Race, sex, and socioeconomic disparities affect the clinical stage of patients presenting for treatment of superficial venous disease.

OBJECTIVE: Superficial venous disease has a U.S. prevalence of nearly 30%, with advanced disease contributing to a significant healthcare burden. Although the risk factors for venous disease are well known, the correlation between race, sex, socioeconomic status, and disease severity on presentation is not well established. The area deprivation index (ADI) is a validated metric with respect to regional geography, social determinants of health, and degree of socioeconomic disadvantage. In the present study, we aimed to identify the disparities and the effect that the ADI, in addition to race and sex, has among patients associated with an advanced venous disease presentation. METHODS: A retrospective review between 2012 and 2022 was performed at four tertiary U.S. institutions to identify patients who underwent endovenous closure of their saphenous veins. Patient demographics, state ADI, comorbidities, CEAP (clinical, etiologic, anatomic, pathophysiologic) classification, and periprocedural outcomes were included. Pearson's correlation was performed between the CEAP classification and ADI. Poisson regression analysis was performed to identify factors predicting for an increasing CEAP classification at presentation. Variables with P < .05 were deemed significant. RESULTS: A total of 2346 patients underwent endovenous saphenous vein closure during the study period, of whom 7 were excluded because of a lack of follow-up data. The mean age was 60.4 ± 14.9 years, 65.9% were women, and 55.4% were White. Of the 2339 patients, 73.3% presented with an advanced CEAP class (≥3). The mean state ADI for the entire cohort was 4.9 ± 3.1. The percent change in the CEAP classification is an increase of 2% and 1% for every level increase in the state ADI for unadjusted (incidence rate ratio [IRR] = 1.02; P < .001) and adjusted (IRR = 1.01; P < .001) models, respectively. Black race has a 12% increased risk of a higher CEAP class on presentation compared with White race (IRR = 1.12; P = .005). Female sex had a 16% lower risk of a higher CEAP presentation compared with male sex (IRR = 0.84; P < .01). CONCLUSIONS: Low socioeconomic status, Black race, and male sex are predictive of an advanced CEAP classification on initial presentation. These findings highlight the opportunity for improved mechanisms for identification of venous disease and at-risk patients before advanced disease progression in known disadvantaged patient populations.

Type IV Hypersensitivity Reaction after Cyanoacrylate Venous Closure.

BACKGROUND: Nonthermal endovenous closure techniques are routinely utilized to treat superficial axial venous reflux. Cyanoacrylate closure is a safe and effective modality implemented for truncal closure. However, an adverse reaction of type IV hypersensitivity (T4H), unique to cyanoacrylate, is a known risk. This study aims to evaluate the real-world incidence of T4H and examine risk factors that may predispose its development. METHODS: A retrospective review between 2012- and 2022 was performed at four tertiary US institutions to examine patients who underwent cyanoacrylate vein closure of their saphenous veins. Patient demographics, comorbidities, CEAP (Clinical [C], Etiological [E], Anatomical [A], and Pathophysiological [P]) classification, and periprocedural outcomes were included. The primary endpoint was development of T4H post procedure. Logistic regression analysis for risk factors predictive of T4H was performed. Variables with a P-value of <0.05 were deemed significant. RESULTS: 595 patients underwent 881 cyanoacrylate venous closures. Mean age was 66.2 ± 14.9, and 66% of patients were female. There were 92 (10.4%) T4H events in 79 (13%) patients. Oral steroids were administered to 23% for persistent and/or severe symptoms. There were no systemic allergic reactions to cyanoacrylate. Multivariate analysis revealed younger age (P = 0.015), active smoking status (P = 0.033), and CEAP 3 (P < 0.001) and 4 (P = 0.005) classifications as independent risk factors associated with development of T4H. CONCLUSIONS: This real-world multicenter study shows the overall incidence of T4H to be 10%. CEAP 3 and 4 patients of younger age and smokers predicted a higher risk of T4H to cyanoacrylate.

VIEW-VLU observational study of the effect of Varithena on wound healing in the treatment of venous leg ulcers.

OBJECTIVE: Chronic venous hypertension, triggered by venous reflux and/or obstruction, leads to skin changes and venous leg ulcers (VLUs). Compression therapy is the standard of care, but many wounds remain unhealed. The objectives of this study were to observe the effects of endovenous chemical ablation with commercially available 1% polidocanol injectable microfoam on VLU healing and recurrence rates. METHODS: The VIEW VLU study was a multicenter, open-label, phase IV registry of patients with active VLUs resulting from venous insufficiency of the great saphenous vein and/or anterior accessory saphenous vein systems who underwent ablation with 1% polidocanol microfoam. Primary outcomes included wound healing rate (change in wound perimeter), wound closure at 12 weeks after treatment, and time to wound closure. Secondary outcomes included VLU recurrence, numeric pain score at the ulcer location, EuroQol five-dimension five-level questionnaire quality-of-life index, and the Venous Clinical Severity Score. Patients were followed for 12 months. RESULTS: We enrolled 76 patients (80 ulcers) from 14 sites across the United States and Canada (mean age 63.6 ± 13.7 years, 39.5% female, mean body mass index 36.3). Of the enrollees, 96.3% presented with great saphenous vein incompetence. The mean baseline wound perimeter was 117.2 ± 107.4 mm and 26.3% of wounds (21/80) were circumferential. The mean ulcer age was 34.8 ± 51.8 weeks at first presentation and the mean compression therapy duration was 26.4 ± 35.9 weeks. The median wound perimeter decreased by 16.3% from baseline in the first 2 weeks after the procedure and by 27.0% at 12 weeks. By 12 weeks, 53.8% of wounds (43/80) were healed. The median time to ulcer closure by Kaplan-Meier analysis was 89 days (95% confidence interval, 62.0-117.0). In a Kaplan-Meier analysis of initially healed wounds, 88.9% (95% confidence interval, 76.9-94.8) remained closed at 12 weeks after closure. The mean numeric pain scores (ulcer site) improved by 41.0% and 64.1% at 12 weeks and 12 months after the procedure, respectively. The health-related quality-of-life index (scale of 0-1) improved from 0.65 ± 0.27 at baseline to 0.72 ± 0.28 at 12 weeks and 0.73 ± 0.30 at 12 months. By 12 weeks after treatment, the mean target leg Venous Clinical Severity Score had significantly decreased by 5.8 points, and by 12 months it had decreased by 10.0 points. CONCLUSIONS: Treatment with 1% polidocanol microfoam was associated with promising wound healing rates and low recurrence rates for VLUs, despite a challenging patient population with recalcitrant ulcers, a large percentage of which were circumferential, in patients with high body mass indexes.

STAT1 pathway mediates amplification of metastatic potential and resistance to therapy.

BACKGROUND: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. CONCLUSIONS: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization.

Local and systemic consequences of large retroperitoneal clot burdens.

BACKGROUND: There is a paucity of data regarding the impact of retroperitoneal hematoma (RPH) volumes, as detected by computed tomography (CT) scanning, on patient morbidity and mortality. Therefore, we wanted to determine the natural history of RPHs and the effect of size on local and systemic outcomes. METHODS: We performed a volumetric analysis of CT-documented RPHs managed at our institution between 1985 and 2006 along with a retrospective chart review. RESULTS: We included 81 cases of RPH in this study. The mean Acute Physiology, Age, and Chronic Health Evaluation II (APACHE II) score was 12.8 +/- 0.72 (score +/- SE). By univariate analysis, the size of the hematoma showed a significant correlation with the development of local mass effects, delayed mass effects, 6-month mortality, major morbidity, pulmonary complications, fluid overload, and the requirement for operative evacuation (p < 0.05). Receiver operating characteristic analysis revealed that a size > or = 1600 cm(3) was > 80% sensitive and specific for predicting a delayed mass effect or an increase in 6-month mortality. Multivariate analysis controlling for factors such as APACHE II and packed red blood cells transfused showed that the volume of the RPH was an independent predictor for the development of local mass effects, pulmonary insufficiency, and fluid overload. CONCLUSIONS: Large RPHs are clearly associated with worse patient outcomes. Surgical intervention may be warranted for the treatment of RPHs > or = 1600 cm(3).

Tumor genotype determines susceptibility to oncolytic herpes simplex virus mutants: strategies for clinical application.

Oncolytic Herpes simplex virus -1 (HSV-1) mutants based on deletion of the gamma134.5 gene are promising therapies for cancer. Deltagamma134.5 mutant replication and cytolysis is tumor cell type specific and severely attenuated in normal tissues. The basis for attenuation lies in the activation of the protein kinase R (PKR)-mediated host cellular defense pathway, which inhibits protein synthesis in infected cells. Tumor cells which overexpress MAPK kinase (MEK) activity support robust replication of Deltagamma134.5 mutants via MEK-mediated inhibition of PKR, resulting in tumor oncolysis. Systemic delivery of gamma(1)34.5 mutants may allow selective targeting and destruction of metastases from a broad range of solid human tumors that overexpress MEK. Barriers to systemic HSV-1 oncolytic therapy include innate immunity, adaptive immunity and hepatic adsorption. Immunomodulating agents may overcome innate immunity to HSV-1-based vectors. Preclinical data combined with the pervasiveness of HSV-1 despite widespread immunity suggest that preexisting immunity may not eliminate oncolytic efficacy. In the future, biopsy-determined tumor MEK status may select patients for Deltagamma134.5 oncolytic therapy.

Systemic delivery of (gamma1)34.5-deleted herpes simplex virus-1 selectively targets and treats distant human xenograft tumors that express high MEK activity.

Deltagamma(1)34.5 mutant herpes simplex type 1 viruses are under active clinical investigation as oncolytic therapy for cancer. Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) activity has been shown to suppress protein kinase R and thereby confer oncolytic susceptibility to some human tumors by R3616, a virus deleted for both copies of gamma(1)34.5. We report that systemic delivery of R3616 can selectively target and destroy human xenograft tumors that overexpress MEK activity compared with tumors that express lower MEK activity. These results suggest systemic delivery of R3616 may be effective in the treatment of some human tumors.