Natural History Cohort Research Articles

MP53-17 CLINICAL VALIDATION OF THE 2005 ISUP GLEASON GRADING SYSTEM IN A COHORT OF INTERMEDIATE AND HIGH RISK MEN UNDERGOING RADICAL PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Staging I1 Apr 2015MP53-17 CLINICAL VALIDATION OF THE 2005 ISUP GLEASON GRADING SYSTEM IN A COHORT OF INTERMEDIATE AND HIGH RISK MEN UNDERGOING RADICAL PROSTATECTOMY Ashley Ross, Stephania Bezerra, Sheila Faraj, Kasra Yousefi, Helen Fedor, Stephanie Glavaris, Misop Han, Alan Partin, Elizabeth Humphreys, Jeffrey Tosoian, Michael H. Johnson, Elai Davicioni, Bruce Trock, Edward Schaeffer, and George Netto Ashley RossAshley Ross More articles by this author , Stephania BezerraStephania Bezerra More articles by this author , Sheila FarajSheila Faraj More articles by this author , Kasra YousefiKasra Yousefi More articles by this author , Helen FedorHelen Fedor More articles by this author , Stephanie GlavarisStephanie Glavaris More articles by this author , Misop HanMisop Han More articles by this author , Alan PartinAlan Partin More articles by this author , Elizabeth HumphreysElizabeth Humphreys More articles by this author , Jeffrey TosoianJeffrey Tosoian More articles by this author , Michael H. JohnsonMichael H. Johnson More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Bruce TrockBruce Trock More articles by this author , Edward SchaefferEdward Schaeffer More articles by this author , and George NettoGeorge Netto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1711AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications aimed at improving the prognostic ability of the Gleason grading system for prostatic carcinoma. We sought to clinically validate the updated Gleason score in a natural history cohort of intermediate and high risk men who underwent radical prostatectomy (RP). METHODS In an IRB-approved study, we queried our institutional database for men with NCCN clinically localized intermediate to high risk prostate cancer who underwent RP during the PSA era. A case-cohort design was utilized, and the primary outcome was metastatic progression. The study cohort included men with complete pathological data and complete clinical follow-up who did not undergo additional treatment prior to the study endpoint. All prostatectomy specimens were re-reviewed by a urologic pathologist blinded to clinical outcome, and Gleason scores were reassigned per the 2005 ISUP system. The association of Gleason score with metastatic disease was assessed using Cox proportional hazards models, and prognostic ability was compared between the original and updated Gleason grading systems. RESULTS At the time of analysis, 260 men met all study criteria. Over median follow-up of 10 years, 99 (38.1%) men subsequently developed metastasis and 161 (61.9%) did not. Men with metastasis were more frequently upgraded (≥ 1-point rise in Gleason score) using the ISUP 2005 criteria than men who did not develop metastasis (30% vs 7%, respectively p<0.001). Using the original Gleason grading system and Gleason score 7 as reference, the presence of Gleason sum 8 or 9 cancer was associated with an increased hazard of metastasis (HR 2.0, 95% CI 1.1-3.7, p=0.03 and HR 6.1, 95% CI 3.4-10.9, p<0.001, respectively). After re-review using the updated 2005 ISUP grading system, the hazard ratios for metastasis increased to 2.4 (95% CI 1.1-5.4, p=0.03) and 9.8 (95% CI: 5.8-16.8, p<0.001) for Gleason score 8 and 9, respectively. In accordance with this, the c-index of Gleason score for metastasis-free survival 5 years after RP increased from 0.70 (95% CI: 0.61-0.79) to 0.82 (95% CI: 0.74-0.88) when samples were re-graded by the 2005 ISUP criteria. CONCLUSIONS Here we present the first clinical validation of the ISUP 2005 criteria in a natural history cohort of at-risk men who underwent RP. Indeed, use of the updated Gleason grading system significantly improves the prognostic ability of Gleason score for subsequent metastatic disease. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e642 Peer Review Report Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ashley Ross More articles by this author Stephania Bezerra More articles by this author Sheila Faraj More articles by this author Kasra Yousefi More articles by this author Helen Fedor More articles by this author Stephanie Glavaris More articles by this author Misop Han More articles by this author Alan Partin More articles by this author Elizabeth Humphreys More articles by this author Jeffrey Tosoian More articles by this author Michael H. Johnson More articles by this author Elai Davicioni More articles by this author Bruce Trock More articles by this author Edward Schaeffer More articles by this author George Netto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP1-04 EVALUATION OF GENOMIC SIGNATURES IN INTERMEDIATE TO HIGH RISK MEN TREATED WITH RADICAL PROSTATECTOMY BUT WITHOUT ADDITIONAL THERAPY UPON PSA RISE

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2015MP1-04 EVALUATION OF GENOMIC SIGNATURES IN INTERMEDIATE TO HIGH RISK MEN TREATED WITH RADICAL PROSTATECTOMY BUT WITHOUT ADDITIONAL THERAPY UPON PSA RISE Michael Johnson, Kasra Yousefi, Nicholas Erho, Voleak Choeurng, Lucia Lam, Helen L. Fedor, Elai Davicioni, Edward Schaeffer, and Ashley Ross Michael JohnsonMichael Johnson More articles by this author , Kasra YousefiKasra Yousefi More articles by this author , Nicholas ErhoNicholas Erho More articles by this author , Voleak ChoeurngVoleak Choeurng More articles by this author , Lucia LamLucia Lam More articles by this author , Helen L. FedorHelen L. Fedor More articles by this author , Elai DavicioniElai Davicioni More articles by this author , Edward SchaefferEdward Schaeffer More articles by this author , and Ashley RossAshley Ross More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.167AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Radical prostatectomy (RP) is a primary treatment option for men with intermediate and high risk prostate cancer. Though many will be effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic findings and clinical disease recurrence. Several genomic tests are currently on the market for use as risk stratification and prognostic aids. Here we evaluate four previously validated genomic signatures in a natural history cohort of at risk men who received no additional treatment until the time of metastatic progression. METHODS Men with NCCN intermediate or high risk localized prostate cancer treated with RP at the Johns Hopkins Medical Institute (1992–2010) with at least 5 years of post-operative follow up were identified. Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis detection were included using a case-cohort design (n=337). Random forest modeling in an independent training dataset (n=359) was used to derive risk scores for Decipher, CCP, GPS and Penney genomic signatures as previously described by Erho et al., 2013 and compared to the CAPRA-S risk scores for predicting metastasis 10 years post-RP. RESULTS Risk scores were computed for 260 patients with complete follow up data. Overall, the four signatures had moderate correlations except for the Decipher and Penney signature that had a strong correlation of 0.66. ROC analysis for the survival data for metastasis 10 years post-RP was 0.76, 0.74, 0.62 and 0.62 for Decipher, Penney, CCP and GPS, respectively. In univariable analysis, all four gene signatures were significant predictors of metastatic progression, but in multivariable analysis adjusting for CAPRA-S score, only Decipher (p<0.0001), Penney (p<0.0001) and CCP (p=0.001) retained significance. CONCLUSIONS We evaluated four previously validated prognostic signatures in a natural history after RP cohort of intermediate to high-risk men. Decipher and Penney signatures were the best predictors of metastasis, although all signatures demonstrated some measure of prognostic significance. Future studies aimed at comparing the risk models and their comparative-effectiveness for postoperative decision-making are warranted. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e2 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Johnson More articles by this author Kasra Yousefi More articles by this author Nicholas Erho More articles by this author Voleak Choeurng More articles by this author Lucia Lam More articles by this author Helen L. Fedor More articles by this author Elai Davicioni More articles by this author Edward Schaeffer More articles by this author Ashley Ross More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Characterization of pulmonary function in Duchenne Muscular Dystrophy.

SummaryDecline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5–24 years). Expiratory flow‐volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10–18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time. Pediatr Pulmonol. 2015; 50:487–494. © 2015 Wiley Periodicals, Inc.

Validation of the Decipher prostate cancer classifier in intermediate to high-risk men treated with radical prostatectomy but without additional therapy upon PSA rise.

173 Background: Radical prostatectomy (RP) is a primary treatment option for men with intermediate and high risk prostate cancer. Though many will be effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic findings and clinical disease recurrence. The Decipher test has been previously shown to predict metastatic progression in cohorts that included adjuvant and salvage therapy after RP. Here we evaluate Decipher in a natural history cohort of at risk men who received no additional treatment until the time of metastatic progression. Methods: Men with NCCN intermediate or high risk localized prostate cancer treated with RP at the Johns Hopkins Medical Institute (1992-2010) with at least 5 years of post-operative follow up were identified. Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis detection were included (n=765). A case-cohort design was used to randomly sample the cohort. The highest Gleason grade cancer tissue was used for RNA extraction and Decipher genomic classifier (GC) scores were calculated with a locked 22-biomarker signature and algorithm. Results: GC results were obtained for 260 patients, 28% had positive margins, 77% had EPE, 28% had SVI, 20% had lymph node invasion and 36% had Gleason ≥8 disease. Median follow up was 9 (IQR 6-12) years and at 15 years post RP the cumulative incidence of BCR, metastasis and prostate cancer specific death was 38%, 21% and 9%. Median GC score was 0.34 (IQR: 0.22-0.52) and was significantly higher among men experiencing metastatic progression during follow up (0.47 vs 0.28 respectively p&lt;0.001). In UVA and MVA (adjusting for clinical covariates), GC had an HR of 1.48 (95% CI: 1.30-1.69, p&lt;0.001) and 1.37 (95% CI: 1.21-1.55, p&lt;0.001) per 10% increase, respectively. Conclusions: The majority of the men in this study had excellent long-term outcomes with surgery alone. Elevated Decipher scores correlated with metastatic events, independent of clinical risk factors. Use of Decipher may allow for selection of candidates for immediate vs. delayed adjuvant or salvage therapy following prostatectomy.

High Incidence of Osteoporosis in a Natural History Cohort of Patients with Moderate to Severe Chronic Graft-Versus-Host Disease and Risk Factor Analysis

High Incidence of Osteoporosis in a Natural History Cohort of Patients with Moderate to Severe Chronic Graft-Versus-Host Disease and Risk Factor Analysis

Paediatric subvalvular aortic stenosis: a systematic review and meta-analysis of natural history and surgical outcome.

Sub-valvular aortic stenosis (SAS) is a common form of left ventricular outflow tract (LVOT) obstruction, which can lead to aortic valve damage. Although surgery for SAS is an accepted treatment, the timing of surgical intervention of SAS remains controversial. This review aims to establish an overview of the natural history and outcome after surgery and factors associated with prognosis in paediatric SAS patients. We searched PubMed and EMBASE for studies that reported factors that negatively affected the prognosis of patients with SAS. Studies were included if they were written in English, published between 1 January 1997 and 31 December 2012 and the mean patient age was <18 years at the time of study entry. Studies were excluded if the study size was <20 patients. A distinction was made between natural history and surgical cohorts. Twenty-four studies were included in this review, encompassing a total of 809 natural history and 1476 surgical patients. Fifty-one percent of natural history patients required surgery. After surgery, there was a substantial reoperation rate. Higher LVOT gradient and the presence of aortic regurgitation (AR) were identified as the foremost independent predictors of a worse outcome. Valve-to-membrane distance was also found to be associated with prognosis, although the results were contradictory. This systematic review underlines the importance of LVOT gradient, aortic valve-to-membrane distance and AR in surgical decision-making in paediatric SAS patients. There is need for collaborative effort to further study the optimal timing of surgery based on LVOT gradient, valve-to-membrane distance and the presence of AR.

Modelling Gaucher disease progression: long-term enzyme replacement therapy reduces the incidence of splenectomy and bone complications.

Long-term complications and associated conditions of type 1 Gaucher Disease (GD) can include splenectomy, bone complications, pulmonary hypertension, Parkinson disease and malignancies. Enzyme replacement therapy (ERT) reverses cytopenia and reduces organomegaly. To study the effects of ERT on long-term complications and associated conditions, the course of Gaucher disease was modelled.The cohort consisted of all diagnosed GD patients in the Netherlands. Mutually exclusive disease states were defined as ‘asymptomatic’, ‘signs/symptoms’, ‘recovery’, ‘splenectomy’, ‘bone complication’, ‘multiple complications’ and ‘malignancy’. A natural history (NH) cohort was delineated based upon historical data on Dutch patients before ERT was available. Cumulative incidence curves were composed for progression from each disease state to the next. Two scenarios were applied for the ERT cohort: time to complications was calculated from A. start of ERT; B. entering the previous disease state.Median time for the development of signs and/or symptoms was 30.1 years (N = 73). In the NH cohort (N = 42), 9% had developed a bone complication after 10 years in the signs/symptoms phase, while 21% had undergone a splenectomy. In the ERT cohort (N = 29 (A), N = 28 (B)), 12% (A) or 4% (B) had developed a bone complication after 10 years in this phase and no patient was splenectomized. No patients in the NH cohort recovered, compared to 50% in the ERT cohort after 3.6 years (N = 28 (A)) or 22.4 years (N = 27 (B)) of treatment. Median time from a first to a second complication was 11 years in the NH cohort (N = 31), whereas 16 respectively 14 percent had developed a second complication after 10 years in the ERT cohort (N = 17, scenario A/B). Fourteen percent (scenario A/B) developed an associated malignancy after 10 years in the phase ‘multiple complications’ (N = 23). Associated malignancies occurred almost exclusively in advanced disease stages, therefore it is suggested that ERT reduces their incidenceLong-term ERT for GD can reduce the incidence of splenectomy and bone complications. As ERT prevents progression to more advanced stages of GD it will most likely result in a reduction of associated malignancies.

Cooperative International Neuromuscular Research Group Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy.

Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). This investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Two hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.

Validating predictors of disease progression in a large cohort of primary-progressive multiple sclerosis based on a systematic literature review.

BackgroundNew agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory.ObjectiveTo analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients.MethodsA systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change.ResultsThe systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change.ConclusionNone of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.

UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model

ObjectivesIn 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the...

Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.MethodsRenal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.ResultsOf 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively).ConclusionsLong term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.

A single lesion—And yet MS?

Barts and The London School of Medicine & Dentistry 2 Newark Street, London E1 2AT, United KingdomThe cornerstone for a clinical diagnosis of multiple sclerosis(MS) is the demonstration of dissemination in space (DIS)and time (DIT) of lesions in the central nervous systemsuggestive of demyelination in the absence of a differentialdiagnosis that would better explain a patient’s symptoms(Polman et al., 2011).In a paper published in Neurology, Schmalstieg et al.(2012) reported seven cases of progressive myelopathy thatneither fulfilled standard criteria for MS nor for any of itsmany differential diagnoses (Miller et al., 2008). Rather,symptoms and signs were attributable to a solitary lesionsuggestive of demyelination in the brainstem or spinal cord.None of the reported cases developed any further lesion,neither clinically nor – where available – on MRI.The case series reported by Schmalstieg et al. consists ofquite a heterogeneous group of patients. Three had aninsidious onset, another three had relapses and remissionsreferable to the same site and one had a sub-acute coursewith partial resolution and subsequent progression after6 months. Only three of their cases had follow-up MRIconfirming short lesions in the brainstem or spinal cord,and for one patient no MRI was available at all. Of the sixcases where cerebro-spinal fluid was tested, four hadunmatched oligoclonal bands. The three cases tested forNMO immunoglobulin G had negative results. The medianfollow-up was 3 years. What unified these cases was thereported solitary lesion causing symptoms.Excluding one outlier who had been symptomatic for 27years, the average disease duration of the cohort was5.5 years, making it difficult to predict whether some of theirpatients will still develop classic DIS, thereby fulfilling currentdiagnostic criteria for MS ( Polman et al., 2011). In a recentstudy, based on the natural history cohort from LondonOntario, over 20% of patients with relapse onset MS had afirst inter-attack interval of 6 years or more (Scalfari et al.,2010). Further, we can only assume patients’ ethnicity in thestudy by Schmalstieg et al. (white Caucasian?), and that theytested negative for antibodies against HTLV-1.However, despite the incomplete nature of their auditdata, and the limited time of follow-up, Schmalstieg et al.highlight a challenge any neurologist with an interest in MSoccasionally faces: the patient with a single lesion ofpresumed demyelinaton who develops a chronic progressivesyndrome clinically undistinguishable from primary progres-sive MS – whilst never fulfilling the criterion for DIS.To some extent, the study by Schmalstieg et al. remindsus of the limited toolbox currently available to clinicians,which does not regularly include techniques such as quanti-tative and high-field MRI or optical coherence tomography,both highly sensitive tools to detect tissue damage as itcharacteristically occurs in MS. For example, whilst corticalMS lesions are well described histologically, only non-standard MRI techniques such a double inversion recovery(DIR; Boulby et al., 2004) are able to detect (a proportionof) such lesions. It would be interesting to investigate thecohort reported by Schmalstieg et al. using DIR or othernovel techniques such as phase sensitive inversion recovery(Sethi et al., 2012) to explore whether the detection ofcortical lesions could help to establish DIS, keeping in mindthat lesions in the cortex have yet to be formally incorpo-rated in a diagnostic algorithm for MS (Geurts et al., 2011).Schmalstieg et al. speculate about potential mechanismsunderlying axonal degeneration in their small cohort, but inthe absence of further data on, for example, brain atrophythe basis for this discussion remains limited. Diagnostically,however, we share their impression that of the small numberof patients in which application of standard diagnostictools does not underpin the disseminated nature of an

Causes of death in patients with hepatitis B: A natural history cohort study in the United States

The natural history of hepatitis B virus (HBV) infection in a U.S. population has not been well described. We identified the causes of death in 6,689 health plan members infected with HBV who were followed between March 1, 1996 and December 31, 2005. Causes of death were grouped into HBV-related (subdivided into decompensated cirrhosis [DCC] and hepatocellular carcinoma [HCC]), cancer, cardiovascular, and other/unknown. The study cohort included 3,244 females and 3,445 males; 68.3% were of Asian-Pacific Islander (API) descent, 11.8% were white (non-Hispanic), and 19.9% were of other or unknown race. Exposure to HBV antivirals and preexisting comorbidities were uncommon. Males had higher overall 10-year death rates than females, both for total deaths (8.9% versus 4.1%) and for HBV-related deaths (4.8% versus 1.2%). The death rate rose markedly with increasing age, and approximately 40% of all deaths in subjects over the age of 40 were HBV related. The death rate from HCC was twice that of DCC. HCC deaths represented 70% of cancer deaths in males and 37% in females. On multivariable analysis, when subjects with antecedent HCC and DCC were excluded, the only significant predictor of HBV mortality in both sexes was age. HBV was the cause of death in over 40% of those who died during the study, and the mortality increased markedly with increasing age over 40 in males and over 50 in females. HBV-related mortality was four times more common in males than in females and was as common in non-Asians as in those of API origin. HBV-related deaths were twice as common from HCC as from DCC.

Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1.

HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies.

Frequency of adverse reactions to first- and second-line anti-tuberculosis chemotherapy in a Korean cohort

To determine the frequency of and risk factors for major adverse drug reactions (MADRs) associated with anti-tuberculosis treatment at a tuberculosis (TB) referral hospital in the Republic of Korea. Data from an ongoing natural history cohort study were analyzed for permanent regimen changes due to adverse drug reactions and confirmed by chart review. Among 655 subjects, there were 132 MADRs in 112 (17%) subjects. The most common MADRs were gastrointestinal (n = 53), musculoskeletal (n = 22), psychiatric (n = 10), visual (n = 9) and peripheral neuropathic (n = 8). MADRs were more frequent in subjects being treated with second-line regimens (16%) compared to first-line regimens (2.5%). Drugs frequently associated with MADRs were amikacin (3/10, 30%), linezolid (8/29, 28%), para-aminosalicylic acid (47/192, 24%), pyrazinamide (31/528, 5.8%), macrolides (2/44, 4.5%) and cycloserine (12/272, 4.4%). Fluoroquinolones accounted for a single MADR (1/377, 0.003%), despite widespread usage. In multivariate analysis, infection with multi- or extensively drug-resistant disease and previous history of anti-tuberculosis treatment were risk factors for MADR, with adjusted hazard ratios of respectively 2.2 (P = 0.02) and 1.6 (P = 0.04). MADRs are common during anti-tuberculosis chemotherapy in this population, occurring in more than one in six subjects. New and less toxic agents to treat drug-resistant TB are urgently needed.

Single Nucleotide Polymorphisms in the PRDX3 and RPS19 and Risk of HPV Persistence and Cervical Precancer/Cancer

BackgroundHost genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer.Methodology/Principal FindingsWe assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1113 genes in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 women with persistent carcinogenic HPV infection (median persistence of 25 months) and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women from the Guanacaste, Costa Rica HPV natural history cohort. For gene and SNP associations, we computed age-adjusted odds ratio and p-trend. Three comparisons were made: 1) association with CIN3/cancer (compared CIN3/cancer cases to random controls), 2) association with persistence (compared HPV persistence to random controls), and 3) progression (compared CIN3/cancers with HPV-persistent group). Regions statistically significantly associated with CIN3/cancer included genes for peroxiredoxin 3 PRDX3, and ribosomal protein S19 RPS19. The single most significant SNPs from each gene associated with CIN3/cancer were PRDX3 rs7082598 (P trend<0.0001), and RPS19 rs2305809 (P trend=0.0007), respectively. Both SNPs were also associated with progression.Conclusions/SignificanceThese data suggest involvement of two genes, RSP19 and PRDX3, or other SNPs in linkage disequilibrium, with cervical cancer risk. Further investigation showed that they may be involved in both the persistence and progression transition stages. Our results require replication but, if true, suggest a role for ribosomal dysfunction, mitochondrial processes, and/or oxidative stress, or other unknown function of these genes in cervical carcinogenesis.

Relationship of Serum Fibroblast Growth Factor 21 with Abnormal Glucose Metabolism and Insulin Resistance: The Baltimore Longitudinal Study of Aging

The relationship of fibroblast growth factor 21 (FGF21) with glucose metabolism and insulin resistance has not been well characterized in community-dwelling adults. The objective of the study was to examine the relationship of FGF21 with glucose metabolism and insulin resistance. Serum FGF21, fasting plasma glucose (FPG), glucose tolerance, and insulin resistance were measured in a cross-sectional study, 2002-2007. The study was the Baltimore Longitudinal Study of Aging, a natural history cohort study of aging in community-dwelling men and women. Seven hundred adults, mean age 63.3 yr, participated in the study. FPG, 2-h plasma glucose, homeostasis model of insulin resistance, whole-body insulin sensitivity (Matsuda index), glucose area under the curve (AUC), and insulin AUC were measured. Overall, the median (25th and 75th percentiles) FGF21 concentration was 225 (126, 370) pg/ml. The proportion of adults with normal, impaired, and diabetic FPG was 77.0, 21.4, and 1.6%, and those with normal, impaired, and diabetic 2-h plasma glucose was 76.7, 19.1, and 4.1%, respectively. Log serum FGF21 (picograms per milliliter), per 1 sd increase, was associated with an FPG (odds ratio 1.43, 95% confidence interval 1.15, 1.77, P = 0.001) and with 2-h plasma glucose (odds ratio 1.39, 95% confidence interval 1.12, 1.73, P = 0.003), in respective multivariate, ordered logistic regression models, adjusted for potential confounders. Serum FGF21 (picograms per milliliter) was associated with the homeostasis model of insulin resistance, the Matsuda index, glucose AUC, and insulin AUC (all P < 0.0001) in respective multivariable linear regression models adjusted for potential confounders. Higher serum FGF21 concentrations were associated with abnormal glucose metabolism and insulin resistance in community-dwelling adults.

Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia.

Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.

Surrogate endpoints for EDSS worsening in multiple sclerosis: A meta-analytic approach: Measuring disability in relapsing-remitting MS

# {#article-title-2} To the Editor: Sormani et al.1 attempt to validate multiple sclerosis (MS) relapse frequencies as surrogates for estimating the prevention of disability progression expected from relapse reduction. In pooled data on relapsing-remitting MS (RRMS), a strong association ( R 2 = 0.71; p < 0.001) was observed between treatment effects on relapses and on defined Expanded Disability Status Scale (EDSS) “worsening” defined in these trials. However, neither Sormani et al. nor the editorialists2 acknowledge that the measures of disability used in these trials could not be validated themselves.3 Trial-defined worsening was no more likely than improvement, identically defined, in placebo arms. The results of Sormani et al., limited to 2-year periods, conflict with natural history analysis of times to cane, bed, and death from MS at 28 years,4 information perhaps not available then.3 Low (1–2), intermediate (3–4), and high (greater than or equal to 5) attack frequencies during RRMS did not differ in times to hard disability endpoints. Frequent relapses from year 3 after onset to conversion to secondary progressive MS (SPMS) are associated with better outcomes, invalidating these relapses as outcomes predicting late disability.3 This epoch characterizes the data in the analysis by Sormani et al. Patients in trials and ethics committees considering their appropriateness should be aware that this measure cannot be validated. Potential benefit of relapse suppression on short-term neurologic dysfunction and possibly on lower, often asymptomatic, levels of the disability scale is conceded. In an untreated natural history cohort, we cannot support conclusions recently endorsed by Rudick and Kappos.2 Clinical trials usually observed for 2 years after randomization need the context of times to hard DSS endpoints as long as 2 …

Microbial Translocation: A Marker of Advanced HIV-1 Infection and a Predictor of Treatment Failure?

To the Editor—We agree that the issue of whether microbial translocation (MT) is a cause or consequence of human immunodeficiency virus type 1 (HIV-1) disease progression is an important question that can only be addressed through longitudinal analyses of natural history cohorts such as the study by Redd et al [1]. A timely and definitive answer to this question will depend on the availability of archived specimens that have been well characterized and properly stored. Specimen banks of this nature are relatively rare in Africa. However, there are issues of equal importance, namely, whether microbe-associated immune activation persists during highly active antiretroviral therapy (HAART) and whether this has an adverse effect on therapeutic outcome. There is already a growing body of evidence indicating that HAART-treated patients have elevated levels of bacterial DNA and plasma lipopolysaccharide (LPS) for at least 2 years after starting therapy [2], with one North American study showing decreased levels of LPS and CD4 T cell cycling after >5 years of maximally suppressive HAART [3]. There is also increasing evidence that elevated levels of LPS are associated with monocyte-macrophage activation and disease pathology, not only in HIV-1-infected patients with dementia [4] and hepatitis C–related liver disease [5], but also in HIV-1–negative patients with tuberculosis [6] and inflammatory bowel disease [7]. LPS has also been linked to T cell activation and proliferation [3], presumably via secretion of proinflammatory mediators by monocyte-macrophages. However, as emphasized by Redd et al, MT does not account for all aspects of immune activation in patients with late-stage disease. We examined the relationship between plasma LPS, HIV-1 viral load, and immune activation, before and after 1 year of nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART), in Africans with advanced HIV-1 disease and CD4 counts <200 cells/μL [8]. We found that some aspects of monocyte activation (CCL2, CXCL10, the frequency of CD14+CD16+ monocytes) were associated with high levels of HIV-1 RNA, whereas others (tumor necrosis factor [TNF], soluble CD14 [sCD14]) were more closely linked to plasma concentrations of LPS or the presence of opportunistic co-infections (interleukin 6). In addition to being independent of HIV-1 replication, LPS-associated activation, as measured by sCD14 and TNF, was independent of T cell activation and was only partially curtailed after 1 year of successful ART. These findings may help explain the results of Rempel et al [9]. Similar to our study, these investigators found that LPS and sCD14 remained elevated in HAART-treated patients. They also found that monocytes isolated from patients with high levels of residual viremia exhibited different patterns of gene expression after in vitro stimulation with LPS and interferon (IFN)–α. IFN-α activation resembled that observed in patients, while the LPS pattern differed from that normally induced following activation with whole bacteria (interleukin 10) or Fc/complement receptor–mediated phagocytosis (interleukin 6, interleukin 1β), leading to the conclusion that these monocytes were not responsive to LPS. However, LPS induced the up-regulation of a large number of genes (n = 992), a finding that is consistent with the ability of LPS to induce 5 different signaling cascades [10]. Whether these altered LPS patterns are due to a superimposed (or counterbalancing) effect of HIV-1 on monocyte activation or a defect in endotoxin tolerance remains to be determined. Additional studies should include HAART-treated patients with undetectable viremia and be performed using whole bacteria and LPS/LPS-binding protein (LBP) in addition to monomeric LPS. To rule out activation during positive selection with anti-CD14 antibodies, monocytes should be isolated using negative as well as positive selection methods. Additional studies are also needed to unravel the relationships between LPS, sCD14, and immune activation. CD14 binds and presents LBP-bound LPS to its signaling complex, lymphocyte antigen 96 (MD-2)/toll-like receptor 4 (TLR4), triggering monocyte-macrophage activation and the release of sCD14 [11]. sCD14 contributes to cell activation by transferring monomeric LPS to membrane CD14 (mCD14), or directly to the MD-2/TLR4 complex in cells that lack mCD14. However, sCD14 can also induce endotoxin tolerance by removing LPS from mCD14 and diverting it to plasma lipoproteins [11], a process that may decrease CD14 shedding. This is further complicated by studies showing that HIV-1 RNA can enhance TLR4-mediated response to LPS, causing dysregulation of endotoxin tolerance [12]. The complex relationships between HIV-1, MT, and immune activation are likely to depend on the integrity of gastrointestinal epithelium, the level of HIV-1 replication, plasma concentrations of LPS-binding protein and endotoxin core antibody, and the presence/absence and type of opportunistic co-infections, as well as the combined effects of these infections on TLR signaling cascades. Understanding these interactions may be critical to the design of strategies aimed at enhancing therapeutic efficacy in Africa where treatment is often delayed until CD4 counts drop to <200 cells/μL.