Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate ...markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.
We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 ...proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is ...sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer’s disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau ...accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also develop seeding activity prior to accumulation of phospho-tau. We measured tau seeding activity across four brain regions (hippocampus, frontal lobe, parietal lobe, and cerebellum) in 104 fresh-frozen human AD brain samples from all Braak stages. We observed widespread seeding activity, notably in regions predicted to be free of phospho-tau deposition, and in detergent-insoluble fractions that lacked tau detectable by ELISA. Seeding activity correlated positively with Braak stage and negatively with MMSE. Our results are consistent with early transcellular propagation of tau seeds that triggers subsequent development of neuropathology. The FRET-based seeding assay may also complement standard neuropathological classification of tauopathies.
We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with ...neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
Background
Morbid obesity and malnutrition are thought to be associated with more frequent perioperative complications after TKA. However, morbid obesity and malnutrition often are co-occurring ...conditions. Therefore it is important to understand whether morbid obesity, malnutrition, or both are independently associated with more frequent perioperative complications. In addition, assessing the magnitude of an increase in complications and whether these complications are major or minor is important for both conditions.
Questions/purposes
We asked: (1) Is morbid obesity independently associated with more frequent major perioperative complications after TKA? (2) Are major perioperative complications after TKA more prevalent among patients with a low serum albumin?
Methods
The National Surgical Quality Improvement Program (NSQIP) database was analyzed from 2006 to 2013. Patients were grouped as morbidly obese (BMI ≥ 40 kg/m
2
) or nonmorbidly obese (BMI ≥ 18.5 kg/m
2
to < 40 kg/m
2
), or by low serum albumin (serum albumin level < 3.5 mg/dL) or normal serum albumin (serum albumin level ≥ 3.5 mg/dL). The study cohort included 77,785 patients, including 35,573 patients with a serum albumin level of 3.5 g/dL or greater and 1570 patients with a serum albumin level less than 3.5 g/dL. Therefore, serum albumin levels were available for only 37,173 of the 77,785 of the patients (48%). There were 66,382 patients with a BMI between 18.5 kg/m
2
and 40 kg/m
2
and 11,403 patients with a BMI greater than 40 kg/m
2
. Data were recorded on patient mortality along with 21 complications reported in the NSQIP. We also developed three composite complication variables to represent risk of any infections, cardiac or pulmonary complications, and any major complications. For each complication, multivariate logistic regression analysis was performed. Independent variables included patient age, sex, race, BMI, American Society of Anesthesiologists classification, year of surgery, and Charlson comorbidity index score.
Results
Mortality was not increased in the morbidly obese group (0.14% vs 0.14%; p = 0.942). Patients who were morbidly obese were more likely to have progressive renal insufficiency (0.30% vs 0.10%; odds ratio OR, 2.47; 95% CI, 1.27–4.29; p < 0.001), superficial infection (1.07% vs 0.55%; OR, 1.87; 95% CI, 1.39–2.51; p < 0.001), and sepsis (0.36% vs 0.23%; OR, 1.70; 95% CI, 1.04–2.53; p = 0.034) compared with patients who were not morbidly obese. Patients who were morbidly obese were less likely to require blood transfusion (8.68% vs 12.06%; OR, 0.70; 95% CI, 0.63–0.77; p < 0.001) compared with patients who were not morbidly obese. Morbid obesity was not associated with any of the other 21 perioperative complications recorded in the NSQIP database. With respect to the composite complication variables, patients who were morbidly obese had an increased risk of any infection (3.31% vs 2.41%; OR, 1.38; 95% CI, 1.16–1.64; p < 0.001) but not for cardiopulmonary or any major complication. The group with low serum albumin had higher mortality than the group with normal serum albumin (0.64% vs 0.15%; OR, 3.17; 95% CI, 1.58–6.35; p = 0.001). Patients in the low serum albumin group were more likely to have a superficial surgical site infection (1.27% vs 0.64%; OR, 1.27; 95% CI, 1.09–2.75; p = 0.020); deep surgical site infection (0.38% vs 0.12%; OR, 3.64; 95% CI, 1.54–8.63; p = 0.003); organ space surgical site infection (0.45% vs 0.15%; OR, 2.71; 95% CI, 1.23–5.97; p = 0.013); pneumonia (1.21 vs 0.29%; OR, 3.55; 95% CI, 2.14–5.89; p < 0.001); require unplanned intubation (0.51% vs 0.17%, OR, 2.24; 95% CI, 1.07–4.69; p = 0.033); and remain on a ventilator more than 48 hours (0.38% vs 0.07%; OR, 4.03; 95% CI, 1.64–9.90; p = 0.002). They are more likely to have progressive renal insufficiency (0.45 % vs 0.12%; OR, 2.71; 95% CI, 1.21–6.07; p = 0.015); acute renal failure (0.32% vs 0.06%; OR, 5.19; 95% CI, 1.96–13.73; p = 0.001); cardiac arrest requiring cardiopulmonary resuscitation (0.19 % vs 0.12%; OR, 3.74; 95% CI, 1.50–9.28; p = 0.005); and septic shock (0.38% vs 0.08%; OR, 4.4; 95% CI, 1.74–11.09; p = 0.002). Patients in the low serum albumin group also were more likely to require blood transfusion (17.8% vs 12.4%; OR, 1.56; 95% CI, 1.35–1.81; p < 0.001). In addition, among the three composite complication variables, any infection (5.0% vs 2.4%; OR, 2.0; 95% CI, 1.53–2.61; p < 0.001) and any major complication (2.4% vs 1.3%; OR, 1.41; 95% CI, 1.00–1.97; p = 0.050) were more prevalent among the patients with low serum albumin. There was no difference for cardiopulmonary complications.
Conclusions
Morbid obesity is not independently associated with the majority of perioperative complications measured by the NSQIP and was associated only with increases in progressive renal insufficiency, superficial surgical site infection, and sepsis among the 21 perioperative variables measured. However, low serum albumin was associated with increased mortality and multiple additional major perioperative complications after TKA. Low serum albumin, more so than morbid obesity, is associated with major perioperative complications. This is an important finding, as low serum albumin may be more modifiable than morbid obesity in patients who are immobile or have advanced knee osteoarthritis.
Level of Evidence
Level III, prognostic study.
Oxidative stress and the reactive oxygen species (ROS) have important roles in osteoarthritis (OA) development and progression. Scavenging ROS by exogenous antioxidant enzymes could be a promising ...approach for OA treatment. However, the direct use of antioxidant enzymes, such as superoxide dismutase (SOD), is challenging due to a lack of effective drug delivery system to knee joints. This study utilized a highly efficient antioxidative nanoparticle based on SOD-loaded porous polymersome nanoparticles (SOD-NPs) for delivery of SOD to mouse knee joints. The resultant SOD-NPs had prolonged mouse joint retention time with predominant accumulation in synovium but not in articular cartilage. Examining human synovial explants revealed that SOD-NPs minimize oxidative damages induced by OA-like insults. Intra-articular injections of SOD-NPs in mice receiving OA surgery were effective in attenuating OA initiation and preventing its further progression. Mechanistically, SOD-NPs reduced ROS production and the synthesis of catabolic proteases in both articular cartilage and synovium. Hence, our work demonstrates the therapeutic potential of SOD-NPs and indicate that targeting synovium holds a great promise for OA therapy.
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on ...clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
COVID-19 created unprecedented challenges in surgical training especially in specialties with high elective case volume. We hypothesized that case volume during total joint arthroplasty fellowship ...training would decrease by 25% given widespread economic shutdowns encountered during the fourth quarter of the 2019-2020 academic year.
Case logs from the Accreditation Council for Graduate Medical Education were obtained for accredited total joint arthroplasty fellowships (2017-2018 to 2020-2021). Case volumes were extracted and summarized as means ± SD. Student’s t tests were used for inter-year comparisons.
One hundred and eighty three arthroplasty fellows from 24 accredited fellowships were included. There was a 14% year-over-year decrease in total case volume during the 2019-2020 academic year (390 ± 108 vs 453 ± 128, P < .001). Case volume rebounded during the 2020-2021 academic year to 465 ± 93 (19% increase, P < .001). Case categories with the most significant percentage declines in 2019-2020 were primary total knee arthroplasty (TKA, −23%), revision total hip arthroplasty (THA, −19%), revision TKA (rTKA, −11%), and primary THA (−10%).
There was a 14% overall decrease in arthroplasty case volume during the 2019-2020 academic year, which correlated with the widespread economic shutdowns during the COVID-19 pandemic. Certain elective case categories like primary TKA experienced the greatest negative impact. Results from this study may inform prospective trainees and faculty during future national emergencies.
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