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Researchers often analyze cancer registry data to assess for differences in survival among cancer treatments. However, the retrospective, nonrandomized design of these analyses raises questions about study validity. To examine the extent to which comparative effectiveness analyses using observational cancer registry data produce results concordant with those of randomized clinical trials. In this comparative effectiveness study, a total of 141 randomized clinical trials referenced in the National Comprehensive Cancer Network Clinical Practice Guidelines for 8 common solid tumor types were identified. Data on participants within the National Cancer Database (NCDB) diagnosed between 2004 and 2014, matching the eligibility criteria of the randomized clinical trial, were obtained. The present study was conducted from August 1, 2017, to September 10, 2019. The trials included 85 118 patients, and the corresponding NCDB analyses included 1 344 536 patients. Three Cox proportional hazards regression models were used to determine hazard ratios (HRs) for overall survival, including univariable, multivariable, and propensity score-adjusted models. Multivariable and propensity score analyses controlled for potential confounders, including demographic, comorbidity, clinical, treatment, and tumor-related variables. The main outcome was concordance between the results of randomized clinical trials and observational cancer registry data. Hazard ratios with an NCDB analysis were considered concordant if the NDCB HR fell within the 95% CI of the randomized clinical trial HR. An NCDB analysis was considered concordant if both the NCDB and clinical trial P values for survival were nonsignificant (P ≥ .05) or if they were both significant (P < .05) with survival favoring the same treatment arm in the NCDB and in the randomized clinical trial. Analyses using the NCDB-produced HRs for survival were concordant with those of 141 randomized clinical trials in 79 univariable analyses (56%), 98 multivariable analyses (70%), and 90 propensity score models (64%). The NCDB analyses produced P values concordant with randomized clinical trials in 58 univariable analyses (41%), 65 multivariable analyses (46%), and 63 propensity score models (45%). No clinical trial characteristics were associated with concordance between NCDB analyses and randomized clinical trials, including disease site, type of clinical intervention, or severity of cancer. The findings of this study suggest that comparative effectiveness research using cancer registry data often produces survival outcomes discordant with those of randomized clinical trial data. These findings may help provide context for clinicians and policy makers interpreting observational comparative effectiveness research in oncology.

Magnetic resonance imaging (MRI) has played a central role in the diagnosis and management of multiple sclerosis (MS). In addition, MRI metrics have become key supportive outcome measures to explore drug efficacy in clinical trials. Conventional MRI measures have contributed to the understanding of MS pathophysiology at the macroscopic level yet have failed to provide a complete picture of underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical progression. Advanced quantitative MRI measures such as magnetization transfer, spectroscopy, diffusion imaging, and relaxometry techniques are somewhat more specific and sensitive for underlying pathology. These measures are particularly useful in revealing diffuse damage in cerebral white and gray matter and therefore may help resolve the dissociation between clinical and conventional MRI findings. In this article, we provide an overview of the array of tools available with brain and spinal cord MRI technology as it is applied to MS. We review the most recent data regarding the role of conventional and advanced MRI techniques in the assessment of MS. We focus on the most relevant pathologic and clinical correlation studies relevant to these measures.

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin–spin relaxometry detected damage in NAWM of MS patients (n=13) vs. age-matched normal controls [(NL) (n=11)]. Baseline characteristics of the MS group were: age (mean±SD) 42.5±5.4 (range 33–51 years), disease duration 9.0±6.4 (range 1–22 years), Expanded Disability Status Scale score 2.5±1.7 (range 1–6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p=0.00047), frontal NAWM (p=0.00015), parietal NAWM (p=0.0069) and callosal genu (p=0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p=0.019). However, the normalized WM volume fractions were similar in both MS and NL (p>0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.

Issue Title: Novel Therapeutics for Alzheimer's Disease

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin–spin relaxometry detected damage in NAWM of MS patients (n = 13) vs. age-matched normal controls [(NL) (n = 11)]. Baseline characteristics of the MS group were: age (mean ± SD) 42.5 ± 5.4 (range 33–51 years), disease duration 9.0 ± 6.4 (range 1–22 years), Expanded Disability Status Scale score 2.5 ± 1.7 (range 1–6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (= 1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p = 0.00047), frontal NAWM (p = 0.00015), parietal NAWM (p = 0.0069) and callosal genu (p = 0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p = 0.019). However, the normalized WM volume fractions were similar in both MS and NL (p > 0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.

Combine MRI measures of disease severity into a composite score in patients with multiple sclerosis (MS). Brain MRI lesion and atrophy measures assessed individually have fairly weak ability to predict clinical progression in MS. In the Comprehensive Longitudinal Investigation of MS at Brigham, we studied 103 patients [age (mean ± SD) 42.7 ± 9.1 years, disease duration 14.1 ± 9.2 years, Expanded Disability Status Scale (EDSS) score 3.3 ± 2.2, 60% (n = 62) relapsing–remitting (RR), 32% (n = 33) secondary progressive (SP), and 8% (n = 8) primary progressive]. Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume, and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1/T2 ratio. MRDSS score averaged 5.1 ± 2.6. Baseline MRI and EDSS correlations were moderate for BPF, T1/T2, and MRDSS and weak for T2LV. MRDSS showed a larger effect size than any of the individual MRI components in distinguishing RR from SP patients. Models containing either T2LV or MRDSS were significantly associated with EDSS disability progression during the 3.2 ± 0.3 year observation period, when adjusting for baseline EDSS score. These results show that combining brain MRI lesion and atrophy measures can predict clinical progression in patients with MS and provide the basis to develop an MRI-based continuous scale as a marker of MS disease severity.

Background Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables. Results PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients. Conclusions CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.

Background Elevated CSF Ï,, is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of Ï,, species in other primary tauopathies. We assessed CSF Ï,, protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) Ï,, with minimal Aβ pathology. Methods 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total Ï,,, and ptau181. Additional, novel ELISAs targeting different N-terminal and central Ï,, epitopes were developed to examine CSF Ï,, components and to investigate interactions between diagnostic group, demographics and genetic variables. Results PSP had lower CSF N-terminal and C-terminal Ï,, concentrations than NC and AD measured with the novel Ï,, ELISAs and the standard AlzBio3 Ï,, and ptau assays. AD had higher total Ï,, and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most Ï,, species, with lower concentrations for male compared to female patients. Conclusions CSF Ï,, fragment concentrations are different in PSP compared with AD despite the presence of severe Ï,, pathology and neuronal injury in both disorders. CSF Ï,, concentration likely reflects multiple factors in addition to the degree of neuronal injury.