These results apply to the current controversy about recommendations for newborn screening for this condition.

Can psychosine and galactocerebrosidase activity predict early-infantile Krabbe's disease presymptomatically?

Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.

Evidence for improved survival in postsymptomatic stem cell-transplanted patients with Krabbe's disease.

Krabbe's disease (KD) is a severe neurodegenerative disorder affecting white matter in the brain and peripheral nerves. Transplantation of hematopoietic stem cells (HSCT), although not curative, has been shown to extend survival and alleviate neurodevelopmental symptoms when treatment precedes the onset of symptoms. Existing evidence, although not tested statistically, seems clearly to show that postsymptomatic transplantation does not improve neurodevelopmental outcomes. The impact of postsymptomatic HSCT treatment on survival, however, is an open question. This study uses a KD registry to examine the effect of HSCT on survival of symptomatic KD patients. Sixteen transplanted patients were matched by age of onset to 68 nontransplanted patients. The potential confounding effect of age of onset was, therefore, avoided. To quantify the effect of HSCT over time, we used Cox regression analysis, and we observed a sustained and nearly 2.2-fold risk of death from KD in patients who were not transplanted relative to those who were transplanted (one-tailed P = 0.0365; 95% lower bound = 1.07). The improvement of survival resulting from HSCT did not appear to depend on the age of symptom onset. Thus, these results establish a long-term, quantitative benefit of HSCT even in patients who are already experiencing symptoms. They also provide a benchmark for improved survival that can be used for potential new treatments for KD. © 2016 Wiley Periodicals, Inc.

Patient and physician factors associated with participation in cervical and uterine cancer trials: an NRG/GOG247 study.

PURPOSE: The aim of this study was to identify patient and physician factors related to enrollment onto Gynecologic Oncology Group (GOG) trials. METHODS: Prospective study of women with primary or recurrent cancer of the uterus or cervix treated at a GOG institution from July 2010 to January 2012. Logistic regression examined probability of availability, eligibility and enrollment in a GOG trial. Odds ratios (OR) and 95% confidence intervals (CI) for significant (p<0.05) results reported. RESULTS: Sixty institutions, 781 patients, and 150 physicians participated, 300/780 (38%) had a trial available, 290/300 had known participation status. Of these, 150 women enrolled (59.5%), 102 eligible did not enroll (35%), 38 (13%) were ineligible. Ethnicity and specialty of physician, practice type, data management availability, and patient age were significantly associated with trial availability. Patients with >4 comorbidities (OR 4.5; CI 1.7-11.8) had higher odds of trial ineligibility. Non-White patients (OR 7.9; CI 1.3-46.2) and patients of Black physicians had greater odds of enrolling (OR 56.5; CI 1.1-999.9) in a therapeutic trial. Significant patient therapeutic trial enrollment factors: belief trial may help (OR 76.9; CI 4.9->1000), concern about care if not on trial (OR12.1; CI 2.1-71.4), pressure to enroll (OR .27; CI 0.12-.64), caregiving without pay (OR 0.13; CI .02-.84). Significant physician beliefs were: patients would not do well on standard therapy (OR 3.6; CI 1.6-8.4), and trial would not be time consuming (OR 3.3; CI 1.3-8.1). CONCLUSIONS: Trial availability, patient and physician beliefs were factors identified that if modified could improve enrollment in cancer cooperative group clinical trials.

A modified Latent Class Model assessment of human papillomavirus-based screening tests for cervical lesions in women with atypical glandular cells: a Gynecologic Oncology Group study.

PURPOSE: In the absence of gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology-, and histology-based tests for significant cervical lesions (SCL) in US women with AGC-NOS Pap smear diagnoses. METHODS: Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n = 122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX); and invasive histological diagnosis, were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity, and prevalence to obtain age-specific false-positive and false-negative rates. RESULTS: The histology-based test was nearly perfect (sensitivity = 1.00, CI = 0.98-1.00; specificity = 0.99, CI = 0.96-1.00). Otherwise, HC2 H-HPV performed best (sensitivity = 1.00, CI = 1.00-1.00; specificity = 0.87, CI = 0.79-0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17 %) at each age, while those of the histological diagnoses were low (<5 % at ages ≤60 and <17 % overall ages). False-negative prediction rates (1-NPV) for HC2 H-HPV were <0.11 % at each age and were uniformly lower than those of other tests, including the histology-based test (<0.25 %). CA-IX together with HC2 H-HPV did not improve performance. CONCLUSIONS: Women with negative HC2 H-HPV can safely forego invasive treatment (i.e., cone or LEEP biopsy, hysterectomy) in favor of observational follow-up. Additional biomarkers must be found for use in combination with HC2 H-HPV to reduce false-positive rates. This novel application of a modified LCM exemplifies methods for potential use in future cancer screening studies when gold standard diagnoses are not available.

Mortality rates due to gynecologic cancers in New York state by demographic factors and proximity to a Gynecologic Oncology Group member treatment center: 1979-2001.

OBJECTIVE: To describe trends in mortality rates, in New York State, due to cervical, endometrial and ovarian cancer and to assess how these rates varied with proximity to a comprehensive cancer treatment center or population density (rural/urban). METHODS: Data were obtained from the Centers for Disease Control and Prevention (CDC)'s Compressed Mortality Files, Census Bureau records, and online maps. Poisson regression models were fitted to estimate death rates (mean number of deaths per 100,000 women per year) due to gynecologic cancer type. Trends in death rates were compared with respect to driving time to the nearest comprehensive cancer treatment center and population density, controlling for race, county income level, and age at death. RESULTS: Cervical and endometrial but not ovarian death rates declined over time. For both cervical and endometrial cancers, death rates varied significantly with driving time and between rural and urban counties. In the case of cervical cancer, the decline over time was steeper in rural than in urban counties. For endometrial cancer, the decline steepened with increasing distance from a treatment center. CONCLUSION: Improvements in cervical and endometrial cancer mortality from 1979 to 2001 followed increases in gynecologic cancer treatment research efforts, number of specialists trained to treat such cases, and in the emphasis on gynecologic cancer in the training of physicians in general. Our results are consistent with an interpretation that the progressive actions by leaders in the gynecologic oncology profession during the late 1960's and early 1970's contributed to improvements in mortality rates in subsequent decades.

Patency of autogenous and polytetrafluoroethylene upper extremity arteriovenous hemodialysis accesses: a systematic review.

OBJECTIVE: Patency rates for autogenous accesses are presumed to be better than for polytetrafluoroethylene (PTFE) accesses, although the strength of the supporting evidence is limited. We undertook this study to test the hypothesis that patency rates for upper extremity autogenous hemodialysis arteriovenous accesses in adults are superior to those for PTFE counterparts. METHODS: A systematic review of relevant literature and meta-analysis of the patency data were performed. Studies were considered acceptable if patency data were reported by either life table or Kaplan-Meier method, including number of patients at risk. RESULTS: The thirty-four studies that satisfied the inclusion criteria were composed predominantly of case series or nonrandomized controlled studies; no randomized, controlled studies comparing autogenous and PTFE accesses were included. The primary patency rate for autogenous accesses was 72% (95% confidence interval [CI], 70%-74%) at 6 months and 51% (95% CI, 48%-53%) at 18 months, and the corresponding primary patency rate for PTFE accesses was 58% (95% CI, 56%-61%) and 33% (95% CI, 31%-36%), respectively. The secondary patency rate for autogenous accesses was 86% (95% CI, 84%-88%) at 6 months and 77% (95% CI, 74%-79%) at 18 months, and the corresponding secondary patency rate for PTFE accesses was 76% (95% CI, 73%-79%) and 55% (95% CI, 51%-59%), respectively. CONCLUSIONS: The patency rate for autogenous upper extremity arteriovenous hemodialysis accesses in adults is superior to that for PTFE counterparts, although the overall quality of the studies in the meta-analysis was less than ideal. Randomized, controlled studies to further examine the differences in outcome between these two access types are necessary.

A risk assessment screening test for very low birth weight.

OBJECTIVES: To develop a risk-assessment screening tool for very low birth weight (VLBW) and to compare our empirically derived tool to the nonempirically derived screening tool used by the State of Florida. METHODS: Birth records from the State of Florida Vital Statistics between 04/01/92 and 12/07/94 were matched with State Healthy Start prenatal records, reported from 04/01/92 through 03/31/94. Known and additional potentially important risk factors were identified from both sources. Generalized Linear Modeling techniques were used to estimate associations between risk factors and VLBW. A risk assessment system was then developed using the estimated model. The resulting screening test was compared with the one used by the Florida State Department of Health in terms of sensitivity and specificity on an independent validation sample. RESULTS: The proposed screening tool had comparable specificity to the Healthy Start screening tool but significantly better sensitivity. Both instruments are simple and easy to implement. CONCLUSIONS: Identification of women at high risk for VLBW would be improved using the model-based screening tool developed in this paper. Public health policy makers should use statistical methods in addition to expert opinion to improve existing risk assessment methods. The actual value of an improved screening instrument is dependent on the availability of effective intervention programs.