The Effectiveness of Lifestyle Interventions in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: To perform a network meta-analysis to determine the effectiveness of lifestyle interventions in exercise tolerance and quality of life (QoL) in people with HFpEF. METHODS: Ten databases were searched for randomized controlled trials that evaluated a diet and/or exercise intervention in people with heart failure with preserved ejection fraction until May 2022. The co-primary outcomes were peak oxygen uptake (V̇O2peak) and Quality of Life as assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). We synthesized data using network meta-analysis. RESULTS: We identified 13 trials, including a total of 869 participants, and we incorporated 6 different interventions. Improvements in V̇O2peak compared to controls were seen for all exercise interventions (2.88 [95% CI: 1.36; 4.39] mL/kg/min) for high-intensity interval training (HIIT); 2.37 [95% CI: 1.02; 3.71] mL/kg/min for low-intensity exercise (LIT) combined with a hypocaloric diet; 2.05 [95% CI: 0.81; 3.29] mL/kg/min for moderate-intensity continuous training (MICT); 1.94 [95% CI: 0.59; 3.29] mL/kg/min for LIT; 1.85 [95% CI: 0.27; 3.44] mL/kg/min for MICT combined with resistance training) but not a hypocaloric diet alone (1.26 [95%CI: -0.08; 2.61] mL/kg/min). Only HIIT (-14.45 [95%CI: -24.81; -4.10] points) and LIT (95% CI: -11.05 [-20.55; -1.54] mL/kg/min) significantly improved MLHFQ scores. Network meta-analysis indicated that HIIT was the most effective intervention for improving both V̇O2peak (mean improvement 2.88 [95% CI: 1.36; 4.39] mL/kg/min, follow-up range, 4 weeks-3 years) and QoL (-14.45 [95% CI: -24.81; -4.10] points, follow-up range, 12-26 weeks) compared to usual care. CONCLUSIONS: This network meta-analysis indicates that HIIT is the most effective lifestyle intervention studied to improve exercise capacity and QoL, with mean improvements exceeding the minimum clinically meaningful thresholds. HIIT is likely to be an underused management strategy in HFpEF, but further studies are needed to confirm long-term improvements in symptoms and clinical outcomes.

Ethnic differences in cardiac structure and function assessed by MRI in healthy South Asian and White European people: A UK Biobank Study.

BACKGROUND: Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI (CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people. METHODS: Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared. RESULTS: 121 matched pairs (77 male/44 female, mean age 58 ± 8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females. CONCLUSIONS: Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.

[Early efficacy and safety of mini open (air/water medium) endoscopy assisted anterior cervical discectomy and fusion in the treatment of cervical spondylotic myelopathy].

Objective: To investigate the efficacy and safety of mini open (air/water medium) endoscopy assisted anterior cervical discectomy and fusion (MOEA-ACDF) for the treatment of cervical spondylotic myelopathy (CSM). Methods: A follow-up study. The clinical data of 30 patients with CSM treated by MOEA-ACDF from January to December in 2021 in the Henan NO.3 Provincial People's Hospital were retrospectively analyzed. Of the patients, 20 were male and 10 were female, the mean age was (49.8±9.3) years (ranged 28-70 years). The CSM occurred at C3-4 level in 2 cases, at C4-5 level in 3 cases, at C5-6 level in 22 cases and at C6-7 level in 3 cases. Each case was compared at the moment of pre-operation and final follow-up by the Japanese Orthopedic Association (JOA) score, C2-7 Cobb angle, and anterior column height of surgical segment. The postoperative complications were recorded. Prevertebral soft tissue edema and hydrops were assessed. The fusion rate was evaluated. The JOA improvement rate was computed at the final follow-up. Results: All the operations were successfully completed and all the patients received follow-up for (12.7±2.7) months (ranged 9-20 months). The mean operation time was (85.3±11.0) min (ranged 65-110 min). The postoperative drainage volume was (16.7±7.4) ml (ranged 5-35 ml). The JOA score and the C2-7 Cobb angle both improved at the final follow-up when compared with those before the operation (15.3±1.3 vs 12.2±2.3, 15.5°±6.1° vs 12.3°±6.0°, both P<0.001). The anterior column height of surgical segment at the final follow-up was (35.6±2.5) mm, and it was higher than that before the operation [(34.1±2.4) mm](P<0.001). No postoperative complications such as dysphagia, hoarseness, cerebrospinal fluid leakage, nerve injury, hematoma occurred. Postoperative review of cervical MRI revealed 3 cases of prevertebral soft tissue edema and hydrops without obvious symptoms. At the final follow-up, cervical spine X-ray or CT showed that all fusion segments met the criteria for osseous fusion, and the fusion rate was 100%. No complications such as neurological aggravation, internal fixation failure, fusion cage sinking, and adjacent segment degeneration was recorded at the final follow-up. At the final follow-up, the comprehensive efficacy evaluated by JOA improvement rate indicated the excellent and good rate was 90.0%(27/30): 19 cases got an excellent outcome, 8 cases got good and 3 cases got medium outcome. Conclusion: MOEA-ACDF combines the endoscopic system with ACDF technology in the treatment of CSM can achieve satisfactory clinical efficacy with high safety, and effectively restore the cervical intervertebral height and physiological curvature.

Association of ambulatory blood pressure with coronary microvascular and cardiac dysfunction in asymptomatic type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) and hypertension commonly coexist and are associated with subclinical myocardial structural and functional changes. We sought to determine the association between blood pressure (BP) and left ventricular (LV) remodeling, systolic/diastolic function, and coronary microvascular function, among individuals with T2D without prevalent cardiovascular disease. METHODS: Participants with T2D and age-, sex-, and ethnicity-matched controls underwent comprehensive cardiovascular phenotyping including fasting bloods, transthoracic echocardiography, cardiovascular magnetic resonance imaging with quantitative adenosine stress/rest perfusion, and office and 24-h ambulatory BP monitoring. Multivariable linear regression was performed to determine independent associations between BP and imaging markers of remodeling and function in T2D. RESULTS: Individuals with T2D (n = 205, mean age 63 ± 7 years) and controls (n = 40, mean age 61 ± 8 years) were recruited. Mean 24-h systolic BP, but not office BP, was significantly greater among those with T2D compared to controls (128.8 ± 11.7 vs 123.0 ± 13.1 mmHg, p = 0.006). Those with T2D had concentric LV remodeling (mass/volume 0.91 ± 0.15 vs 0.82 ± 0.11 g/mL, p < 0.001), decreased myocardial perfusion reserve (2.82 ± 0.83 vs 3.18 ± 0.82, p = 0.020), systolic dysfunction (global longitudinal strain 16.0 ± 2.3 vs 17.2 ± 2.1%, p = 0.004) and diastolic dysfunction (E/e' 9.30 ± 2.43 vs 8.47 ± 1.53, p = 0.044) compared to controls. In multivariable regression models adjusted for 14 clinical variables, mean 24-h systolic BP was independently associated with concentric LV remodeling (ß = 0.165, p = 0.031), diastolic dysfunction (ß = 0.273, p < 0.001) and myocardial perfusion reserve (ß = - 0.218, p = 0.016). Mean 24-h diastolic BP was associated with LV concentric remodeling (ß = 0.201, p = 0.016). CONCLUSION: 24-h ambulatory systolic BP, but not office BP, is independently associated with cardiac remodeling, coronary microvascular dysfunction, and diastolic dysfunction among asymptomatic individuals with T2D. (Clinical trial registration. URL: https://clinicaltrials.gov/ct2/show/NCT03132129 Unique identifier: NCT03132129).

Unusual dermoscopic patterns of basal cell carcinoma mimicking melanoma.

BACKGROUND: Basal cell carcinoma can simulate melanoma and specific dermoscopic criteria have not yet been defined in a large cohort. OBJECTIVE: To identify dermoscopic "trump" characteristics for differential diagnosis, identify cluster groups and assess the clinical impact of this study's findings. METHODS: Retrospective, multicentric comparative study of atypical, non-facial basal cell carcinoma (≥1 seven-point checklist criteria) and melanoma (with at least one BCC criteria) at dermoscopy. Observed dermoscopic features were used to develop a proposed score. Lesion clusters were defined with hierarchical analysis. Clinical impact was assessed with a blinded reader study following this study's results. RESULTS: A total of 146 basal cell carcinoma and 76 melanoma were included. Atypical vascular pattern was common to most lesions (74.5%). Twelve trump features were included in the proposed score (sensitivity 94.1% and specificity 79.5%). Cluster analysis identified 3 basal cell carcinoma and 3 melanoma clusters. Findings improved overall diagnostic accuracy and confidence (26.8% and 13.8%, respectively; p < 0.001). CONCLUSIONS: These findings support the notion that atypical vascular pattern should be considered a shared feature of both melanoma and atypical basal cell carcinoma. Our proposed score improves diagnostic accuracy and confidence. Absence of pigmented features was associated with lower diagnostic accuracy and confidence.

Immunotherapy in Glioblastoma: Current Approaches and Future Perspectives.

Glioblastoma (GBM) is the most common malignant brain tumor. Despite multimodality treatment with surgical resection, radiation therapy, chemotherapy, and tumor treating fields, recurrence is universal, median observed survival is low at 8 months and 5-year overall survival is poor at 7%. Immunotherapy aims to generate a tumor-specific immune response to selectively eliminate tumor cells. In treatment of GBM, immunotherapy approaches including use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment has been studied. While there have been no major breakthroughs to date and broad implementation of immunotherapy for GBM remains elusive, multiple studies are underway. In this review, we discuss immunotherapy approaches to GBM with an emphasis on molecularly informed approaches.

The predictive value of absolute lymphocyte counts on tumor progression and pseudoprogression in patients with glioblastoma.

BACKGROUND: Differentiating true glioblastoma multiforme (GBM) from pseudoprogression (PsP) remains a challenge with current standard magnetic resonance imaging (MRI). The objective of this study was to explore whether patients' absolute lymphocyte count (ALC) levels can be utilized to predict true tumor progression and PsP. METHODS: Patients were considered eligible for the study if they had 1) GBM diagnosis, 2) a series of blood cell counts and clinical follow-ups, and 3) tumor progression documented by both MRI and pathology. Data analysis results include descriptive statistics, median (IQR) for continuous variables and count (%) for categorical variables, p values from Wilcoxon rank sum test or Fisher's exact test for comparison, respectively, and Kaplan-Meier analysis for overall survival (OS). OS was defined as the time from patients' second surgery to their time of death or last follow up if patients were still alive. RESULTS: 78 patients were included in this study. The median age was 56 years. Median ALC dropped 34.5% from baseline 1400 cells/mm3 to 917 cells/mm3 after completion of radiation therapy (RT) and temozolomide (TMZ). All study patients had undergone surgical biopsy upon MRI-documented progression. 37 had true tumor progression (47.44%) and 41 had pseudoprogression (52.56%). ALC before RT/TMZ, post RT/TMZ and at the time of MRI-documented progression did not show significant difference between patients with true progression and PsP. Although not statistically significant, this study found that patients with true progression had worse OS compared to those with PsP (Hazard Ratio [HR] 1.44, 95% CI 0.86-2.43, P = 0.178). This study also found that patients with high ALC (dichotomized by median) post-radiation had longer OS. CONCLUSION: Our results indicate that ALC level in GBM patients before or after treatment does not have predictive value for true disease progression or pseudoprogression. Patients with true progression had worse OS compared to those who had pseudoprogression. A larger sample size that includes CD4 cell counts may be needed to evaluate the PsP predictive value of peripheral blood biomarkers.

Effects of maternal and post-weaned rumen-protected folic acid supplementation on slaughter performance and meat quality in offspring lambs.

The present study was undertaken to evaluate the influence of rumen-protected folic acid (RPFA) on slaughter performance, visceral organ and gastrointestinal tract coefficients, and meat quality in lambs. Sixty-six lambs from 120 Hu ewes were selected based on body weight and maternal diets and then assigned to six groups using a randomised block experimental design in a 3 × 2 factorial arrangement. The first factor was folic acid (FA) as RPFA in the maternal diet (0 mg/kg (M0F), 16 mg/kg (M16F) or 32 mg/kg (M32F) on DM basis). The second factor was FA in the lambs' diet from weaning until slaughter (0 mg/kg (OC) or 4·0 mg/kg (OF)). The results indicated that the addition of 16 mg/kg FA to the maternal diet increased pre-slaughter weight (PSW), dressing and meat percentage, the reticulum and omasum coefficients, length of the jejunum and ileum, tail fat and perirenal fat coefficient and a* value of the meat colour. The addition of RPFA to the lambs' diet increased PSW, dressing and meat percentage, eye muscle area, abomasum weight, weight and length of the small intestine, but reduced the coefficients of tail fat. An M × O interaction was observed for the weights of heart, lungs, rumen and total stomach, weight and coefficient of omental fat and the girth rib value. Collectively, RPFA in the maternal and lambs' diet improved slaughter performance and meat quality by stimulating the morphological development of the gastrointestinal tract and the distribution of fat in the body.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

[Study on lipid-lowering mechanism of active peptide DP17 from Eupolyphaga steleophaga in hyperlipidemia rats].

The aim of this paper was to investigate the mechanism of the active peptide DP17 of Eupolyphaga steleophaga in the treatment of hyperlipidemia rats. HPLC and MADIL-TOF/TOF-MS were used for the amino acid sequence analysis and solid-phase synthesis on the active peptide of E. steleophaga which were obtained by biomimetic enzymatic hydrolysis, separation and purification. The hyperlipidemia model was established by feeding with high-fat diet.Twenty days later, the rats in the blank group and the model group were given the saline and the rats in remaining groups were given the corresponding drugs by oral administration. After administration for 4 weeks, the levels of triglyceride(TG), total cholesterol(TC) and low density lipoprotein(LDL) in serum, the levels of TG, TC, adenosine monophosphate(AMP), adenosine triphosphate(ATP) in liver tissues and TG in feces were detected, respectively. Hematoxylin-eosin(HE) staining was used to observe the pathological changes of liver tissues. The Real-time fluorescence quantitative PCR method was used to detect the expression of acetyl coa carboxylase(ACC) and hydroxymethylglutaryl-coa reductase(HMGCR) mRNA in liver tissues. The expression of mammalian target of rapamycin(mTORC1) protein and adenosine 5'-monophosphate-activated protein kinase(AMPK) in liver tissues were detected by Western blot. The analysis showed that the amino acid sequence of active peptide from E. steleophaga was DAVPGAGPAGCHPGAGP(DP17). The results of pharmacological experiments showed that after oral administration of DP17 in rats, the levels of TG, TC and LDL in serum as well as TG and TC levels in liver tissues were significantly decreased(P<0.05), while the levels of AMP, ATP in liver tissues and TG content in feces were significantly increased(P<0.05); the liver steatosis of rats was significantly relieved; the expression of ACC, HMGCR mRNA and mTORC1 protein in liver tissues were significantly reduced, while the expression of AMPK phosphorylated protein was significantly increased(P<0.05). DP17, the active peptide of E. steleophag can significantly reduce lipid accumulation in liver tissues, and it may play a role in reducing blood lipids by regulating the energy metabolism balance in the body and activating AMPK/mTOR signaling pathway.

Neutrophil-to-lymphocyte ratio as a predictor of survival in patients with triple-negative breast cancer.

PURPOSE: Peripheral blood lymphopenia and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with poor outcomes in various malignancies. However, existing literature has largely focused on baseline parameters. The aim of this study is to assess the impact of radiation therapy (RT) and chemotherapy on absolute lymphocyte counts (ALC) and NLR in relation to survival outcomes in patients with triple-negative breast cancer (TNBC). METHODS: A retrospective analysis was performed on 126 patients with TNBC treated at Washington University between 2005 and 2010. Cox proportional hazard model with time-varying covariates was applied to estimate the effect of time-varying ALC and NLR separately on overall survival (OS) and disease-free survival (DFS). RESULTS: All patients received RT and 112 patients received either neoadjuvant chemotherapy or adjuvant chemotherapy, or both. Patients deceased had lower ALC and higher NLR compared to patients alive throughout the treatment course, even 1 year after treatment completion (ALC, 1 vs. 1.3, P = 0.03 and NLR, 3.9 vs. 2.6, P = 0.03). High ALC was associated with superior OS on both continuous and binary scales (cutoff of 1 K/ul) (HR 0.14; 95% CI 0.05-0.34; P < 0.001 and HR 0.28; 95% CI 0.13-0.61; P = 0.01, respectively). Additionally, high NLR was weakly associated with inferior OS on continuous scales (HR 1.1; 95% CI 1.06-1.15; P < 0.001). CONCLUSIONS: Post-treatment lymphopenia and NLR elevation can persist until 1 year after treatment completion. Both portend shorter survival for patients with TNBC. Our data support the use of ALC and NLR to identify high risk patients who may benefit from clinical trials rather than standard of care therapy.

Impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients.

PURPOSE: Corticosteroids are commonly used to alleviate symptoms from cerebral vasogenic edema in glioblastoma (GBM) patients. This study evaluated the impact of overall corticosteroid exposure during chemoradiotherapy (CRT) on acute severe lymphopenia (ASL) and survival outcomes of GBM patients. METHODS: GBM patients treated with CRT from 2007 to 2016 were retrospectively analyzed. Overall corticosteroid exposure was estimated as the average daily dexamethasone dose during 6 weeks of CRT. ASL was defined as grade 3 or higher lymphopenia within 3 months of starting CRT. ASL rates, overall survival (OS), and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Multivariable analysis (MVA) was performed using logistic and Cox regression to identify independent predictors of ASL and survival outcomes, respectively. RESULTS: Of the 319 eligible patients, the median daily dexamethasone use was 2 mg/day. The high-dose dexamethasone cohort (> 2 mg/day) had significantly higher ASL and worse OS than the low-dose dexamethasone cohort: 3-month ASL of 43.7% versus 19.8% (p < 0.003) and median OS of 12.6 months versus 17.9 months (p < 0.001), respectively. On MVA, higher dexamethasone use was independently associated with higher ASL and worse OS, but not worse PFS. A subset analysis of patients with gross-total resection found that higher dexamethasone use was significantly associated with ASL, but not OS. CONCLUSION: Increased corticosteroid use among GBM patients during CRT appears to be an independent risk factor for developing subsequent ASL. Its apparent association with worse OS may be influenced by other confounding factors and would need to be validated through prospective investigations.

A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma.

PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety. RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase). CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Solar Terrestrial Relations Observatory (STEREO) Observations of Stream Interaction Regions in 2007 - 2016: Relationship with Heliospheric Current Sheets, Solar Cycle Variations, and Dual Observations.

We have conducted a survey of 575 slow-to-fast stream interaction regions (SIRs) using Solar Terrestrial Relations Observatory (STEREO) A and B data, analyzing their properties while extending a Level-3 data product through 2016. Among 518 pristine SIRs, 54% are associated with heliospheric current sheet (HCS) crossings, and 34% are without any HCS crossing. The other 12% of the SIRs often occur in association with magnetic sectors shorter than three days. The SIRs with HCS crossings have slightly slower speeds but higher maximum number densities, magnetic-field strengths, dynamic pressures, and total pressures than the SIRs without an HCS. The iron charge state is higher throughout the SIRs with an HCS than the SIRs without an HCS, by about 1/3 charge unit. In contrast with the comparable phases of Solar Cycle 23, slightly more SIRs and higher recurrence rates are observed in the years 2009 - 2016 of Cycle 24, with a lower HCS association rate, possibly attributed to persistent equatorial coronal holes and more pseudo-streamers in this recent cycle. The solar-wind speed, peak magnetic field, and peak pressures of SIRs are all lower in this cycle, but the weakening is less than for the comparable background solar-wind parameters. Before STEREO-B lost contact in October 2014, 151 SIR pairs were observed by the twin spacecraft. Of the dual observations, the maximum speed is the best correlated of the plasma parameters. We have obtained a sample of plasma-parameter differences analogous to those that would be observed by a mission at Lagrange points 4 or 5. By studying several cases with large discrepancies between the dual observations, we investigate the effects of HCS relative location, tilt of stream interface, and small transients on the SIR properties. To resolve the physical reasons for the variability of SIR structures, mesoscale multi-point observations and time-dependent solar-wind modeling are ultimately required.

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Hypoxia induces production of citrullinated proteins in human fibroblast-like synoviocytes through regulating HIF1α.

Hypoxia is a prominent microenvironment feature in a range of disorders including cancer, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel disease (IBD), infection and obesity. Hypoxia promotes biological functions of fibroblast-like synoviocytes via regulating hypoxia-inducible factor 1α (HIF1α). Dysregulated protein citrullination in RA drives the production of antibodies to citrullinated proteins, a highly specific biomarker of RA. However, the mechanisms promoting citrullination in RA are not yet fully elucidated. In this study, we investigated whether pathophysiological hypoxia as found in the rheumatoid synovium modulates the citrullination in human fibroblast-like synoviocytes (HFLS). Here, we found that peptidylarginine deiminase 2 (PAD2) and citrullinated proteins were increased in HFLS after exposure to hypoxia. Moreover, knocking down HIF1α by HIF1α siRNA ameliorated the expression of PAD2 and citrullinated proteins. Collectively, this study provides a new mechanism involved in generating citrullinated proteins: hypoxia promotes citrullination and PAD production in HFLS. Concurrently, we also proposed a novel hypoxia involved mechanism in RA pathogenesis. This study deepens our understanding of the role of hypoxia in the pathogenesis of RA and provides a potential therapeutic strategy for RA.

Severe Treatment-Related Lymphopenia in Patients with Newly Diagnosed Rectal Cancer.

BACKGROUND: Although treatment-related lymphopenia (TRL) is common in many cancers no data exists in rectal cancer. METHODS: Serial lymphocyte counts were analyzed retrospectively in patients with newly diagnosed rectal cancer, serial blood counts, and complete records at Johns Hopkins Hospital. RESULTS: Fifty-seven patients with normal pretreatment lymphocyte counts were studied. Two months after beginning chemoradiation, 35% of these patients developed grade III-IV lymphopenia [median lymphocyte counts fell from 1590 to 490 cell/mm3 (p < 0.001)] which persisted throughout one year of observation. CONCLUSION: Severe and prolonged TRL is common in rectal cancer. Further studies are required to determine TRL's relationship to survival.

Impact of concurrent versus adjuvant chemotherapy on the severity and duration of lymphopenia in glioma patients treated with radiation therapy.

Prolonged severe lymphopenia has been shown to persist beyond a year in glioma patients after radiation therapy (RT) with concurrent and adjuvant chemotherapy. This study examines the differential impact of concurrent versus adjuvant chemotherapy on lymphopenia after RT. WHO grade II-III glioma patients who received RT with concurrent and/or adjuvant chemotherapy from 2007 to 2016 were retrospectively analyzed. Concurrent chemotherapy was temozolomide (TMZ), and adjuvant chemotherapy was either TMZ or procarbazine/lomustine/vincristine (PCV). Absolute lymphocyte count (ALC) was analyzed at baseline, 1.5, 3, 6, and 12 months after the start of RT. Univariable and multivariable logistic regression were used to identify the clinical variables in predicting acute or late lymphopenia. There were 151 patients with evaluable ALC: 91 received concurrent and adjuvant TMZ (CRT + ADJ), 32 received only concurrent TMZ (CRT), and 28 received only adjuvant TMZ or PCV (ADJ). There were 9 (10%) versus 6 (19%) versus 0 (0%) cases of grade 3 lymphopenia (ALC < 500/mm3) at 6 weeks and 4 (6%) versus 0 (0%) versus 3 (17%) cases at 12 months in CRT + ADJ, CRT and ADJ groups, respectively. On multivariable analyses, concurrent chemotherapy (odds ratio [OR] 72.3, p < 0.001), female sex (OR 10.8, p < 0.001), and older age (OR 1.06, p = 0.002) were the most significant predictors for any grade ≥ 1 lymphopenia (ALC < 1000/mm3) at 1.5 months. Older age (OR 1.08, p = 0.02) and duration of adjuvant chemotherapy (OR 1.19, p = 0.003) were significantly associated with grade ≥ 1 lymphopenia at 12 months. Thus, concurrent chemotherapy appears as the dominant contributor to the severity of acute lymphopenia after RT in WHO grade II-III glioma patients, and duration of adjuvant chemotherapy appears as the key factor to prolonged lymphopenia.

Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma.

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.