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BACKGROUND: Disruptions in sleep and pain are frequent complaints following total knee arthroplasty (TKA). Perioperative sleep disturbances may lead to decreased pain tolerance as well as other consequences. The purpose of this study is to evaluate the effectiveness of self-guided meditation for improving sleep quality following TKA. METHODS: TKA patients, at a single institution, between August 2019 and March 2020 were exposed to a self-guided meditation video during the perioperative period via an online, digital platform. Patients were given an institutionally designed questionnaire to assess sleep quality in the perioperative period. Knee injury and Osteoarthritis Outcome Score-Joint Replacement form, Veterans RAND 12-item Health Survey, and satisfaction scores were also collected. Results were compared between those who reported utilizing the video and those who did not. RESULTS: A total of 380 patients were evaluated. One hundred eighty-nine patients reported utilizing the video, while 191 did not. No significant differences were found among baseline age, gender, or preoperative outcome variables between groups. Postoperatively, the video group's reported time spent actually sleeping improved an average of 52 minutes more than the nonvideo group (95% confidence interval 49.8-52.8 minutes, P < .001). The video group also showed significantly larger decreases in overall sleep awakenings (P < .001), however not pain-related disturbances (P = .726). No significant differences in patient-reported outcome measures were noted between groups. CONCLUSIONS: Sleep quality is an important component of TKA recovery. These findings provide evidence that nonpharmacologic interventions, such as self-guided meditation, may help improve sleep quality in the perioperative period. Future studies are warranted to further investigate their potential benefits.

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Mitral regurgitation (MR) coexists in a significant proportion of patients with severe aortic stenosis (AS), and portends inferior therapeutic outcomes. In severe AS, MR is thought to contribute to a low-flow state by decreasing forward stroke volume. We investigated concomitant MR on the clinical and echocardiographic features of patients with "paradoxical" low-flow (PLF) and normal-flow (NF) severe AS. Clinical and echocardiographic profiles of 886 consecutive patients with index echocardiographic diagnosis of severe AS (AVA < 1.0 cm2) were analysed retrospectively. All patients had preserved ejection fraction (LVEF ≥ 50%, n = 645), and were divided into PLF (stroke volume index, SVI < 35 mL/m2) and NF AS. They were then further subdivided based on the presence or absence of moderate-or-severe MR (msMR). A higher prevalence of concomitant msMR was observed in patients with PLF AS (14.9%; n = 33/221) compared to those with NF AS (8.0%; n = 34/424). Concomitant msMR was associated with echocardiographic features of increased diastolic dysfunction in both PLF AS and NF AS patients, as evidenced by increased LA diameter (PLF AS 52.9 ± 12.5 to 43.9 ± 8.9 mm; NF AS 29.6 ± 10.8 to 42.4 ± 8.8 mm; p < 0.001) and increased transmitral E/A ratio (PLF AS 1.26 ± 0.56 to 0.92 ± 0.43; NF AS 1.19 ± 0.63 to 0.94 ± 0.45; p = 0.004). Amongst patients with NF AS, msMR was additionally associated with increased E:e' ratio (25.5 ± 15.1 vs 19.3 ± 10.8; p = 0.025). Concomitant MR was more common in PLF AS compared to NF. Although possibly related to the MR, patients severe AS and MR appeared to have more severe diastolic dysfunction. Further studies are warranted to evaluate prognosis and guide management.

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PURPOSE: In patients with cancer who have an abnormal biomarker finding, the source of the biomarker in the bloodstream must be located for confirmation of diagnosis, staging, and therapy planning. We evaluated if immuno-PET with the radiolabeled high-affinity antibody HuMab-5B1 (MVT-2163), binding to the cancer antigen CA19-9, can identify the source of elevated biomarkers in patients with pancreatic cancer. PATIENTS AND METHODS: In this phase I dose-escalating study, 12 patients with CA19-9-positive metastatic malignancies were injected with MVT-2163. Within 7 days, all patients underwent a total of four whole-body PET/CT scans. A diagnostic CT scan was performed prior to injection of MVT-2163 to correlate findings on MVT-2163 PET/CT. RESULTS: Immuno-PET with MVT-2163 was safe and visualized known primary tumors and metastases with high contrast. In addition, radiotracer uptake was not only observed in metastases known from conventional CT, but also seen in subcentimeter lymph nodes located in typical metastatic sites of pancreatic cancer, which were not abnormal on routine clinical imaging studies. A significant fraction of the patients demonstrated very high and, over time, increased uptake of MVT-2163 in tumor tissue, suggesting that HuMab-5B1 labeled with beta-emitting radioisotopes may have the potential to deliver therapeutic doses of radiation to cancer cells. CONCLUSIONS: Our study shows that the tumor antigen CA19-9 secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and offers new opportunities for noninvasive characterization of tumors in patients.

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BACKGROUND: Blood pressure (BP) is an important determinant of functional outcome in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA). Current guidelines recommend a BP target of 185/110 mmHg before IV-tPA bolus and maintaining it at less than 180/105 mmHg for the first 24 hours. However, the effect of blood pressure on various outcome measures after systemic thrombolysis remains unclear. METHODS: Following a systematic search of Medline and EMBASE, all observational studies reporting effect of pretreatment BP on 90-day functional outcome as measured by the modified Rankin Scale (mRS) and/ or incidence of symptomatic intracranial hemorrhage (sICH) in AIS patients receiving thrombolytic therapy were included. RESULTS: Of 2181 studies screened, 26 studies, involving 38,937 subjects, met inclusion criteria. Higher prethrombolysis systolic BP was significantly-associated with poorer 90-day functional outcome (Mean difference 3.87 mmHg; 95% confidence interval [CI] 1.18-6.56) and increased incidence of sICH (Mean difference 5.31; 95% CI 2.22-8.40). When studies were stratified by different cut-offs for functional outcome (mRS 0-1 versus 0-2) and definitions of sICH used (Randomized controlled trials or SITS-MOST), there was no significant difference in mean difference between the subgroups. CONCLUSIONS: Our data showed that higher prethrombolysis SBP was associated with poorer outcomes in thrombolysed acute ischemic stroke patients. This may suggest that more aggressive lowering of BP below the current recommendations prior to thrombolysis could be beneficial. The effect of early BP trends after tPA infusion could not be evaluated due to limited available data. Ongoing randomized clinical trials, like ENCHANTED, may provide further insights into the current guidelines and optimal BP levels.

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PURPOSE: Ipilimumab induces durable remission in about 15-20% of patients with metastatic melanoma. However, reliable predictors of response to ipilimumab are currently lacking. Whole-body metabolic tumor volume (wMTV) has been shown to be a strong prognostic factor in a variety of malignancies treated with chemotherapy, but few results have been reported for patients treated with immunotherapy. The purpose of this study was to investigate the prognostic value of wMTV and other metabolic parameters from baseline 18F-FDG PET/CT scans in patients with melanoma being treated with ipilimumab. METHODS: The prognostic impact of wMTV, as well as mean standardized uptake values and total lesion glycolysis, was evaluated in 142 consecutive patients with melanoma treated with single-agent ipilimumab therapy. Metabolic parameters were dichotomized by their respective medians and correlated with overall survival (OS). In addition, the prognostic value of metabolic parameters combined with known clinical prognostic factors was evaluated in multivariate analyses. RESULTS: The median OS time in all patients was 14.7 months (95% CI 10.45-18.93 months). wMTV was a strong independent prognostic factor for OS (p = 0.001). The median survival in patients with a metabolic volume above the median was 10.8 months (95% CI 5.88-15.81 months) as compared with 26.0 months (95% CI 3.02-49.15 months) in patients with an MTV below the median. A multivariate model including wMTV and known clinical prognostic factors, such as age and the presence of brain metastases, further improved the identification of patient subgroups with different OS times. CONCLUSION: wMTV appears to be a strong independent prognostic factor in melanoma patients treated with ipilimumab, and can be determined semiautomatically from routine 18F- FDG PET/CT scans. wMTV, combined with clinical prognostic factors, could be used to personalize immunotherapy and in future clinical studies.

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Immune checkpoint inhibitors (ICIs) are now commonly used to treat patients with metastatic malignant melanoma. Although concerns have been raised that the inflammatory response induced by ICIs may limit the ability of 18F-FDG PET/CT to assess tumor response, systematic analyses on the use of 18F-FDG PET/CT in this setting are mostly lacking. Thus, we set out to evaluate the association between tumor response on 18F-FDG PET/CT and prognosis in patients with metastatic malignant melanoma treated with ipilimumab. Methods: We analyzed 60 consecutive patients with metastatic melanoma who underwent 18F-FDG PET/CT scans both before and after treatment to evaluate treatment response after completion of ipilimumab therapy. Tumor response was assessed by the change in the sum of SULpeak (voxels with the highest average SUL [SUV normalized to lean body mass]) of up to 5 lesions according to PERCIST5. New lesions on PET that appeared suggestive of metastases were considered progressive metabolic disease (PMD). Because immunotherapy may cause new inflammatory lesions that are detectable on 18F-FDG PET/CT, we also evaluated an immunotherapy-modified response classification (imPERCIST5). In this classification, new lesions do not define PMD per se; rather, PMD requires an increase in the sum of SULpeak by 30%. The correlation between tumor response according to these 3 definitions and overall survival (OS) was evaluated and compared with known prognostic factors. Results: In responders and nonresponders, the 2-y OS was 66% versus 29% for imPERCIST5 (P = 0.003). After multivariate analysis, imPERCIST5 remained prognostic (hazard ratio, 3.853; 95% confidence interval, 1.498-9.911; P = 0.005). New sites of focal 18F-FDG uptake occurred more often in patients with PMD (n = 24) by imPERCIST5 than in those with stable metabolic disease (n = 7) or partial metabolic response (n = 4). In patients with partial metabolic response, 2 of 4 isolated new lesions regressed spontaneously during follow-up. Conclusion: In patients with metastatic melanoma treated with ipilimumab, tumor response according to PERCIST was associated with OS. Our data suggest that PMD should not be defined by the appearance of new lesions, but rather by an increase in the sum of SULpeak.

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BACKGROUND: Tumor-associated immune cells are prognostic in non-small cell lung cancer (NSCLC) but findings have been conflicting. OBJECTIVES: To determine the prognostic role of immune cells according to localization in NSCLC patients. METHODS: A systematic literature review and meta-analysis was performed on dendritic cell (DC), tumor associated macrophages (TAM), mast cells (MC), natural killer (NK) cells, T and B cells and tumor CTLA-4 and PD-L1 studies. RESULTS: We analysed 96 articles (n= 21,752 patients). Improved outcomes were seen with increased tumor DCs (overall survival (OS) hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.44-0.68), NK cells (OS HR 0.45; 0.31-0.65), TAMs (OS HR 0.33; 0.17-0.62), M1 TAMs (OS HR 0.10; 0.05-0.21), CD3+ T cells (disease specific survival (DSS) HR 0.64; 0.48-0.86), CD8+ T cells (OS HR 0.78; 0.66-0.93), B cells (OS HR 0.65; 0.42-0.99) and with increased stroma DC (DSS HR 0.62; 0.47-0.83), NK cells (DSS HR 0.51; 0.32-0.82), M1 TAMs (OS HR 0.63; 0.42-0.94), CD4+ T cells (OS HR 0.45; 0.21-0.94), CD8+ T cells (OS HR 0.77; 0.69-0.86) and B cells (OS HR 0.74;0.56-0.99). Poor outcomes were seen with stromal M2 TAMs (OS HR 1.44; 1.06-1.96) and Tregs (relapse free survival (RFS) HR 1.80; 1.34-2.43). Tumor PD-L1 was associated with worse OS (1.40; 1.20-1.69), RFS (1.67) and DFS (1.24). CONCLUSION: Tumor and stroma DC, NK cells, M1 TAMs, CD8+ T cells and B cells were associated with improved prognosis and tumor PD-L1, stromal M2 TAMs and Treg cells had poorer prognosis. Higher quality studies are required for confirmation.

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Major advances with the development of epidermal growth factor receptor tyrosine kinase inhibitors and immune check-point inhibitors have ushered in a new era in lung cancer therapy. Whilst pre-clinical studies suggest EGFR-driven NSCLC inhibit antitumor immunity through the activation of the PD-1/PD-L1 pathway, epidemiology studies suggest EGFR mutant NSCLC are more likely to have decreased PD-L1 expression. The superiority of single agent PD-1/PD-L1 inhibitors over docetaxel in pre-treated EGFR mutant NSCLC appears to be moderated. Several mechanisms for a poor response to immune checkpoint have been proposed including a lower tumor mutation burden, and an uninflamed and immunosuppressive tumor microenvironment. Predictive biomarkers to PD-1/PD-L1 inhibitors sensitivity in patients with EGFR mutations are required. The role of EGFR TKI in combination with an immune checkpoint inhibitor is currently being investigated intensively in multiple clinical trials and outcomes from these trials are immature and the optimal sequence, schedule and dosing remains to be determined. A careful evaluation will be required in view of the increased toxicities reported in some of the early studies of combination therapy.

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Changes in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy.

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