Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways.

BACKGROUND: In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive. METHODS: Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model. RESULTS: Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1ß, and caused further DNA damage and promoted the apoptosis rate of tumor cells. CONCLUSIONS: Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

Bisphenol A: Unveiling Its Role in Glioma Progression and Tumor Growth.

Gliomas represent the most common and lethal category of primary brain tumors. Bisphenol A (BPA), a widely recognized endocrine disruptor, has been implicated in the progression of cancer. Despite its established links to various cancers, the association between BPA and glioma progression remains to be clearly defined. This study aimed to shed light on the impact of BPA on glioma cell proliferation and overall tumor progression. Our results demonstrate that BPA significantly accelerates glioma cell proliferation in a time- and dose-dependent manner. Furthermore, BPA has been found to enhance the invasive and migratory capabilities of glioma cells, potentially promoting epithelial-mesenchymal transition (EMT) characteristics within these tumors. Employing bioinformatics approaches, we devised a risk assessment model to gauge the potential glioma hazards associated with BPA exposure. Our comprehensive analysis revealed that BPA not only facilitates glioma invasion and migration but also inhibits apoptotic processes. In summary, our study offers valuable insights into the mechanisms by which BPA may promote tumorigenesis in gliomas, contributing to the understanding of its broader implications in oncology.

The Privileged Status of Peer Faces: Subordinate-level Neural Representations of Faces in Emerging Adults.

Faces can be represented at a variety of different subordinate levels (e.g., race) that can become "privileged" for visual recognition in perceivers and is reflected as patterns of biases (e.g., own-race bias). The mechanisms encoding privileged status are likely varied, making it difficult to predict how neural systems represent subordinate-level biases in face processing. Here, we investigate the neural basis of subordinate-level representations of human faces in the ventral visual pathway, by leveraging recent behavioral findings indicating the privileged nature of peer faces in identity recognition for adolescents and emerging adults (i.e., ages 18-25 years). We tested 166 emerging adults in a face recognition paradigm and a subset of 31 of these participants in two fMRI task paradigms. We showed that emerging adults exhibit a peer bias in face recognition behavior, which indicates a privileged status for a subordinate-level category of faces that is not predicted based on experience alone. This privileged status of peer faces is supported by multiple neural mechanisms within the ventral visual pathway, including enhanced neural magnitude and neural size in the neural size in the fusiform area (FFA1), which is a critical part of the face-processing network that fundamentally supports the representations of subordinate-level categories of faces. These findings demonstrate organizational principles that the human ventral visual pathway uses to privilege relevant social information in face representations, which is essential for navigating human social interactions. It will be important to understand whether similar mechanisms support representations of other subordinate-level categories like race and gender.

Neural similarity in nucleus accumbens during decision-making for the self and a best friend: Links to adolescents' self-reported susceptibility to peer influence and risk taking.

Adolescence is marked by increased peer influence on risk taking; however, recent literature suggests enormous individual variation in peer influence susceptibility to risk-taking behaviors. The current study uses representation similarity analysis to test whether neural similarity between decision-making for self and peers (i.e., best friends) in a risky context is associated with individual differences in self-reported peer influence susceptibility and risky behaviors in adolescents. Adolescent participants (N = 166, Mage = 12.89) completed a neuroimaging task in which they made risky decisions to receive rewards for themselves, their best friend, and their parents. Adolescent participants self-reported peer influence susceptibility and engagement in risk-taking behaviors. We found that adolescents with greater similarity in nucleus accumbens (NACC) response patterns between the self and their best friend reported greater susceptibility to peer influence and increased risk-taking behaviors. However, neural similarity in ventromedial prefrontal cortex (vmPFC) was not significantly associated with adolescents' peer influence susceptibility and risk-taking behaviors. Further, when examining neural similarity between adolescents' self and their parent in the NACC and vmPFC, we did not find links to peer influence susceptibility and risk-taking behaviors. Together, our results suggest that greater similarity for self and friend in the NACC is associated with individual differences in adolescents' peer influence susceptibility and risk-taking behaviors.

EEF1E1 promotes glioma proliferation by regulating cell cycle through PTEN/AKT signaling pathway.

The cell cycle, a pivotal regulator of cell proliferation, can be significantly influenced by the phosphatase and tensin homolog (PTEN)/AKT signaling pathway's modulation of cyclin-related proteins. In our study, we discovered the crucial role of EEF1E1 in this process, as it appears to downregulate PTEN expression. Furthermore, our findings affirmed that EEF1E1 modulates downstream cell cycle-related proteins by suppressing the PTEN/AKT pathway. Cell cycle assay results revealed that EEF1E1 downregulation stunted the advancement of glioma cells in both the G1 and S phases. A suite of assays-Cell Counting Kit-8, colony formation, and ethyl-2'-deoxyuridine-substantiated that the EEF1E1 downregulation markedly curtailed glioma proliferation. We further validated this phenomenon through animal studies and coculture experiments on brain slices. Our comprehensive investigation indicates that EEF1E1 knockdown can effectively inhibit the glioma cell proliferation by regulating the cell cycle via the PTEN/AKT signaling pathway. Consequently, EEF1E1 emerges as a potential therapeutic target for glioma treatment, signifying critical clinical implications.

Introducing the female Cambridge face memory test - long form (F-CFMT+).

The Cambridge Face Memory Test (CFMT) is one of the most used assessments of face recognition abilities in the science of face processing. The original task, using White male faces, has been empirically evaluated for psychometric properties (Duchaine & Nakayama, 2006), while the longer and more difficult version (CFMT+; Russell et al., 2009) has not. Critically, no version exists using female faces. Here, we present the Female Cambridge Face Memory Test - Long Form (F-CFMT+) and evaluate the psychometric properties of this task in comparison to the Male Cambridge Face Memory Test - Long Form (M-CFMT+). We tested typically developing emerging adults (18 to 25 years old) in both Cambridge face recognition tasks, an old-new face recognition task, and a car recognition task. Results indicate that the F-CFMT+ is a valid, internally consistent measure of unfamiliar face recognition that can be used alone or in tandem with the M-CFMT+ to assess recognition abilities for young adult White faces. When used together, performance on the F-CFMT+ and M-CFMT+ can be directly compared, adding to the ability to understand face recognition abilities for different kinds of faces. The two tasks have high convergent validity and relatively good divergent validity with car recognition in the same task paradigm. The F-CFMT+ will be useful to researchers interested in evaluating a broad range of questions about face recognition abilities in both typically developing individuals and those with atypical social information processing abilities.

Accurate Medication Adherence Measurement Using Administrative Data for Frequently Hospitalized Patients.

Background: Pharmacy administrative claims data remain an accessible and efficient source to measure medication adherence for frequently hospitalized patient populations that are systematically excluded from the landmark drug trials. Published pharmacotherapy studies use medication possession ratio (MPR) and proportion of days covered (PDC) to calculate medication adherence and usually fail to incorporate hospitalization and prescription overlap/gap from claims data. To make the cacophony of adherence measures clearer, this study created a refined hospital-adjusted algorithm to capture pharmacotherapy adherence among patients with end-stage renal disease (ESRD). Methods: The United States Renal Data System (USRDS) registry of ESRD was used to determine prescription-filling patterns of those receiving new prescriptions for oral P2Y12 inhibitors (P2Y12-I) between 2011 and 2015. P2Y12-I-naïve patients were followed until death, kidney transplantation, discontinuing medications, or loss to follow-up. After flagging/censoring key variables, the algorithm adjusted for hospital length of stay (LOS) and medication overlap. Hospital-adjusted medication adherence (HA-PDC) was calculated and compared with traditional MPR and PDC methods. Analyses were performed with SAS software. Results: Hospitalization occurred for 78% of the cohort (N = 46 514). The median LOS was 12 (interquartile range [IQR] = 2-34) days. MPR and PDC were 61% (IQR = 29%-94%) and 59% (IQR = 31%-93%), respectively. After applying adjustments for overlapping coverage days and hospital stays independently, HA-PDC adherence values changed in 41% and 52.7% of the cohort, respectively. When adjustments for overlap and hospital stay were made concurrently, HA-PDC adherence values changed in 68% of the cohort by 5.8% (HA-PDC median = 0.68, IQR = 0.31-0.93). HA-PDC declined over time (3M-6M-9M-12M). Nearly 48% of the cohort had a ≥30 days refill gap in the first 3 months, and this increased over time (P < .0001). Conclusions: Refill gaps should be investigated carefully to capture accurate pharmacotherapy adherence. HA-PDC measures increased adherence substantially when adjustments for hospital stay and medication refill overlaps are made. Furthermore, if hospitalizations were ignored for medications that are included in Medicare quality measures, such as Medicare STAR program, the apparent reduction in adherence might be associated with lower quality and health plan reimbursement.

Trends for and Clinical Factors Associated with Choice of Oral P2Y12 Inhibitors for Patients on Chronic Dialysis.

BACKGROUND: Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD). METHODS: From 2011-2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed. RESULTS: Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P<0.05). Patients receiving hemodialysis versus peritoneal dialysis were less likely to receive prasugrel over clopidogrel, adjusted odds ratio (aOR) 0.67 (0.55-0.82). Each additional year of dialysis decreased the odds of receiving prasugrel over clopidogrel, aOR 0.91 (0.85-0.98). History of atrial fibrillation reduced the odds of receiving ticagrelor or prasugrel over clopidogrel, aOR 0.69 (0.54-0.89) and 0.73 (0.60-0.89), respectively. Concomitant oral anticoagulant use was not associated with choice of P2Y12-I. Occurrence of non-ST segment elevation myocardial infarction or percutaneous coronary intervention within the 6-month period prior to the index date favored ticagrelor over prasugrel, aOR 1.31 (1.06-1.62) and 1.29 (1.01-1.66), respectively. However, prescribing trends favoring ticagrelor over prasugrel were not observed for deployment of drug-eluting, or multiple coronary stents. CONCLUSION: Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.

Pupillary response: cognitive effort for breast cancer survivors.

PURPOSE: The purpose of this cross-sectional comparative pilot study was to evaluate cognitive effort, indexed by pupillary response (PR), for breast cancer survivors (BCS) with complaints of cognitive dysfunction following chemotherapy. STUDY AIMS: Compare the cognitive effort employed by BCS to healthy controls (HC) during neuropsychological tests (NPT) for memory, sustained attention, verbal fluency, visuospatial ability, processing speed and executive function; and Investigate the relationship between PR-indexed cognitive effort and participants' self-report of cognitive function. METHODS: Self-report of cognitive function was collected from 23 BCS and 23 HC. PR was measured during NPT. Independent two-sample t tests or Wilcoxon rank sum tests were used to compare group scores. Between-group effect size (Cohen's d) was calculated for each outcome. Correlation between mean self-report scores and PR values, as well as 95% confidence intervals, was calculated. RESULTS: No group differences were demonstrated for NPT performance. BCS reported more issues with cognitive function than HC (p < .0001). A group effect for BCS was seen with PR-indexed cognitive effort for components of most NPT (p < .05). PR was correlated with most self-report measures of cognitive function (r = 0.33-0.45). CONCLUSIONS: PR sensitivity to cognitive effort across a variety of NPT and correlation with self-report of cognitive function was demonstrated. The portability, affordability, and "real-time" aspects of PR are attractive for potential use in the clinic setting to assess cognitive function. A larger study is needed to confirm these results. Prospective investigation of PR in BCS is needed to demonstrate sensitivity to cognitive function changes over time.

Qigong intervention for breast cancer survivors with complaints of decreased cognitive function.

PURPOSE: The purpose of this pilot study was to evaluate the feasibility of an 8-week Qigong intervention to improve objectively and subjectively assessed cognitive function in breast cancer survivors who were 2 months to 8 years post completion of chemotherapy and radiation therapy. METHODS: A randomized, single-blind, three-arm intervention pilot was conducted to compare Qigong to gentle exercise and survivorship support. Feasibility was measured by recruitment, group session attendance, and adherence to home practice for the two exercise groups. Changes in self-report and objectively measured cognitive function were compared between the three groups from baseline (T1) to completion of the intervention (T2) and 4 weeks post intervention (T3). RESULTS: Fifty participants consented (83% of desired sample) with an overall attrition rate of 28%. Attrition was highest for the gentle exercise group (50%). Group attendance adherence ranged from 44 to 67%. The a priori established rate of 75% weekly attendance was not achieved, nor was the goal of 75% adherence to home practice for the two exercise groups (7 to 41%). Self-report of cognitive function improved most for the Qigong group (p = .01). Improvement was demonstrated for the Trail Making A (gentle exercise, p = .007) and F-A-S verbal fluency (support group, p = .02) tests. Qigong participants reported the most reduction of distress (p = .02). CONCLUSIONS: The study results suggest that mindfulness-based exercise may be superior to gentle exercise alone or survivorship support for improving self-report of cognitive function and distress after treatment for breast cancer. The mindfulness component may enhance the positive impact of exercise on cognitive function.

Defining optimal cutoff value of MGMT promoter methylation by ROC analysis for clinical setting in glioblastoma patients.

Resistance to temozolomide (TMZ) chemotherapy poses a significant challenge in the treatment of glioblastoma (GBM). Hypermethylation in O6-methylguanine-DNA methyltransferase (MGMT) promoter is thought to play a critical role in this resistance. Pyrosequencing (PSQ) has been shown to be accurate and robust for MGMT promoter methylation testing. The unresolved issue is the determination of a cut-off value for dichotomization of quantitative MGMT PSQ results into "MGMT methylated" and "MGMT unmethylated" patient subgroups as a basis for further treatment decisions. In this study, receiver operating characteristic (ROC) curve analysis was used to identify an optimal cutoff of MGMT promoter methylation by testing mean percentage of methylation of 4 CpG islands (76-79) within MGMT exon 1. The area under the ROC (AUC) as well as the best cutoff to classify the methylation were calculated. Positive likelihood ratio (LR+) was chosen as a diagnostic parameter for defining an optimal cut-off. Meanwhile, we also analyzed whether mean percentage of methylation at the investigated CpG islands could be regarded as a marker for evaluating prognostication. ROC analysis showed that the optimal threshold was 12.5% (sensitivity: 60.87%; specificity: 76%) in response to the largest LR+ 2.54. 12.5% was established to distinguish MGMT promoter methylation, which was confirmed using validation set. According to the cutoff value, the MGMT promoter methylation was found in 58.3% of GBM. Mean methylation level of the investigated CpG sites strong correlated with overall survival (OS), which means GBM patients with a high level of methylation survived longer than those with low level of methylation(log-rank test, P = 0.017). In conclusion, ROC curve analysis enables the best cutoff for discriminating MGMT promoter methylation status. LR+ can be used as a key factor that evaluates cutoff. The promoter methylation level of MGMT by PSQ in GBM patients had prognostic value.

How is race perceived during adolescence? A meta-analysis of the own-race bias.

Adolescence is a critical developmental period that is marked by drastic changes in face recognition, which are reflected in patterns of bias (i.e., superior recognition for some individuals compared to others). Here, we evaluate how race is perceived during face recognition and whether adolescents exhibit an own-race bias (ORB). We conducted a Bayesian meta-analysis to estimate the summary effect size of the ORB across 16 unique studies (38 effect sizes) with 1,321 adolescent participants between the ages of ∼10-22 years of age. This meta-analytic approach allowed us to inform the analysis with prior findings from the adult literature and evaluate how well they fit the adolescent literature. We report a positive, small ORB (Hedges's g = 0.24) that was evident under increasing levels of uncertainty in the analysis. The magnitude of the ORB was not systematically impacted by participant age or race, which is inconsistent with predictions from perceptual expertise and social cognitive theories. Critically, our findings are limited in generalizability by the study samples, which largely include White adolescents in White-dominant countries. Future longitudinal studies that include racially diverse samples and measure social context, perceiver motivation, peer reorientation, social network composition, and ethnic-racial identity development are critical for understanding the presence, magnitude, and relative flexibility of the ORB in adolescence. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Case report: a case report of excision of giant lipoma in the posterior neck.

Lipomas, benign tumors originating from the anomalous proliferation of adipocytes, predominantly emerge in regions rich in adipose tissue. However, their presence in the head and neck areas remains rare, constituting approximately 13% of all diagnosed lipoma cases. This study presents a case involving a substantial subcutaneous lipoma located at the posterior neck, measuring about 20 cm × 19 cm × 10 cm. The patient presented with swelling and pain in the back of the neck. And the considerable dimensions of this lipoma significantly impacted the patient's quality of life and aesthetic appearance. Concurrently, the patient exhibited symptoms indicative of degenerative cervical spine disease and cervical disc herniation. After admission, a comprehensive examination, including ultrasound, CT scan, and MRI, was conducted. Given the clinical complexity, the decision for surgical intervention was deemed essential. The surgical strategy entailed a meticulous total excision of the tumor through an incision made in the posterior cross-neck, coupled with the strategic removal of excess skin. To facilitate wound healing, postoperative management included the use of negative pressure drainage. Pathological examination conclusively identified the mass as a lipoma. Postoperative follow-ups indicated successful recovery, as evidenced by the restoration of the neck's aesthetic contour and the complete resolution of the previously observed restrictions in sagittal neck movement.

Clinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort.

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial.

Neural tracking of social hierarchies in adolescents' real-world social networks.

In the current study, we combined sociometric nominations and neuroimaging techniques to examine adolescents' neural tracking of peers from their real-world social network that varied in social preferences and popularity. Adolescent participants from an entire school district (N = 873) completed peer sociometric nominations of their grade at school, and a subset of participants (N = 117, Mage = 13.59 years) completed a neuroimaging task in which they viewed peer faces from their social networks. We revealed two neural processes by which adolescents track social preference: (1) the fusiform face area, an important region for early visual perception and social categorization, simultaneously represented both peers high in social preference and low in social preference; (2) the dorsolateral prefrontal cortex (DLPFC), which was differentially engaged in tracking peers high and low in social preference. No regions specifically tracked peers high in popularity and only the inferior parietal lobe, temporoparietal junction, midcingulate cortex and insula were involved in tracking unpopular peers. This is the first study to examine the neural circuits that support adolescents' perception of peer-based social networks. These findings identify the neural processes that allow youths to spontaneously keep track of peers' social value within their social network.

Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.

BACKGROUND: No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD). METHODS: We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm. RESULTS: Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1ß in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups. CONCLUSIONS: We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma.

BACKGROUND: Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively. METHODS: Patients with locally advanced (T1N1-3M0 or T2-3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging-laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m2 /Leucovorin 400 mg/m2 /5-FU bolus 400 mg/m2 then infusion 2400 mg/m2 for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post-neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4-8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI-related markers PD-L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy. RESULTS: Thirty-seven patients completed the preoperative treatment. Twenty-nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08-0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73-0.98) had ypRR with TRS ≤2. Twenty-six patients finished adjuvant therapy with a median 36.3-month follow-up. Three patients had recurrence/metastatic disease (at 9-, 10-, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD-L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059). CONCLUSIONS: The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long-time survival benefits.

Cabozantinib plus durvalumab in advanced gastroesophageal cancer and other gastrointestinal malignancies: Phase Ib CAMILLA trial results.

This is the phase Ib part of the phase I/II CAMILLA trial evaluating cabozantinib plus durvalumab in advanced chemo-refractory proficient mismatch repair or microsatellite stable (pMMR/MSS) gastrointestinal malignancies including gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma, colorectal cancer (CRC), and hepatocellular carcinoma (HCC). Thirty-five patients are enrolled. There are no observed dose-limiting toxicities during dose escalation. The overall grade 3/4 treatment-related adverse event rate is 34%. Among evaluable patients (n = 30), the objective response rate (ORR) is 30%, disease control rate (DCR) 83.3%, 6-month progression-free survival (PFS) 36.7%, median PFS 4.5 months, and median overall survival (OS) 8.7 months. Responses are seen in 4 of 17, 3 of 10, and 2 of 3 patients with CRC, G/GEJ/E adenocarcinoma, and HCC, respectively. Participants with a PD-L1 combined positive score (CPS) ≥5 have numerically higher ORR, PFS, and OS. Cabozantinib plus durvalumab demonstrates a tolerable safety profile and potential efficacy in previously treated advanced pMMR/MSS gastrointestinal malignancies.

Treatment Outcomes for Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Real-World, Multisite Study of the Impact of Immunosuppression on Pulmonary Function Trajectory.

BACKGROUND: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice. RESEARCH QUESTION: How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD? STUDY DESIGN AND METHODS: Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia [UIP] vs non-UIP) on treatment trajectory. RESULTS: Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression. INTERPRETATION: Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings.

Challenging stereotypes of teens: Reframing adolescence as window of opportunity.

In this review, we seek to challenge negative stereotypes of adolescence and unpack the many ways that the developing brain contributes to positive development during the adolescent years. In particular, we will show that risk-taking is not inevitable and risks can be highly adaptive and positive; adolescents are not overly self-centered but engage in other-oriented prosocial behaviors in remarkable ways; adolescents are not only susceptible to negative peer influence but can resist negative peer influence and conform more to positive peer influence; and adolescents do not orient away from the family, but the family remains a constant and important source of influence into adolescence. We outline considerations that researchers can use to reframe their research questions to provide a more balanced perspective on adolescent development, thereby promoting positive development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).