5125 Background: Multiparametric MRI (mpMRI) is used in active surveillance (AS) for prostate cancer (PC) but has limited specificity. This prospective trial evaluated whether combining 18F-DCFPyL PSMA PET with mpMRI improves the detection of clinically significant PC (csPC) in patients on AS and reduces unnecessary biopsies prompted by false-positive mpMRI. Methods: In this IRB-approved, single-arm Phase II study, 91 patients on AS underwent PSMA PET and mpMRI on a dedicated PET/MRI scanner followed by systematic and targeted biopsies. PET and mpMRI were interpreted independently. The primary outcome was the diagnostic accuracy of mpMRI versus the combined PSMA PET/MRI for csPC. Results: Among 246 targeted lesions, the area under the curve (AUC) for combined PSMA PET/MRI was (0.77) compared to mpMRI alone (0.70) (p=0.2). PSMA PET/MRI showed improved specificity (64.6% vs. 27.5%) with a comparable negative predictive value (89.1% vs. 89.7%). Of 57 csPC lesions, 6 (10.5%) were uniquely identified by the combination. Half of the biopsies for false-positive mpMRI or PET lesions (122/246; 50%) encompassing 17/91 (19%) of patients could have been avoided with combined imaging. Management changed in 9% of patients based on PET/MRI. Conclusions: In this first-in-field trial the addition of PSMA PET to mpMRI with dedicated PET/MRI imaging enhances sensitivity in detecting csPC and may reduce the need for unnecessary biopsies in AS patients. Incorporating PSMA PET/MRI into clinical practice could refine surveillance protocols and support biopsy omission in select men with negative imaging. The single health-system nature of the trial may limit the generalizability of our findings. Diagnostic accuracy of the mpMRI, PSMA PET/MRI, and for the combination, assessed using the “AND” operator. a Parameter MRI, PIRADS≥3 PSMA-PET, Likert≥3 MRI, PIRADS≥4 PSMA-PET, Likert≥4 MRI PIRADS≥3 ANDPET Likert≥3 MRI PIRADS≥3 ANDPET Likert≥4 MRI PIRADS≥4 ANDPET Likert≥3 MRI PIRADS≥4 ANDPET Likert≥4 Accuracy 41.9% 48.0% 63.8% 63.8% 66.7% 72.8% 78.5% 79.3% Sensitivity 89.5% 84.2% 71.9% 73.7% 73.7% 64.9% 63.2% 57.9% Specificity 27.5% 37.0% 61.4% 60.8% 64.6% 75.1% 83.1% 85.7% PPV 27.1% 28.7% 36.0% 36.2% 38.5% 44.0% 52.9% 55.0% NPV 89.7% 88.6% 87.9% 88.5% 89.1% 87.7% 88.2% 87.1% Number of lesions (% of 257) 188 (76) 167 (68) 114 (46) 116 (47) 109 (44) 84 (34) 68 (28) 60 (24) a The detection of clinically significant cancer was considered on per-lesion analysis. MRI = magnetic resonance imaging; PET = positron emission tomography; PI-RADS = Prostate Imaging Reporting and Data System; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen. PPV= positive predictive value, NPV = negative predictive value.

Background:We previously reported results from a randomized phase 2 trial evaluating a DNA vaccine (pTVG-HP) versus placebo (GM-CSF vaccine adjuvant alone) in patients with PSA-recurrent, nonmetastatic, non-castrate prostate cancer (NCT01341652). The primary endpoint of 2-year metastasis-free survival (MFS) was not different between the treatment arms. This trial was reopened for long-term evaluation at one study site. Methods and Results:The median follow-up for long-term overall survival was 4.1 years (range 0.1-13.8+ years). Median overall survival of 48 patients treated with pTVG-HP was 13.4 years versus 8.6 years for 49 patients treated with placebo (log-rank test p-value=0.020). Long-term follow-up information on survival and subsequent treatments was available for 59 patients. Of these, 56 were treated with subsequent androgen deprivation therapy (ADT). When analyzing overall survival for this cohort, the adjusted hazard ratio was 0.56 (p=0.021) when comparing pTVG-HP vs. placebo, after adjusting for ADT and subsequent treatment exposure. The median time to beginning ADT was 2.2 years for patients randomized to pTVG-HP versus 1.4 years for patients randomized to placebo (p=0.192). The median time to the next therapy for castration-resistant disease after beginning ADT was 4.7 years for patients randomized to pTVG-HP versus 2.1 years for patients randomized to placebo (p=0.112). Conclusions:These results suggest that pTVG-HP may have had single-agent benefit that could not be appreciated using a MFS endpoint, challenging the notion that MFS can uniformly serve as a surrogate endpoint for overall survival in this stage of disease.

Introduction:Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods:In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results:All 20 SP participants (median age 57.5 (range 42-75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion:In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration:https://clinicaltrials.gov/study/, identifier NCT05419011.

Background: Compared to immunocompetent individuals, those who are immunocompromised, including solid organ transplant (SOT) recipients, have higher SARS-CoV-2-related morbidity and mortality. We determined the duration of SARS-CoV-2 RNA positivity to evaluate viral persistence in SOT recipients. Methods: This study prospectively followed SOT recipients who recently tested positive for SARS-CoV-2. The duration of viral RNA shedding in nasal swabs and stool samples was tracked, and viral genome sequencing was performed where possible. Persistent infection was defined as a positive nucleic acid amplification test (NAAT) for SARS-CoV-2 at 28 days or later after initial infection. This duration was chosen based on the CDC recommendation that immunocompromised individuals isolate for at least 20 days 1, compared to 10 days for non-immunocompromised individuals. Results: Of 30 SOT recipients, 12 (40%) had SARS-CoV-2 RNA in nasal swabs or stool 28 or more days after the first positive SARS-CoV-2 test. IC-015 had high viral loads (Ct<30) at 28 days, with continued detection for 54 days. Conclusion: In 12 of 30 SOT subjects, SARS-CoV-2 RNA was detected at or beyond 28 days post-detection (dpd), despite vaccination and antibody and/or antiviral treatment in most participants. Three subjects tested positive for SARS-CoV-2 RNA past 50 dpd. The CDC recommendation for 20 days of isolation may be insufficient for SOT recipients. Viral persistence in the setting of host immune suppression, coupled with exposure to antiviral treatments, raises concern about the selection of unusual viral variants. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement CDC Contract Number: 200-2021-11060- FY21 BAA Topic 8 Wisconsin-Madison; 435100-A24-ELCProjE-00 Wisconsin Department of Health Services, ELC; Department of Surgery start up funds (JGW) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UW-Madison Health Sciences IRB of the University of Wisconsin gave ethical approval for this work, study ID 2022-0499. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. All data are available at: https://dholk.primate.wisc.edu/project/dho/public/manuscripts/published/Longitudinal%20Assessment%20of%20Solid%20Organ%20Transplant%20Recipients%20with%20SARS-CoV-2%20Infection/begin.view#

BACKGROUND:Pulmonary hypertension (PH) resulting from heart failure with preserved ejection fraction (PH-HFpEF) can lead to right ventricular-pulmonary arterial (RV-PA) uncoupling despite normal steady hemodynamics (eg, pulmonary vascular resistance). Unsteady hemodynamics, quantified by characteristic pulmonary impedance (ZC), may be useful in differentiating those patients with PH-HFpEF who have sufficient coupling from those who have insufficient coupling. We hypothesized that abnormal pulsatile hemodynamics with exercise, quantified by ZC, could precisely detect abnormal cardiopulmonary function in PH-HFpEF. RESEARCH QUESTION:Can ZC with exercise detect abnormal pulmonary vascular response and RV-PA uncoupling in PH-HFpEF? STUDY DESIGN AND METHODS:Our approach was pilot tested in a small cohort of patients with PH-HFpEF (n = 8), precapillary PH (n = 5), and no PH (n = 2) who underwent rest-exercise (every 25 W)-recovery testing with repeated measurements of characteristic impedance (ZC, from invasive cardiopulmonary exercise and echocardiography for pulmonary vascular pressure-flow) and coupling (end systolic elastance [Ees] to effective arterial elastance [Ea] ratio, from RV pressure-volume loops). Analysis included disease-specific autoregressive correlation structure of order 1 (for repeated measures in time-series analysis). RESULTS:Metrics of steady pulmonary hemodynamics with exercise changed in a similar fashion in the 2 disease groups. In contrast, at rest in PH-HFpEF (vs precapillary PH), ZC was low (0.22 [0.14] mm Hg/L/min vs 0.70 [0.20] mm Hg/L/min; P < .0001) and Ees to Ea ratio was high (1.10 [0.36] vs 0.58 [0.22]; P = .0007). During exercise in PH-HFpEF, ZC increased and Ees to Ea ratio decreased, but both remained unchanged in precapillary PH. In PH-HFpEF, a significant negative correlation was found between ZC and Ees to Ea ratio (slope, -0.96; r2 = 0.18; P < .0001) that was absent in precapillary PH (slope, -0.20; r2 = 0.11; P = .53). INTERPRETATION:Despite the small sample size, RV-PA uncoupling with exercise was significantly negatively correlated with ZC in PH-HFpEF, which was not evident in precapillary PH, suggesting that abnormal exercise pulsatile hemodynamics may be key to RV failure in left-sided heart disease.

Chimeric antigen receptor (CAR) T cells have limited efficacy against solid tumors including neuroblastoma. Here, we evaluated whether low-dose radiation delivered by radiopharmaceutical therapy (RPT), known to potentiate immune checkpoint inhibitors, can synergize with CRISPR-edited GD2 TRAC-CAR T cells to improve outcomes in neuroblastoma. We found that in the localized model of neuroblastoma, low-dose radiation delivered by 177Lu-NM600, an alkylphosphocholine mimetic RPT agent, followed 9 days later by GD2 TRAC-CAR T cells led to complete tumor regression. Irradiation of neuroblastoma before GD2 TRAC-CAR T cells enhanced the release by CAR T cells of perforin, granzyme B, tumor necrosis factor-α, and interleukin-7 while abrogating transforming growth factor-β1. Low-dose RPT up-regulated the death receptor Fas on neuroblastoma, potentially enabling CAR-independent killing. This suggests that low-dose RPT can enhance suboptimal CAR T cell efficacy against solid tumors. However, optimization of radiation dose and timing may be needed for each patient and RPT agent to account for varied tumor radiosensitivity and dosimetry.

Background and ObjectivesStandard treatment of patients with stage II/III esophageal or gastroesophageal junction (E/GEJ) cancer involves neoadjuvant chemoradiation (nCRT), resection, and immunotherapy. Our trial evaluated the addition of perioperative avelumab to standard treatments.MethodsPatients with resectable E/GEJ cancers received avelumab with nCRT and adjuvant avelumab after resection. Primary endpoints for phase I and II portions were safety and pathologic complete response (pCR) rate, respectively. Secondary endpoints included recurrence-free survival (RFS), surgical complication prevalence, and R0 resection rate.ResultsTwenty-two patients enrolled in the study. Median follow-up during data cutoff was 23.9 months. There were no dose-limiting toxicities during the run-in phase. Nineteen patients (86.4%) underwent resection with R0 resection rate of 78.9% and with pCR rate of 26%. Most common treatment-related adverse events (TRAE) were cytopenias from chemoradiation. Aside from one grade >= 3 avelumab-related hypersensitivity, no grade >= 3 avelumab TRAEs were seen. Median RFS was not reached, and 1-year RFS and overall survival were 71% and 81%, respectively. The study was terminated before full planned accrual due to standard practice change based on the CheckMate 577 trial.ConclusionsThe addition of perioperative avelumab to nCRT was tolerable and demonstrated promising outcomes.

BACKGROUND:Compared with immunocompetent individuals, those who are immunocompromised, including solid organ transplant (SOT) recipients, have higher SARS-CoV-2-related morbidity and mortality. We determined the duration of SARS-CoV-2 RNA positivity to evaluate viral persistence in SOT recipients. METHODS:This study prospectively followed SOT recipients who recently tested positive for SARS-CoV-2. The duration of viral RNA shedding in nasal swabs and stool samples was tracked, and viral genome sequencing was performed where possible. Persistent infection was defined as a positive nucleic acid amplification test (NAAT) for SARS-CoV-2 at 28 days or later after initial infection. This duration was chosen based on the U.S. Centers for Disease Control and Prevention (CDC) recommendation that immunocompromised individuals isolate for at least 20 days [1], compared with 10 days for non-immunocompromised individuals. RESULTS:Of 30 SOT recipients, 12 (40%) had positive SARS-CoV-2 RNA in nasal swabs or stool (cycle threshold [Ct] < 40) at 28 or more days after the first positive SARS-CoV-2 test. Immunocompromised (IC) subject 015 had high viral loads (Ct < 30) at 28 days, with continued detection for 54 days. CONCLUSIONS:In 12 of 30 SOT subjects, SARS-CoV-2 RNA was detected at or beyond 28 days post-detection (dpd), despite vaccination and antibody and/or antiviral treatment in most participants. Three subjects tested positive for SARS-CoV-2 RNA past 50 dpd. Viral persistence in the setting of host immune suppression, coupled with exposure to antiviral treatments, raises concern about the selection of unusual viral variants.

Purpose Standardized reporting of treatment response in oncology patients has traditionally relied on methods like RECIST, PERCIST and Deauville score. These endpoints assess only a few lesions, potentially overlooking the response heterogeneity of all disease. This study hypothesizes that comprehensive spatial-temporal evaluation of all individual lesions is necessary for superior prognostication of clinical outcome. Methods [ 18 F]FDG PET/CT scans from 241 patients (127 diffuse large B-cell lymphoma (DLBCL) and 114 non-small cell lung cancer (NSCLC)) were retrospectively obtained at baseline and either during chemotherapy or post-chemoradiotherapy. An automated TRAQinform IQ software (AIQ Solutions) analyzed the images, performing quantification of change in regions of interest suspicious of cancer (lesion-ROI). Multivariable Cox proportional hazards (CoxPH) models were trained to predict overall survival (OS) with varied sets of quantitative features and lesion-ROI, compared by bootstrapping with C-index and t-tests. The best-fit model was compared to automated versions of previously established methods like RECIST, PERCIST and Deauville score. Results Multivariable CoxPH models demonstrated superior prognostic power when trained with features quantifying response heterogeneity in all individual lesion-ROI in DLBCL (C-index = 0.84, p < 0.001) and NSCLC (C-index = 0.71, p < 0.001). Prognostic power significantly deteriorated ( p < 0.001) when using subsets of lesion-ROI (C-index = 0.78 and 0.67 for DLBCL and NSCLC, respectively) or excluding response heterogeneity (C-index = 0.67 and 0.70). RECIST, PERCIST, and Deauville score could not significantly associate with OS (C-index < 0.65 and p > 0.1), performing significantly worse than the multivariable models ( p < 0.001). Conclusions Quantitative evaluation of response heterogeneity of all individual lesions is necessary for the superior prognostication of clinical outcome.

Background: Common biologic samples used to diagnose COVID-19 include nasopharyngeal, nasal, or oropharyngeal swabs, and salivary samples. The performance characteristics of a sucked "lollipop" swab to detect SARSCoV-2 virus is assessed in four small sub-studies. Methods: In each sub-study, a flocked swab was sucked for 20 s and submitted for PCR detection of SARS-CoV-2 virus. Results: Across all studies, 52 of 69 (75.4%) COVID-19 positive participants had positive "lollipop" swabs. Twelve of the 17 COVID-19 positive participants with negative "lollipop" swabs had known corresponding cycle threshold values of >37 from their nasal/nasopharyngeal swabs, an indication of low viral load at time of sampling. In a paired samples sub-study, the sensitivity and specificity of the "lollipop" swabs were 100% and 98%. Conclusions: "Lollipop" swabs performed satisfactorily especially in individuals with acute infection of COVID-19. "Lollipop" swabs are a simple method of sample collection for detecting SARS-CoV-2 virus and warrants additional consideration.

While chimeric antigen receptor (CAR) T cells have achieved significant success against hematological malignancies, efficacy against neuroblastoma has been limited. Virus-free CRISPR-edited GD2 TRAC-CAR T cells have been developed as a potential means of improving CAR T efficacy but are not curative. Radiopharmaceutical therapy (RPT) is a promising approach to enhance the effectiveness of immunotherapies, including immune checkpoint inhibitors. However, it remains unclear whether RPT can synergize with GD2 TRAC-CAR T cells to improve outcomes in neuroblastoma. Dosimetry studies were conducted to measure the absorbed radiation dose delivered by lutetium-177 (177Lu) in both in vitro and in vivo models. Tumor-bearing mice were treated sequentially with low dose radiation by 177Lu-NM600, an alkylphosphocholine mimetic radiopharmaceutical agent, followed 9 days later by GD2 TRAC-CAR T cells generated in a virus-free manner by CRISPR/Cas9. Tumor burden was monitored through bioluminescence imaging and tumor size measurements. Mechanistic studies were performed using flow cytometry, multiplex assay and single-cell proteomic analysis. Low dose radiation delivered by 177Lu-NM600 synergized with GD2 TRAC-CAR T cells in a localized neuroblastoma model, resulting in complete tumor regression in all mice. The optimal combination was dependent on both the radiation dose and timing to minimize the negative impact of radiation on CAR T cell viability. Irradiation of neuroblastoma cells by low-dose RPT before GD2 TRAC-CAR T cells enhanced the release by CAR T cells of perforin, granzyme B and cytokines like TNF-α and IL-7 while abrogating TGF-β1 secretion. Additionally, low-dose RPT upregulated Fas on neuroblastoma cells, potentially enabling a CAR-independent killing. This study demonstrates that low-dose RPT can enhance CAR T cell efficacy to treat a solid tumor. Findings suggest that optimization of radiation dose and timing may be needed for each patient and RPT to account for effects of varied tumor radiosensitivity and dosimetry. ### Competing Interest Statement QHS is an inventor on patent applications related to this publication. AS: None DC: None MHF is an inventor on patent applications related to this publication. JCE: None MBI: None ASO: None OK: None IMO: None RH received patent royalties from Wisconsin Alumni Research Foundation; consulting fees from Archeus Technologies Inc and Monopar Therapeutics. JW is the founder and member of the Science Advisory Board of Archeus Technologies which holds the licensing rights to NM600 chelates. BPB received stock/stock options from Voximetry Inc. KS received grant support from Synthego and Spotlight Therapeutics; patent royalties from Wisconsin Alumni Research Foundation; honoraria from ISCT, is an inventor on patent applications related to this publication; Scientific Advisory Board Member for Notch Therapeutics and Andson Biotech. PMS received support from the University of Wisconsin, Midwest Athletes For Childhood Cancer and the National Cancer Institute. CMC received honoraria from Bayer, Nektar Therapeutics, Novartis, WiCell Research Institute, consulting fees and equity interest from Elephas and is an inventor on patent applications related to this publication. ZSM is a member of the Scientific Advisory Boards for Archeus Technologies, Seneca Therapeutics, Cali Biomedical, and NorthStar Medical Radioisotopes; a consultant for Johnson & Johnson; received royalties from patents held by the Wisconsin Alumni Research Foundation; holds equity options from Archeus Technologies, Cali Biomedical, and Seneca Therapeutics; received research funding provided to the University of Wisconsin from Point Biopharma and Telix Pharmaceuticals and is an inventor on patent applications related to this publication.

We have previously reported two single-agent phase I trials, evaluating the dose or schedule, of a DNA vaccine (pTVG-HP) encoding prostatic acid phosphatase (PAP) administered with GM-CSF as the adjuvant. These were in patients with PSA-recurrent, radiographically non-metastatic, prostate cancer (PCa). We report here the long-term safety and overall survival of these patients. Specifically, 22 patients with non-metastatic, castration-sensitive PCa (nmCSPC) were treated with pTVG-HP, 100-1500 mu g, administered over 12 weeks and followed for 15 y. 17 patients with non-metastatic castration-resistant PCa (nmCRPC) were treated with 100 mu g pTVG-HP with different schedules of administration over 1 y and followed for 5 y. No adverse events were detected in long-term follow-up from either trial that were deemed possibly related to vaccination. Patients with nmCSPC had a median overall survival of 12.3 y, with 5/22 (23%) alive at 15 y. 8/22 (36%) died due to prostate cancer with a median survival of 11.0 y, and 9/22 (41%) died of other causes. Patients with nmCRPC had a median overall survival of 4.5 y, with 8/17 (47%) alive at 5 y. The presence of T-cells specific for the PAP target antigen was detectable in 6/10 (60%) individuals with nmCSPC, and 3/5 (60%) individuals with nmCRPC, many years after immunization. The detection of immune responses to the vaccine target years after immunization suggests durable immunity can be elicited in patients using a DNA vaccine encoding a tumor-associated antigen.Trial Registration: NCT00582140 and NCT00849121

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral–immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8 Gy fraction (arm A) or three 8 Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral–immunocytokine at 12 mg/m 2 on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral–immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.

Long noncoding RNAs (lncRNAs) participate in transcriptional, epigenetic, and post-transcriptional regulation of gene expression and may influence carcinogenesis. MALAT1 is a lncRNA that is expressed in endocrine and many other neoplasms and it has been shown to have oncogenic and/or tumor suppressor effects in tumor development. Olfactory neuroblastomas arise in the nasal cavity while sympathetic neuroblastomas are present mainly in the adrenal and periadrenal regions. These neoplasms have overlapping histopathological features. Rare cases of sympathetic neuroblastomas metastatic to the nasal cavity have been reported. PHOX2B has been shown to be relatively specific for sympathetic neuroblastomas, but only a limited number of cases of olfactory neuroblastomas have been examined for PHOX2B expression. This study aimed to explore the potential utilization of MALAT1 and PHOX2B in distinguishing these two entities. Tissue microarrays (TMA) were created for olfactory neuroblastomas (n = 26) and sympathetic neuroblastomas (n = 52). MALAT1 lncRNA expression was assessed by in situ hybridization using RNAScope technology. TMA slides were scanned by Vectra multispectral imaging system and image analysis and quantification were performed with inForm software. PHOX2B expression was analyzed by immunohistochemistry. MALAT1 showed predominantly nuclear expression in both tumor types and MALAT1 expression was 2-fold higher in olfactory neuroblastomas compared to sympathetic neuroblastomas (p < 0.0001). PHOX2B showed nuclear staining in most sympathetic neuroblastomas (51/52, 98 %) while only 1 olfactory neuroblastoma (3.8 %) was focally positive for this marker. These findings suggest immunostaining of PHOX2B could be an excellent marker in distinguishing between these two tumor types.

Introduction: Passive leg raise (PLR) is a simple, dynamic maneuver that has been used to increase preload to the heart. We hypothesize that PLR may offer a new and efficient office-based tool for assessing blood pressure (BP) control in older adults. Methods: One hundred and three veterans (≥60 years old) without known cardiovascular disease and varying degrees of blood pressure control were included in this cross-sectional cohort study. Twenty-four hour ambulatory BP monitoring identified Veterans with optimal and suboptimal BP control (≥125/75 mmHg). Bioimpedance electrodes (Baxter Medical, Deerfield, Illinois, USA) and brachial BP were used to calculate hemodynamic parameter changes across PLR states [pre-PLR, active PLR (3 min), and post-PLR]. Multiple linear regression was used to assess associations between BP control status with changes in hemodynamic parameters between PLR states. Results: The 24-h ambulatory BP monitoring identified 43 (42%) older Veterans with optimal BP control (mean age of 70.5 ± 7.0 years) and 55 (54%) with suboptimal BP (mean age of 71.3 ± 8.7 years). Veterans with suboptimal BP control had significantly reduced change in total peripheral resistance (ΔTPR) (7.0 ± 156.0 vs. 127.3 ± 145.6 dynes s/cm5; P = 0.002) following PLR compared with Veterans with optimal BP control. Suboptimal BP control (β = −0.35, P = 0.004) had a significant association with reduced ΔTPR, even after adjusting for demographic variables. Conclusion: Measuring PLR-induced hemodynamic changes in the office setting may represent an alternative way to identify older adults with suboptimal BP control when 24-h ambulatory BP monitoring is not available.