Diffusion tensor imaging of deep gray matter in children treated for brain malignancies.

PURPOSE: Previous DTI studies reported microstructural changes in white matter of patients receiving treatment for brain malignancies. The primary aim of this prospective pilot longitudinal study was to examine if DTI can detect microstructural changes in deep gray matter (as evaluated by the apparent diffusion coefficient, ADC) between pediatric patients treated with cranial radiation therapy and typically developing healthy children. The relationship between ADC and neurobehavioral performance was also examined. METHODS: ADC was measured at 1.5 T in the caudate, putamen, globus pallidus, thalamus, and hippocampus in nine patients (mean age 11.8 years) and nine age-matched healthy controls. The study was designed with four visits: baseline, 6-month, 15-month, and 27-month follow-ups. RESULTS: Patients had 24 % higher overall mean ADC in the hippocampus compared with controls (p = 0.003). Post hoc analyses revealed significantly elevated ADC at baseline (p = 0.003) and at the 27-month follow-up (p = 0.006). Nevertheless, patients performed normally on a verbal memory test considered to be a hippocampus-related function. Relative to controls, patients' performance on the tests of the visual-spatial working memory decreased over time (group by visit, p = 0.036). Both patients and controls showed a decline in motor speed with increasing ADC in the globus pallidus and putamen. CONCLUSIONS: Childhood brain malignancies and their treatment may affect gray matter microstructure as measured by water diffusion. Significant findings in the hippocampus but not other regions suggest that differences in tissue sensitivity to disease- and treatment-related injury among gray matter regions may exist. ADC in basal ganglia may be associated with motor performance.

Screening for prostate cancer using multivariate mixed-effects models.

Using several variables known to be related to prostate cancer, a multivariate classification method is developed to predict the onset of clinical prostate cancer. A multivariate mixed-effects model is used to describe longitudinal changes in prostate specific antigen (PSA), a free testosterone index (FTI), and body mass index (BMI) before any clinical evidence of prostate cancer. The patterns of change in these three variables are allowed to vary depending on whether the subject develops prostate cancer or not and the severity of the prostate cancer at diagnosis. An application of Bayes' theorem provides posterior probabilities that we use to predict whether an individual will develop prostate cancer and, if so, whether it is a high-risk or a low-risk cancer. The classification rule is applied sequentially one multivariate observation at a time until the subject is classified as a cancer case or until the last observation has been used. We perform the analyses using each of the three variables individually, combined together in pairs, and all three variables together in one analysis. We compare the classification results among the various analyses and a simulation study demonstrates how the sensitivity of prediction changes with respect to the number and type of variables used in the prediction process.

Prospective study of the association of serum gamma-glutamyltransferase with cervical intraepithelial neoplasia III and invasive cervical cancer.

Epidemiologic studies indicate that elevated levels of gamma-glutamyltransferase (GGT), a key enzyme of glutathione metabolism, might be associated with increased cancer risk. Furthermore, preclinical studies support a role for GGT in tumor invasion and progression. However, the relationship between GGT and risks of cervical intraepithelial neoplasia III (CIN-III) and invasive cervical cancer (ICC) have not been evaluated. We investigated the association of enzymatically determined GGT in blood serum with subsequent incidence of CIN-III and ICC in a prospective population-based cohort of 92,843 women ages 18 to 95, of whom 79% had at least one gynecologic examination including Pap smear testing during follow-up. Cox regression was used to compute adjusted hazard ratios (HR) with 95% confidence intervals for the association of GGT with CIN-III and ICC. During median follow-up of 13.8 years, 702 CIN-III and 117 ICC diagnoses were observed. Compared with normal low GGT (<17.99 units/L), risk of ICC was significantly elevated for all other baseline GGT categories, with adjusted HRs of 2.31 (1.49-3.59) for normal high GGT (18.00-35.99 units/L), 2.76 (1.52-5.02) for elevated GGT (36.00-71.99 units/L), and 3.38 (1.63-7.00) for highly elevated GGT [>72.00 units/L; P trend < 0.0001, HR log unit increase 3.45 (1.92-6.19)]. In contrast, associations between GGT serum levels and CIN-III risk were not statistically significant in the main analysis. Exclusion of the first 2 or 5 years of follow-up did not change the results. Effects did not differ by age, body mass index, or socioeconomic status. Our findings implicate GGT in the progression of premalignant cervical lesions to invasive cancer.

Use of penalized splines in extended Cox-type additive hazard regression to flexibly estimate the effect of time-varying serum uric acid on risk of cancer incidence: a prospective, population-based study in 78,850 men.

PURPOSE: We sought to investigate the effect of serum uric acid (SUA) levels on risk of cancer incidence in men and to flexibly determine the shape of this association by using a novel analytical approach. METHODS: A population-based cohort of 78,850 Austrian men who received 264,347 serial SUA measurements was prospectively followed-up for a median of 12.4 years. Data were collected between 1985 and 2003. Penalized splines (P-splines) in extended Cox-type additive hazard regression were used to flexibly model the association between SUA, as a time-dependent covariate, and risk of overall and site-specific cancer incidence and to calculate adjusted hazard ratios with their 95% confidence intervals. RESULTS: During follow-up 5189 incident cancers were observed. Restricted maximum-likelihood optimizing P-spline models revealed a moderately J-shaped effect of SUA on risk of overall cancer incidence, with statistically significantly increased hazard ratios in the upper third of the SUA distribution. Increased SUA (>/=8.00 mg/dL) further significantly increased risk for several site-specific malignancies, with P-spline analyses providing detailed insight about the shape of the association with these outcomes. CONCLUSIONS: Our study is the first to demonstrate a dose-response association between SUA and cancer incidence in men, simultaneously reporting on the usefulness of a novel methodological framework in epidemiologic research.

Wnt5A regulates expression of tumor-associated antigens in melanoma via changes in signal transducers and activators of transcription 3 phosphorylation.

There are currently no effective therapies for metastatic melanoma and targeted immunotherapy results in the remission of only a very small percentage of tumors. In this study, we show that the noncanonical Wnt ligand, Wnt5A, can increase melanoma metastasis in vivo while down-regulating the expression of tumor-associated antigens important in eliciting CTL responses (e.g., MART-1, GP100, and tyrosinase). Melanosomal antigen expression is governed by MITF, PAX3, and SOX10 and is inhibited upon signal transducers and activators of transcription 3 (STAT3) activation, via decreases in PAX3 and subsequently MITF expression. Increasing Wnt5A in Wnt5A-low cells activated STAT3, and STAT3 was decreased upon Wnt5A knockdown. Downstream targets such as PAX3, MITF, and MART-1 were also affected by Wnt5A treatment or knockdown. Staining of a melanoma tissue array also highlighted the inverse relationship between MART-1 and Wnt5A expression. PKC activation by phorbol ester mimicked Wnt5A effects, and Wnt5A treatment in the presence of STAT3 or PKC inhibitors did not lower MART-1 levels. CTL activation studies showed that increases in Wnt5A correspond to decreased CTL activation and vice versa, suggesting that targeting Wnt5A before immunotherapy may lead to the enhancement of current targeted immunotherapy for patients with metastatic melanoma.

Association of gamma-glutamyltransferase and risk of cancer incidence in men: a prospective study.

Although several epidemiologic studies have shown that gamma-glutamyltransferase (GGT) is independently associated with cardiovascular disease and all-cause mortality, its relationship with cancer incidence remains widely unexplored. In several experimental models, the ability of cellular GGT to modulate crucial redox-sensitive functions has been established, and it thus may play a role in tumor progression, as has been repeatedly suggested. We prospectively investigated the association between GGT and risk of overall and site-specific cancer incidence in a large population-based cohort of 79,279 healthy Austrian men with serial GGT measurements. Median follow-up was 12.5 years. Adjusted Cox proportional hazards models were calculated to evaluate GGT as an independent predictor for cancer incidence, and nonparametric regression splines were fitted to flexibly capture the dose-response relationship. Elevated GGT significantly increased overall cancer risk, showing a clear dose-response relationship (P for GGT log-unit increase < 0.0001; P for trend < 0.0001). In comparison with the reference GGT concentration (25 units/L), we found adjusted relative risks (95% confidence intervals) equalling 1.19 (1.15-1.22) for GGT concentrations of 60 units/L, 1.32 (1.28-1.36) for 100 units/L, 1.67 (1.60-1.75) for 200 units/L, and 2.30 (2.14-2.47) for 400 units/L. In cancer site-specific models, GGT was significantly associated with malignant neoplasms of digestive organs, the respiratory system/intrathoracic organs, and urinary organs (all P < 0.0001). Age of participants significantly modified the association of GGT and cancer risk (P < 0.001), revealing markedly stronger associations in participants ages

Proton magnetic resonance spectroscopic imaging to differentiate between nonneoplastic lesions and brain tumors in children.

PURPOSE: To investigate whether in vivo proton magnetic resonance spectroscopic imaging (MRSI) can differentiate between 1) tumors and nonneoplastic brain lesions, and 2) high- and low-grade tumors in children. MATERIALS AND METHODS: Thirty-two children (20 males and 12 females, mean age = 10 +/- 5 years) with primary brain lesions were evaluated retrospectively. Nineteen patients had a neuropathologically confirmed brain tumor, and 13 patients had a benign lesion. Multislice proton MRSI was performed at TE = 280 msec. Ratios of N-acetyl aspartate/choline (NAA/Cho), NAA/creatine (Cr), and Cho/Cr were evaluated in the lesion and the contralateral hemisphere. Normalized lesion peak areas (Cho(norm), Cr(norm), and NAA(norm)) expressed relative to the contralateral hemisphere were also calculated. Discriminant function analysis was used for statistical evaluation. RESULTS: Considering all possible combinations of metabolite ratios, the best discriminant function to differentiate between nonneoplastic lesions and brain tumors was found to include only the ratio of Cho/Cr (Wilks' lambda, P = 0.012; 78.1% of original grouped cases correctly classified). The best discriminant function to differentiate between high- and low-grade tumors included the ratios of NAA/Cr and Cho(norm) (Wilks' lambda, P = 0.001; 89.5% of original grouped cases correctly classified). Cr levels in low-grade tumors were slightly lower than or comparable to control regions and ranged from 53% to 165% of the control values in high-grade tumors. CONCLUSION: Proton MRSI may have a promising role in differentiating pediatric brain lesions, and an important diagnostic value, particularly for inoperable or inaccessible lesions.

Living with achondroplasia: quality of life evaluation following cervico-medullary decompression.

Achondroplasia is the most common of the heritable skeletal dysplasias. Cervico-medullary compression is a frequently encountered and potentially lethal neurological complication. Cervico-medullary decompression (CMD) at the foramen magnum is often employed to relieve the pressure on the emerging cervical cord. Given the inherent risks associated with major surgery, there has been a substantial debate regarding the best criteria for CMD. Our objectives for this study are to explore the quality of life of patients who had undergone CMD, and to assess whether surgery is associated with mortality and increased long-term morbidity. A Medical Outcome Study 36-item Short Form General Health Survey designed to evaluate eight general health concepts as well as achondroplasia-related issues, was administered to patients assessed in the neurosurgery department in Johns Hopkins Hospital between 1977 and 1998. One hundred and sixty-seven patients were eligible for inclusion. Forty-three could not be contacted, and two refused consent. One hundred and twenty-two patients were assessed. Fifty-six (46%) individuals had CMD and 66 (54%) did not. There was 1 case of mortality in the CMD group and 12 cases in the non-CMD group. In the non-CMD group, all deaths, as far as we know, were unrelated to cervico-medullary compression. In this cohort of surviving patients (n = 109), the quality of life of the 55 (50.5%) who had undergone CMD is comparable to that of the 54 (49.5%) who did not have surgery, controlled for age and sex. CMD is indicated for patients with achondroplasia with significant symptomatic foramen magnum compression. It can be life saving. It can abolish profound central apnea that may cause sudden death and alleviate neurological complications associated with damage of the significantly compressed spinal cord. With regards to long-term outcome evaluation, the quality of life of individuals with achondroplasia who had CMD is similar to those age- and sex-matched patients who did not have this surgery. Moreover, CMD, with all its inherent surgical risks, does not appear to be associated with higher mortality or increased long-term morbidity.