How structural and functional MRI can inform dual-site tACS parameters: A case study in a clinical population and its pragmatic implications

BackgroundAbnormalities in frontoparietal network (FPN) were observed in many neuropsychiatric diseases including substance use disorders. A growing number of studies are using dual-site-tACS with frontoparietal synchronization to engage this network. However, a computational pathway to inform and optimize parameter space for frontoparietal synchronization is still lacking. In this case study, in a group of participants with methamphetamine use disorders, we proposed a computational pathway to extract optimal electrode montage while accounting for stimulation intensity using structural and functional MRI.MethodsSixty methamphetamine users completed an fMRI drug cue-reactivity task. Four main steps were taken to define electrode montage and adjust stimulation intensity using 4x1 high-definition (HD) electrodes for a dual-site-tACS; (1) Frontal seed was defined based on the maximum electric fields (EF) predicted by simulation of HD montage over DLPFC (F3/F4 in EEG 10–10), (2) frontal seed-to-whole brain context-dependent correlation was calculated to determine connected regions to frontal seeds, (3) center of connected cluster in parietal cortex was selected as a location for placing the second set of HD electrodes to shape the informed montage, (4) individualized head models were used to determine optimal stimulation intensity considering underlying brain structure. The informed montage was compared to montages with large electrodes and classic frontoparietal HD montages (F3-P3/F4-P4) in terms of tACS-induced EF and ROI-to-ROI task-based/resting-state connectivity.ResultsCompared to the large electrodes, HD frontoparietal montages allow for a finer control of the spatial peak fields in the main nodes of the FPN at the cost of lower maximum EF (large-pad/HD: max EF[V/m] = 0.37/0.11, number of cortical sub-regions that EF exceeds 50% of the max = 77/13). For defining stimulation targets based on EF patterns, using group-level head models compared to a single standard head model results in comparable but significantly different seed locations (6.43 mm Euclidean distance between the locations of the frontal maximum EF in standard-space). As expected, significant task-based/resting-state connections were only found between frontal-parietal locations in the informed montage. Cue-induced craving score was correlated with frontoparietal connectivity only in the informed montage (r = ?0.24). Stimulation intensity in the informed montage, and not in the classic HD montage, needs 40% reduction in the parietal site to reduce the disparity in EF between stimulation sites.ConclusionThis study provides some empirical insights to montage and dose selection in dual-site-tACS using individual brain structures and functions and proposes a computational pathway to use head models and functional MRI to define (1) optimum electrode montage for targeting FPN in a context of interest (drug-cue-reactivity) and (2) proper transcranial stimulation intensity.     

The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.     

小分子抗血管生成药物在非小细胞肺癌中的研究进展

肺癌是世界上发病率最高的癌症之一，且尚无二线进展后的标准治疗方案，而肿瘤血管生成目前已被确定为恶性肿瘤的重要治疗靶点，小分子多靶点血管激酶抑制剂可通过抑制血管生成相关信号通路，抑制肿瘤血管的生成。目前已开展多项小分子抗血管生成药物治疗非小细胞肺癌的临床试验，且已有部分血管内皮生长因子受体酪氨酸激酶抑制剂（vascular endothelial growth factor receptor-tyrosine kinase inhibitors, VEGFR-TKIs）获批治疗晚期非小细胞肺癌，本文基于国内外多项小分子抗血管生成药物治疗非小细胞肺癌的发展现状，归纳了多个VEGFR-TKIs及成纤维细胞生长因子受体（fibroblast growth factor receptor, FGFR）-TKI单药或联合[包括分别与化疗、表皮生长因子受体（epidermal growth factor receptor, EGFR）-TKIs、免疫治疗、放疗等联合）]治疗非小细胞肺癌的疗效与安全性研究，同时探讨了VEGFR-TKIs可能存在的耐药机制及疗效预测指标等，并对未来抗血管治疗非小细胞肺癌的发展趋势以及存在的潜在问题进行展望，同时为肺癌后续的精准治疗及个体化治疗提供新的思路。     

Fruit and Vegetable Intake and Stomach Cancer among Male Adults: A Case-Control Study in Northern Viet Nam

Objective: This study investigated the association between fruit and vegetable intake and stomach cancer, with considering the impacts of Helicobacter pylori (H. pylori) infection and tobacco smoking. Methods: A case-control study featuring 80 male incident stomach-cancer cases and 126 male controls was conducted in a general hospital in Viet Nam. A semi-quantitative food frequency and demographic lifestyle questionnaire were used; and venous blood samples were collected to determine H. pylori status by IgG ELISA. The respective associations between fruit and vegetable intake and stomach cancer were examined using unconditional logistic regression analysis with adjustments for possible cofactors. Results: Fruit intake and stomach cancer showed a weak inverse association when this became non-significant after adjusting for H. pylori infection (OR = 0.50, 95%CI: 0.22–1.12, p trend = 0.094). Stratifying by H. pylori status returned a negative trend for fruit intake and stomach cancer among H. pylori-negative participants (OR = 0.21, 95%CI: 0.06–0.69, p trend = 0.010), but no significant interaction for H. pylori-positive participants (OR = 0.76, 95%CI: 0.21–2.68, p trend = 0.670). Vegetable intake and stomach cancer showed no association, regardless of H. pylori status. Compared to ever-smokers with low intake, never-smokers with high vegetable (OR = 0.25, 95% CI: 0.06–0.95) and fruit intake (OR = 0.20, 95%CI: 0.06–0.65) showed the lowest odds of stomach cancer. Conclusions: Fruit, but not vegetable, intake showed a weak inverse association with stomach cancer. H. pylori infection and tobacco-smoking status may influence the protective effects of fruit and vegetable intake on stomach cancer.