Summary Background Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received ...radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. Methods We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov , number NCT01295827. Findings Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8–34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio HR 0·56 95% CI 0·34–0·91, p=0·019; median progression-free survival 4·4 months 95% CI 2·1–8·6 vs 2·1 months 1·6–2·3) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 0·30–0·84, p=0·0084; median progression-free survival 6·3 months 95% CI 2·1–10·4 vs 2·0 months 1·8–2·1). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 95% CI 0·36–0·94, p=0·026; median overall survival 10·7 months 95% CI 6·5–18·9 vs 5·3 months 2·7–7·7) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 95% CI 0·36–0·96, p=0·034; median overall survival 11·6 months 95% CI 6·5–20·5 vs 5·3 months 3·0–8·5). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Interpretation Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. Funding US National Institutes of Health.
Recent advances in spatially resolved transcriptomics (SRT) technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To ...elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and histology in SRT data analysis. Through graph convolution, SpaGCN aggregates gene expression of each spot from its neighboring spots, which enables the identification of spatial domains with coherent expression and histology. The subsequent domain guided differential expression (DE) analysis then detects genes with enriched expression patterns in the identified domains. Analyzing seven SRT datasets using SpaGCN, we show it can detect genes with much more enriched spatial expression patterns than competing methods. Furthermore, genes detected by SpaGCN are transferrable and can be utilized to study spatial variation of gene expression in other datasets. SpaGCN is computationally fast, platform independent, making it a desirable tool for diverse SRT studies.
Objective
To see whether the distribution patterns of phosphorylated 43kDa TAR DNA‐binding protein (pTDP‐43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of ...neuropathological stages.
Methods
pTDP‐43 immunohistochemistry was performed on 70μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.
Results
ALS cases with the lowest burden of pTDP‐43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X–XII, and spinal cord α‐motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP‐43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP‐43 lesions showed pTDP‐43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP‐43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP‐43 pathology.
Interpretation
pTDP‐43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP‐43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP‐43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS. Ann Neurol 2013;74:20–38
The stereotypical distribution of TAR DNA-binding 43 protein (TDP-43) aggregates in frontotemporal lobar degeneration (FTLD-TDP) suggests that pathological TDP-43 spreads throughout the brain via ...cell-to-cell transmission and correlates with disease progression, but no in vivo experimental data support this hypothesis. We first develop a doxycycline-inducible cell line expressing GFP-tagged cytoplasmic TDP-43 protein (iGFP-NLSm) as a cell-based system to screen and identify seeding activity of human brain-derived pathological TDP-43 isolated from sporadic FTLD-TDP and familial cases with Granulin (FTLD-TDP-GRN) or C9orf72 repeat expansion mutations (FTLD-TDP-C9+). We demonstrate that intracerebral injections of biologically active pathogenic FTLD-TDP seeds into transgenic mice expressing cytoplasmic human TDP-43 (lines CamKIIa-hTDP-43
, rNLS8, and CamKIIa-208) and non-transgenic mice led to the induction of de-novo TDP-43 pathology. Moreover, TDP-43 pathology progressively spreads throughout the brain in a time-dependent manner via the neuroanatomic connectome. Our study suggests that the progression of FTLD-TDP reflects the templated cell-to-cell transneuronal spread of pathological TDP-43.
Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present ...international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (
n
= 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.
Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic ...mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100–1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.
•Transgenic mice expressing the C9orf72 repeat expansion were generated•C9-BACexp mice develop widespread RNA foci and RAN peptide pathology•Expanded C9orf72 led to altered nucleolin distribution•RNA foci and RAN peptides can be suppressed by ASOs to human C9orf72
Repeat expansions in C9orf72 are the most common cause of ALS and FTD. O’Rourke et al. generated BAC transgenic mice with expanded human C9orf72 that develop widespread RNA foci and DPR proteins, but lack neurodegeneration.
Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein ...aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer’s disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
•TDP-43 regulates microglial phagocytosis and clearance of Aβ•Depletion of microglial TDP-43 results in enhanced synapse loss•Depletion of microglial TDP-43 promotes amyloid clearance in a mouse model of AD•TDP-43 pathology is associated with lower amyloid deposition in post-mortem brains
Paolicelli et al. show that TDP-43 is a regulator of microglial phagocytosis. They found that mice lacking microglial TDP-43 display enhanced amyloid clearance but also significant synapse loss. They also show that TDP-43 pathology is associated with reduced amyloid burden in human brains.
Obesity has various deleterious effects on health largely associated with metabolic abnormalities including abnormal glucose and lipid homeostasis that are associated with vascular injury and known ...cardiac, renal, and cerebrovascular complications. Advanced age is also associated with increased adiposity, decreased lean mass, and increased risk for obesity‐related diseases. Although many of these obesity‐ and age‐related disease processes have long been subsumed to be secondary to metabolic or vascular dysfunction, increasing evidence indicates that obesity also modulates nonvascular diseases such as Alzheimer's disease (AD) dementia. The link between peripheral obesity and neurodegeneration will be explored, using adipokines and AD as a template. After an introduction to the neuropathology of AD, the relationship between body weight, obesity, and dementia will be reviewed. Then, population‐based and experimental studies that address whether leptin modulates brain health and mitigates AD pathways will be explored. These studies will serve as a framework for understanding the role of adipokines in brain health.
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