Background: With the rising use of immune checkpoint inhibitors (ICI) across varying tumors types, immune-related colitis is an increasingly encountered, serious adverse event requiring appropriate ...management. The incidence across ICI treatment regimens and tumor types is unclear.
Objective: To characterize the incidence of immune-related colitis among various ICI regimens and tumor types.
Methods: Thirty-four original studies of prospective ICI trials were identified based on a PubMed search completed on November 1st, 2016. Seventeen studies compared incidences across tumor types. The incidences of all-grade, grade 3-4 (severe) colitis, and grade 3-4 (severe) diarrhea were collected.
Results: Thirty-four studies containing 8863 patients were included in the meta-analysis. The overall incidence during ipilimumab monotherapy was 9.1% for all-grade colitis, 6.8% for severe colitis, and 7.9% for severe diarrhea. The incidence was lowest during PD-1/PD-L1 inhibitor monotherapy with 1.3% for all-grade colitis, 0.9% for severe colitis and 1.2% for severe diarrhea, while combination ipilimumab and nivolumab resulted in the highest incidences of all-grade colitis (13.6%), severe colitis (9.4%) and severe diarrhea (9.2%) among ICIs. Among melanoma, NSCLC, RCC patients, incidences of colitis and diarrhea with PD-1/PD-L1 inhibitor monotherapy did not significantly differ. Severe colitis incidence was similar with ipilimumab monotherapy at 3 mg/kg and 10 mg/kg (7.1% vs 5.1%, respectively), but significantly higher for severe diarrhea with 10mg/kg (11.5% vs 5.2%).
Conclusions: The incidence of immune-related colitis and severe diarrhea was higher with ipilimumab-containing regimens compared with PD-1/PD-L1 inhibitors. There was no significant difference in immune-related colitis between different tumor types with PD-1/L1 inhibitors.
Variants of TREM2 are associated with Alzheimer’s disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human ...TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.
•Elevating TREM2 gene dosage altered microglial morphology and interaction with Aβ•Increasing TREM2 gene dosage reprograms microglial responsivity in AD mouse brains•Transcriptomic profiling identified three groups of TREM2 gene-dosage-dependent genes•Extra TREM2 gene dosage ameliorates neuropathology and memory deficits in AD mice
Augmenting TREM2 gene dosage in AD mouse models leads to reduced amyloid burden and neuropathology and improved memory performance. Gene expression profiling reveals a reprogrammed disease-associated microglial response that may underlie the phenotypic improvement in AD models.
The web-based e-learning system (WELS) has emerged as a new means of skill training and knowledge acquisition, encouraging both academia and industry to invest resources in the adoption of this ...system. Traditionally, most pre- and post-adoption tasks related to evaluation are carried out from the viewpoints of technology. Since users have been widely recognized as being a key group of stakeholders in influencing the adoption of information systems, their attitudes toward this system are pivotal. Therefore, based on the theory of multi-criteria decision making and the research products of user satisfaction from the fields of human–computer interaction and information systems, this study proposed a multi-criteria methodology from the perspective of learner satisfaction to support those evaluation-based activities taking place at the pre- and post-adoption phases of the WELS life cycle. In addition, by following this methodology, this study empirically investigated learners’ perceptions of the relative importance of decision criteria. This investigation carried out a survey of college students, and the data thus obtained was then analyzed by analytic hierarchy process in order to derive an integrated preference structure of learners as a ground for evaluation. We found that learners regarded the learner interface as being the most important dimension of decision criteria. Future applications of these results are recommended and the implications are discussed.
Conventional biventricular (BiV) pacing cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients. Recently, multiple novel CRT delivering technologies such as ...His-Bundle pacing have been investigated as alternative pacing strategies for optimal treatment benefit. Electromechanical Wave Imaging (EWI), a high frame-rate echocardiography-based modality, is capable of visualizing the change from dyssynchronous activation to resynchronized BiV-paced ventricles in 3D. This proof-of-concept study introduces a new EWI-based dispersion metric to further characterize ventricular activation. Patients with His-Bundle device implantation (n = 4), left-bundle branch block (n = 10), right-ventricular (RV) pacing (n = 10), or BiV pacing (n = 15) were imaged, as well as four volunteers in normal sinus rhythm (NSR). EWI successfully mapped the ventricular activation resulting from His-Bundle pacing. Additionally, very similar activation patterns were obtained in the NSR subjects, confirming recovery of physiological activation with His pacing. The dispersion metric was the most sensitive EWI-based metric that identified His pacing as the most efficient treatment (lowest activation time spread), followed by BiV and RV pacing. More specifically, the dispersion metric significantly (p < 0.005) distinguished His pacing from the other two pacing schemes as well as LBBB. The initial findings presented herein indicate that EWI and its new dispersion metric may provide a useful resynchronization evaluation clinical tool in CRT patients under both novel His-Bundle pacing and more conventional BiV pacing strategies.
MicroRNAs are single-stranded RNA of 18-24 nt expressed endogenously that play important roles in cancer development. Here, we show that expression of miR-378 enhances cell survival, reduces ...caspase-3 activity, and promotes tumor growth and angiogenesis. Proteomic analysis indicates reduced expression of suppressor of fused (Sufu), a potential target of miR-378, which was confirmed in vitro and in vivo. Expression of a luciferase construct containing the target site in Sufu was repressed when cotransfected with miR-378. Transfection of a Sufu construct reversed the effect of miR-378, suggesting an important role for miR-378 in tumor cell survival. We also discovered that miR-378 targets Fus-1. Expression of luciferase constructs harboring the target sites in Fus-1 was repressed by miR-378. Fus-1 constructs with or without its 3' UTR were also generated. Cotransfection experiments showed that the presence of miR-378 repressed Fus-1 expression. Suppression of Fus-1 expression by siRNA against Fus-1 enhanced cell survival. Transfection of the Fus-1 construct reversed the function of miR-378 in cell survival. Our results suggest that miR-378 transfection enhanced cell survival, tumor growth, and angiogenesis through repression of the expression of two tumor suppressors, Sufu and Fus-1.
In patients with advanced renal-cell carcinoma, treatment with cabozantinib plus nivolumab and ipilimumab resulted in longer progression-free survival than treatment with nivolumab and ipilimumab ...alone.
Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to ...examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib n=599 and vemurafenib plus cobimetinib n=240), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine n=207 and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab n=331), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine n=320 and n=221) were classified according to BMI as normal (694 36% patients), overweight (711 37%), or obese (513 27%). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio HR 0·77 95% CI 0·66–0·90 for progression-free survival and 0·74 0·58–0·95 for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 0·57–0·91 for progression-free survival and 0·60 0·45–0·79 for overall survival) and immunotherapy (HR 0·75 0·56–1·00 and 0·64 0·47–0·86). No associations were observed with chemotherapy (HR 0·87 0·65–1·17, pinteraction=0·61 for progression-free survival and 1·03 0·80–1·34, pinteraction=0·01 for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 0·40–0·70), but no associations observed in women (HR 0·85 0·61–1·18, pinteraction=0·03).
Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations.
ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
CD4⁺ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like ...receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.
Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).
To determine if stereotactic ablative ...radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.
The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.
Patients were randomized in a 2:1 ratio to receive SABR or observation.
The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.
In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).
Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.
ClinicalTrials.gov Identifier: NCT02680587.
PDF
