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1.
Immunotherapy ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33086925

RESUMO

Biomarkers for immune checkpoint inhibitors (ICIs) are limited in gastrointestinal cancer. Peripheral blood lymphocyte subset and associated dynamic changes were retrospectively analyzed in patients with gastrointestinal cancer treated with ICIs. Cox regression and Kaplan-Meier analyses were conducted for survival. A total of 80 patients were enrolled. Baseline CD4+/CD8+ T cells were lower in patients who experienced tumor progression by 6 months than in patients who did not (1.160 ± 0.652 vs 1.705 ± 0.924, respectively; p = 0.003). In multivariate analyses, decline in CD4+ T cells after the first dose of ICIs (CD4-C1-decline) was an independent prognostic factor for overall survival (hazard ratio: 13.00; 95% CI: 2.24-75.54; p = 0.004). Furthermore, CD4-C1-decline was a preferable indicator for progression in patients with deficient mismatch repair/microsatellite instability-high (p = 0.027). Early change in CD4+ T cell counts in peripheral blood may act as a prognostic biomarker for gastrointestinal cancer patients treated with ICIs.

2.
J Clin Oncol ; : JCO2001888, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026938

RESUMO

PURPOSE: Patients with advanced esophageal cancer have a poor prognosis and limited treatment options after first-line chemotherapy. PATIENTS AND METHODS: In this open-label, phase III study, we randomly assigned (1:1) 628 patients with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, that progressed after one prior therapy, to pembrolizumab 200 mg every 3 weeks for up to 2 years or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). Primary end points were overall survival (OS) in patients with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 10, in patients with squamous cell carcinoma, and in all patients (one-sided α 0.9%, 0.8%, and 0.8%, respectively). RESULTS: At final analysis, conducted 16 months after the last patient was randomly assigned, OS was prolonged with pembrolizumab versus chemotherapy for patients with CPS ≥ 10 (median, 9.3 v 6.7 months; hazard ratio [HR], 0.69 [95% CI, 0.52 to 0.93]; P = .0074). Estimated 12-month OS rate was 43% (95% CI, 33.5% to 52.1%) with pembrolizumab versus 20% (95% CI, 13.5% to 28.3%) with chemotherapy. Median OS was 8.2 months versus 7.1 months (HR, 0.78 [95% CI, 0.63 to 0.96]; P = .0095) in patients with squamous cell carcinoma and 7.1 months versus 7.1 months (HR, 0.89 [95% CI, 0.75 to 1.05]; P = .0560) in all patients. Grade 3-5 treatment-related adverse events occurred in 18.2% of patients with pembrolizumab versus 40.9% in those who underwent chemotherapy. CONCLUSION: Pembrolizumab prolonged OS versus chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.

3.
Med Sci Monit ; 26: e924671, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33077705

RESUMO

BACKGROUND Despite the promising results of immunotherapy in cancer treatment, new response patterns, including pseudoprogression and hyperprogression, have been observed. Radiomics is the automated extraction of high-fidelity, high-dimensional imaging features from standard medical images, allowing comprehensive visualization and characterization of the tissue of interest and corresponding microenvironment. This study assessed whether radiomics can predict response to immunotherapy in patients with malignant tumors of the digestive system. MATERIAL AND METHODS Computed tomography (CT) images of patients with malignant tumors of the digestive system obtained at baseline and after immunotherapy were subjected to radiomics analyses. Radiomics features were extracted from each image. The formula of the screened features and the final predictive model were obtained using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. RESULTS Imaging analysis was feasible in 87 patients, including 3 with pseudoprogression and 7 with hyperprogression. One hundred ten radiomics features were obtained before and after treatment, including 109 features of the target lesions and 1 of the aorta. Four models were constructed, with the model constructed from baseline and post-treatment CT features having the best classification performance, with a sensitivity, specificity, and AUC of 83.3%, 88.9%, and 0.806, respectively. CONCLUSIONS Radiomics can predict the response of patients with malignant tumors of the digestive system to immunotherapy and can supplement conventional evaluations of response.

4.
Adv Ther ; 37(11): 4585-4598, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32901330

RESUMO

INTRODUCTION: In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial. METHODS: In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized. RESULTS: A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib. CONCLUSIONS: The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population. TRIAL REGISTRATION: Clinical Trials identifier NCT02314819.

5.
PLoS One ; 15(9): e0239536, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32997700

RESUMO

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) has created unprecedented medical challenges. There remains a need for validated risk prediction models to assess short-term mortality risk among hospitalized patients with COVID-19. The objective of this study was to develop and validate a 7-day and 14-day mortality risk prediction model for patients hospitalized with COVID-19. METHODS: We performed a multicenter retrospective cohort study with a separate multicenter cohort for external validation using two hospitals in New York, NY, and 9 hospitals in Massachusetts, respectively. A total of 664 patients in NY and 265 patients with COVID-19 in Massachusetts, hospitalized from March to April 2020. RESULTS: We developed a risk model consisting of patient age, hypoxia severity, mean arterial pressure and presence of kidney dysfunction at hospital presentation. Multivariable regression model was based on risk factors selected from univariable and Chi-squared automatic interaction detection analyses. Validation was by receiver operating characteristic curve (discrimination) and Hosmer-Lemeshow goodness of fit (GOF) test (calibration). In internal cross-validation, prediction of 7-day mortality had an AUC of 0.86 (95%CI 0.74-0.98; GOF p = 0.744); while 14-day had an AUC of 0.83 (95%CI 0.69-0.97; GOF p = 0.588). External validation was achieved using 265 patients from an outside cohort and confirmed 7- and 14-day mortality prediction performance with an AUC of 0.85 (95%CI 0.78-0.92; GOF p = 0.340) and 0.83 (95%CI 0.76-0.89; GOF p = 0.471) respectively, along with excellent calibration. Retrospective data collection, short follow-up time, and development in COVID-19 epicenter may limit model generalizability. CONCLUSIONS: The COVID-AID risk tool is a well-calibrated model that demonstrates accuracy in the prediction of both 7-day and 14-day mortality risk among patients hospitalized with COVID-19. This prediction score could assist with resource utilization, patient and caregiver education, and provide a risk stratification instrument for future research trials.


Assuntos
Infecções por Coronavirus/mortalidade , Modelos Logísticos , Pneumonia Viral/mortalidade , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Feminino , Mortalidade Hospitalar , Hospitalização , Humanos , Masculino , Massachusetts , Pessoa de Meia-Idade , New York , Pandemias , Curva ROC , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco , Estados Unidos
6.
Lancet Oncol ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32966810

RESUMO

BACKGROUND: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.

7.
Lancet Oncol ; 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32966811

RESUMO

BACKGROUND: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. METHODS: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. FINDINGS: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). INTERPRETATION: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. FUNDING: Hutchison MediPharma.

8.
Artigo em Inglês | MEDLINE | ID: mdl-32893447

RESUMO

Driven by the persisting poor understanding of the sluggish kinetics of the hydrogen evolution reaction (HER) on Pt in alkaline media, a direct correlation of the interfacial water structure and activity is still yet to be established. Herein, using Pt and Pt-Ni nanoparticles we first demonstrate a strong dependence of the proton donor structure on the HER activity and pH. The structure of the first layer changes from the proton acceptors to the donors with increasing pH. In the base, the reactivity of the interfacial water varied its structure, and the activation energies of water dissociation increased in the sequence: the dangling O-H bonds < the trihedrally coordinated water < the tetrahedrally coordinated water. Moreover, optimizing the adsorption of H and OH intermediates can re-orientate the interfacial water molecules with their H atoms pointing towards the electrode surface, thereby enhancing the kinetics of HER. Our results clarified the dynamic role of the water structure at the electrode-electrolyte interface during HER and the design of highly efficient HER catalysts.

9.
Gastrointest Endosc ; 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32950597

RESUMO

BACKGROUND AND AIMS: At present, surveillance strategy for pre-malignant esophageal lesions in China is based solely on the pathologic diagnosis in Lugol's chromoendoscopy (LCE). In this study, we sought to determine the degree to which various unstained features under LCE may lead to improved ability to predict the risk of progression in esophageal lesions. METHODS: We re-examined and followed up on 1058 subjects who had Lugol-unstained lesions (LUL) together with a pathologic diagnosis, which was lower than severe dysplasia at baseline screening based on a population-based randomized controlled trial over a median time of 5.8 years. We established a logistic regression model and calculated the adjusted cumulative incidence of severe dysplasia or malignancy. RESULTS: LUL size was predictive of progression to malignant lesions in individuals with a nondysplastic diagnosis (adjusted OR 6-10 mm VS ≤5 mm =6.7; 95% CI, 1.7-25.7; adjusted OR >10 mm VS ≤5 mm =27.9; 95% CI, 7.3-105.7), and the corresponding adjusted cumulative incidence of malignant lesions was 3.6 and 13.2 per 100 persons. This is higher than that of small (≤5mm) lesions, which showed mild dysplasia (2.7 per 100 persons), a condition for which surveillance every 3 years is recommended. 65.3% of interval cancers missed at surveillance under the current approach would be detected if individuals with medium (6-10 mm) and large (>10 mm) nondysplastic LULs were additional monitored. CONCLUSIONS: We propose a modified surveillance strategy that combines findings under LCE examination and the pathologic analysis, where follow-up endoscopy is recommended for individuals with relatively large nondysplastic lesions.

10.
Sci Rep ; 10(1): 15019, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929157

RESUMO

This study tested the hypothesis that autistic traits influence the neuronal habituation that underlies the processing of others' pain. Based on their autism-spectrum quotient (AQ), two groups of participants were classified according to their autistic traits: High-AQ and Low-AQ groups. Their event-related potentials in response to trains of three identical audio recordings, exhibiting either painful or neutral feelings of others, were compared during three experimental tasks. (1) In a Pain Judgment Task, participants were instructed to focus on pain-related cues in the presented audio recordings. (2) In a Gender Judgment Task, participants were instructed to focus on non-pain-related cues in the presented audio recordings. (3) In a Passive Listening Task, participants were instructed to passively listen. In the High-AQ group, an altered empathic pattern of habituation, indexed by frontal-central P2 responses of the second repeated painful audio recordings, was found during the Passive Listening Task. Nevertheless, both High-AQ and Low-AQ groups exhibited similar patterns of habituation to hearing others' voices, both neutral and painful, in the Pain Judgment and Gender Judgment Tasks. These results suggest altered empathic neuronal habituation in the passive processing of others' vocal pain by individuals with autistic traits.

12.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32792358

RESUMO

BACKGROUND: Despite the great achievements made in immune-checkpoint-blockade (ICB) in cancer therapy, there are no effective predictive biomarkers in gastrointestinal (GI) cancer. METHODS: This study included 93 metastatic GI patients treated with ICBs. The first cohort comprising 73 GI cancer patients were randomly assigned into discovery (n=44) and validation (n=29) cohorts. Comprehensive genomic profiling was performed on all samples to determine tumor mutational burden (TMB) and copy-number alterations (CNAs). A subset of samples was collected for RNA immune oncology (IO) panel sequencing, microsatellite instability (MSI)/mismatch repair and program death ligand 1 (PD-L1) expression evaluation. In addition, 20 gastric cancer (GC) patients were recruited as the second validation cohort. RESULTS: In the first cohort of 73 GI cancer patients, a lower burden of CNA was observed in patients with durable clinical benefit (DCB). In both the discovery (n=44) and validation (n=29) subsets, lower burden of CNA was associated with an improved clinical benefit and better overall survival (OS). Efficacy also correlated with a higher TMB. Of note, a combinatorial biomarker of TMB and CNA may better stratify DCB patients from ICB treatment, which was further confirmed in the second validation cohort of 20 GC patients. Finally, patients with lower burden of CNA revealed increased immune signatures in our cohort and The Cancer Genome Atlas data sets as well. CONCLUSIONS: Our results suggest that the burden of CNA may have superior predictive value compared with other signatures, including PD-L1, MSI and TMB. The joint biomarker of CNA burden and TMB may better stratify DCB patients, thereby providing a rational choice for GI patients treated with ICBs.

13.
J Immunother Cancer ; 8(2)2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32792359

RESUMO

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of gastrointestinal cancer. However, biomarkers correlated with the efficacy of ICIs in gastrointestinal cancer are still lacking. In this study, we performed 395-plex immune oncology (IO)-related gene target sequencing in tumor samples from 96 patients with metastatic gastrointestinal cancer patients treated with ICIs, and a linear support vector machine learning strategy was applied to construct a predictive model. ResultsAll 96 patients were randomly assigned into the discovery (n=72) and validation (n=24) cohorts. A 24-gene RNA signature (termed the IO-score) was constructed from 395 immune-related gene expression profiling using a machine learning strategy to identify patients who might benefit from ICIs. The durable clinical benefit rate was higher in patients with a high IO-score than in patients with a low IO-score (discovery cohort: 92.0% vs 4.3%, p<0.001; validation cohort: 85.7% vs 17.6%, p=0.004). The IO-score may exhibit a higher predictive value in the discovery (area under the receiver operating characteristic curve (AUC)=0.97)) and validation (AUC=0.74) cohorts compared with the programmed death ligand 1 positivity (AUC=0.52), tumor mutational burden (AUC=0.69) and microsatellite instability status (AUC=0.59) in the combined cohort. Moreover, patients with a high IO-score also exhibited a prolonged overall survival compared with patients with a low IO-score (discovery cohort: HR, 0.29; 95% CI 0.15 to 0.56; p=0.003; validation cohort: HR, 0.32; 95% CI 0.10 to 1.05; p=0.04). Taken together, our results indicated the potential of IO-score as a biomarker for immunotherapy in patients with gastrointestinal cancers.

14.
Diabetes Metab Syndr Obes ; 13: 2551-2562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765034

RESUMO

Purpose: Thermogenesis function has made brown/beige adipocyte an attractive target for obesity. Human brown adipose tissue activity is impaired in obesity in vivo. The present study aims to compare the differences in beige adipocyte differentiation potential of subcutaneous adipose tissue derived from normal weight and obese Chinese individuals in vitro. Methods: Adipose-derived stem cells (ADSCs) isolated from subcutaneous fat tissues of normal weight (NW) and obese (OB) groups were induced to differentiate into mature adipocyte with white adipocyte (WA)- and beige adipocyte (BA)-induction treatment. The expression of beige adipocyte marker protein UCP-1 and specific thermogenic genes was detected in differentiated adipocytes via Western blot and rt PCR, and the adipocyte mitochondrial function and lipolysis ability were also measured by oxygen consumption rate (OCR) and glycerol release rate, respectively. Results: Either with WA-induction or BA-induction, the expression of UCP-1 and beige adipocyte-specific thermogenic genes in differentiated adipocytes was higher in the NW compared to the OB group, followed by higher OCR and lipolysis ability in NW group than OB group. With BA-induction, expression of UCP-1 and thermogenic genes increased significantly, followed by the increasement in adipocytes OCR and lipolysis rate in NW group compared with WA-induction treatment, but no significant difference was observed in OB group. Conclusion: Compromised beige adipocyte differentiation plasticity was found in subcutaneous white adipose tissue derived from obese Chinese individuals, which may be due part to the downregulation of ß3-adrenergic receptor expression in adipocytes. Discovery of therapeutic agents to active brown adipose tissue through specific pathways could provide a promising approach for treating obesity in the future.

15.
Front Med ; 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32779094

RESUMO

Immunotherapy has recently led to a paradigm shift in cancer therapy, in which immune checkpoint inhibitors (ICIs) are the most successful agents approved for multiple advanced malignancies. However, given the nature of the non-specific activation of effector T cells, ICIs are remarkably associated with a substantial risk of immune-related adverse events (irAEs) in almost all organs or systems. Up to 90% of patients who received ICIs combination therapy experienced irAEs, of which majority were low-grade toxicity. Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs. In this review, the mechanisms of action of ICIs and how they may cause irAEs are described. Some unsolved challenges, however really engrossing issues, such as the association between irAEs and cancer treatment response, tumor response to irAEs therapy, and ICIs in challenging populations, are comprehensively summarized.

16.
Ophthalmic Res ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32781448

RESUMO

PURPOSE: To quantitatively analyze the perfusion characteristics of choroidal metastasis using contrast-enhanced ultrasound (CEUS), and compare its perfusion characteristics with these of choroidal hemangioma and choroidal melanoma. METHODS: The patients who were clinically diagnosed as choroidal metastasis were recruited as the study group and the patients who were diagnosed as choroidal hemangioma and choroidal melanoma during the same period were included as the comparison group. All patients underwent CEUS examination, and Sonoliver was used to obtain the data on quantitative parameters of the tumor and the adjacent normal orbital tissues, including maximum of intensity (IMAX), rise time (RT), time to peak (TTP), and mean transit time (mTT). Wilcoxon signed rank test was performed to compare the quantitative parameters of choroidal metastasis and normal orbital tissues. Kruskal-Wallis was adopted to compare the quantitative parameters of the three types of tumors, and Bonferroni was used to correct the results of the multiple comparisons. Receiver operating characteristic (ROC) curve analysis was used to identify valuable parameters. RESULTS: Twenty-six patients (26 eyes) with choroidal metastasis, fifty-five patients (55 eyes) with choroidal hemangioma and forty-nine patients (49 eyes) with choroidal melanoma were enrolled in this study. The IMAX of choroidal metastasis was significantly higher than that of normal orbital tissues, while RT, TTP and mTT were significantly shorter than these of normal orbital tissues (all p values were < 0.001). The IMAX of choroidal metastasis was lower than that of choroidal hemangioma, and RT, TTP and mTT were shorter than these of choroidal hemangioma and choroidal melanoma (p = 0.002, p = 0.004, p = 0.007). ROC curve analysis showed that areas under the ROC curves (AUCs) of RT and mTT (AUC = 0.851, 95% CI 0.783-0.918 and 0.849, 95% CI 0.783-0.915) were larger. CONCLUSION: Quantitative analysis with CEUS can reflect the perfusion characteristics of choroidal metastasis and can exhibit the difference between its perfusion characteristics and these of choroidal hemangioma and choroidal melanoma. RT and mTT may serve as useful parameters for differentiating choroidal metastasis from choroidal hemangioma and choroidal melanoma.

17.
J Neuroinflammation ; 17(1): 255, 2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32861243

RESUMO

BACKGROUND: After spinal cord injury (SCI), destructive immune cell subsets are dominant in the local microenvironment, which are the important mechanism of injury. Studies have shown that inflammasomes play an important role in the inflammation following SCI, and apoptosis-associated speck-like protein containing a card (ASC) is the adaptor protein shared by inflammasomes. Therefore, we speculated that inhibiting ASC may improve the local microenvironment of injured spinal cord. Here, CRID3, a blocker of ASC oligomerization, was used to study its effect on the local microenvironment and the possible role in neuroprotection following SCI. METHODS: Murine SCI model was created using an Infinite Horizon impactor at T9 vertebral level with a force of 50 kdynes and CRID3 (50 mg/kg) was intraperitoneally injected following injury. ASC and its downstream molecules in inflammasome signaling pathway were measured by western blot. The immune cell subsets were detected by immunohistofluorescence (IHF) and flow cytometry (FCM). The spinal cord fibrosis area, neuron survival, myelin preservation, and functional recovery were assessed. RESULTS: Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1ß, and IL-18 activation, which consequently suppressed M1 microglia, Th1 and Th1Th17 differentiation, and increased M2 microglia and Th2 differentiation. Accordingly, the improved histology and behavior have also been found. CONCLUSIONS: CRID3 may ameliorate murine SCI by inhibiting inflammasome activation, reducing proinflammatory factor production, restoring immune cell subset balance, and improving local immune microenvironment, and early administration may be a promising therapeutic strategy for SCI.

18.
Water Environ Res ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32762110

RESUMO

By summarizing 187 relevant research articles published in 2019, the review is focused on the research progress of physicochemical processes for wastewater treatment. This review divides into two sections, physical processes and chemical processes. The physical processes section includes three sub-sections, that is, adsorption, granular filtration, and dissolved air flotation, whereas the chemical processes section has five sub-sections, that is, coagulation/flocculation, advanced oxidation processes, electrochemical, capacitive deionization, and ion exchange. PRACTITIONER POINTS: Totally 187 research articles on wastewater treatment have been reviewed and discussed. The review has two major sections with eight sub-topics.

19.
Clin Infect Dis ; 2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32827436

RESUMO

BACKGROUND: Population-based literature suggest SARS-CoV-2 infection may disproportionately affect racial/ethnic minorities; however, patient-level observations of hospitalization outcomes by race/ethnicity are limited. The aim of this study was to characterize COVID-19-associated morbidity and in-hospital mortality by race/ethnicity. METHODS: This was a retrospective analysis of nine Massachusetts hospitals including all consecutive adult patients hospitalized with laboratory-confirmed COVID-19. Measured outcomes were assessed and compared by patient-reported race/ethnicity, classified as White, Black, Latinx, Asian, or other. Students t-test, Fischer exact test, and multivariable regression analyses were performed. RESULTS: 379 patients (62.9±16.5 years; 55.7% men) with confirmed COVID-19 were included (49.9% White, 13.7% Black, 29.8% Latinx, 3.7% Asian), of which 376 (99.2%) were insured (34.3% private, 41.2% public, 23.8% public with supplement). Latinx patients were younger, had fewer cardiopulmonary disorders, were more likely to have obesity, more frequently reported fever and myalgia, and had lower D-dimer levels compared to White patients (p&0.05). On multivariable analysis controlling for age, gender, obesity, cardiopulmonary comorbidities, hypertension, and diabetes, no significant differences in in-hospital mortality, ICU admission, or mechanical ventilation by race/ethnicity were found. Diabetes was a significant predictor for mechanical ventilation (OR 1.89; 95% CI 1.11-3.23) while older age was a predictor of in-hospital mortality (OR 4.18; 95% CI 1.94-9.04). CONCLUSIONS: In this multi-center cohort of hospitalized COVID-19 patients in the largest health system in Massachusetts, there was no association between race/ethnicity and clinically relevant hospitalization outcomes, including in-hospital mortality, after controlling for key demographic/clinical characteristics. These findings serve to refute suggestions that certain races/ethnicities may be biologically predisposed to poorer COVID-19 outcomes.

20.
Cancer Immunol Res ; 8(10): 1251-1261, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32855157

RESUMO

We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti-PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti-PD-1/PD-L1 immunotherapy in melanoma, non-small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti-PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti-PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti-PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti-PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses.See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243.

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