Use of a Glass Membrane Pumping Emulsification Device Improves Systemic and Tumor Pharmacokinetics in Rabbit VX2 Liver Tumor in Transarterial Chemoembolization

PurposeTo evaluate the phamacokinetics of epirubicin in conventional transarterial chemoembolization using a developed pumping emulsification device with a microporous glass membrane in VX2 rabbits.Materials and MethodsEpirubicin solution (10 mg/mL) was mixed with ethiodized oil (1:2 ratio) using the device or 3-way stopcock. Forty-eight rabbits with VX2 liver tumor implanted 2 weeks prior to transarterial chemoembolization were divided into 2 groups: a device group (n = 24) and a 3-way-stopcock group (n = 24). Next, 0.5 mL of emulsion was injected into the hepatic artery, followed by embolization using 100–300-μm microspheres. The serum epirubicin concentrations (immediately after, 5 minutes after, and 10 minutes after) and the tumor epirubicin concentrations (20 minutes after and 48 hours after) were measured after transarterial chemoembolization. Histopathologic evaluation was performed with a fluorescence microscope.ResultsThe area under the curve and maximum concentrations of epirubicin in plasma were 0.45 ± 0.18 μg min/mL and 0.13 ± 0.06 μg/mL, respectively, in the device group and 0.71 ± 0.45 μg min/mL and 0.22 ± 0.17 μg/mL, respectively, in the 3-way-stopcock group (P = .013 and P = .021, respectively). The mean epirubicin concentrations in VX2 tumors at 48 hours in the device group and the 3-way-stopcock group were 13.7 ± 6.71 and 7.72 ± 3.26 μg/g tissue, respectively (P = .013). The tumor necrosis ratios at 48 hours were 62 ± 11% in the device group and 51 ± 13% in the 3-way-stopcock group (P = .039).ConclusionsConventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.     

Midterm Outcomes of Angioplasty for Pediatric Renovascular Hypertension

PurposeTo evaluate the midterm outcomes of percutaneous transluminal renal angioplasty (PTRA) for pediatric renovascular hypertension (RVH).Materials and MethodsThe clinical data of patients who underwent PTRA for RVH in the authors’ hospital from 2012 to 2019 were retrospectively analyzed. Postprocedural blood pressure, glomerular filtration rate (GFR) of the affected kidney, restenosis, and complications were closely monitored.ResultsPTRA was performed in a total of 30 children (20 boys and 10 girls), with a mean age of 7.3 years ± 0.7 (range, 40 days to 13.9 years) and a mean weight of 25.0 kg ± 2.3 (range, 3.4–53 kg). The median follow-up period was 26.5 months (range, 1 month to 7.5 years). Technical success was achieved in 26 (86.7%) of the 30 patients. Restenosis developed in 3 patients (10.0%). Only 1 patient underwent stent implantation, and the stent fractured 8 months later, requiring further intervention. There were no other complications. In terms of clinical benefit of blood pressure control after the initial PTRA procedure, 15 patients (50%) were cured and 7 patients (23.3%) showed improvement. There was no significant difference in the etiology, lesion location, and lesion length between patients with clinical benefit and failure (P = .06, P = .202, and P = .06, respectively). GFR of the affected kidney was significantly improved from 19.9 mL/min ± 11.2 to 38.1 mL/min ± 11.9 at the 6-month follow-up after PTRA (P < .001).ConclusionsThe overall results of PTRA for pediatric RVH caused by different etiologies are promising. PTRA not only provided a clinical benefit of blood pressure control in 73.3% of the patients but also significantly improved the function of the affected kidney.     

Hepatic Arterial Blood Flow Modulation in Patients with Hepatocellular Carcinoma: A Pilot Study of the Influence of Intraarterial Norepinephrine Assessed with CT Perfusion

PurposeThis pilot study aims to evaluate the effect of hepatic intraarterial norepinephrine injection in vasculature modulation for hepatocellular carcinoma (HCC) tumors.Materials and MethodsThis is a single-center prospective study of patients with HCC with proven single-lobe tumors > 3 cm. Eight patients were included, with a mean age of 63 y ± 8. All patients had Barcelona Clinic Liver Cancer stage B HCC and an Eastern Cooperative Oncology Group performance status of 0. Mean tumor size was 6.1 cm ± 1.8; all tumors were hypervascular. Patients underwent CT hepatic perfusion before and after injection of 24 μg of norepinephrine intraarterially (4 μg/mL; total 6 mL injected at a rate of 1 mL/s). Color-coded perfusion maps were used to assess the effects of local therapy on hepatic perfusion values. Tumor-to-liver ratio (TLR) was calculated from the ratio of tumor perfusion to background liver perfusion value.ResultsSeven of 8 patents had significant (P = .04) absolute increase in tumor perfusion vs background liver, varying from incremental (–2 mL/min/100 mL) to 290 mL/min/100 mL. There was a nonsignificant increase in TLR from 2.7 ± 1.3 to 2.9 ± 1.4 after norepinephrine injection (P = .8). Mean peak time to maximal increase in tumor perfusion after injection was 6.1 s (range, 4.5–9.1 s). Norepinephrine injection was well tolerated without major adverse events.ConclusionsNorepinephrine causes increased blood flow toward HCC tumors, but with a corresponding smaller increase in blood flow to noncancerous liver tissue, with no observed systemic side effects.     

Prostatic Artery Embolization Using 100–300-μm Trisacryl Gelatin Microspheres to Treat Lower Urinary Tract Symptoms Attributable to Benign Prostatic Hyperplasia: A Single-Center Outcomes Analysis with Medium-Term Follow-up

PurposeTo report medium-term outcomes of prostatic artery embolization (PAE) using 100–300-μm trisacryl gelatin microspheres to treat lower urinary tract symptoms (LUTS) from benign prostatic hyperplasia (BPH) and to evaluate how cone-beam computed tomography-measured prostate gland volume (PGV), median lobe enlargement (MLE), age, and Charlson Comorbidity Index (CCI) affect these results.Materials and MethodsSeventy-four consecutive patients who underwent PAE from April 2014 through August 2018 were retrospectively reviewed. Patients had International Prostate Symptom Score (IPSS) >12, Quality of Life (QoL) score >2, prostate gland volume (PGV) >40 mL, age older than 45 years, and medical therapy failure. Twelve patients were excluded for bladder pathology or prostate cancer. Patients (n = 62, age = 71.8 ± 9.3 years, CCI = 3.5 ± 1.7, PGV = 174 ± 110 mL) had pre-procedure IPSS = 22.4 ± 5.6, QoL score = 4.4 ± 0.9, and post-void residual (PVR) = 172 ± 144 mL. Post-procedure values were compared to baseline at 1, 3, 6, 12, and 24 months. Associations between outcomes and PGV, MLE, age, and CCI were evaluated. Adverse event recording used Clavien-Dindo classification.ResultsOne month after PAE (n = 37), IPSS improved to 7.6 ± 5.2 (P < .0001) and QoL score improved to 1.7 ± 1.4 (P < .0001). At 3 months (n = 32), improvements continued, with IPSS = 6.4 ± 5.1 (P < .0001), QoL score = 1.2 ± 1.2 (P < .0001), PVR = 53 ± 41 mL (P < .001), and PGV = 73 ± 38 mL (P < .0001). Results were sustained at 6 months (n = 35): IPSS = 6.4 ± 4.1 (P < .0001), QoL score = 1.2 ± 1.2 (P < .0001), PVR = 68 ± 80 mL (P < .0001), PGV = 60 ± 19 mL (P < .001). At 12 months, patients (n = 26) had IPSS = 7.3 ± 5.5 (P < .0001), QoL score = 1.2 ± 0.8 (P <.0001), PVR = 89 ± 117 mL (P < .0001), PGV = 60 ± 48 mL (P < .01). At 24 months, patients (n = 8) had IPSS = 8.0 ± 5.4 (P < .0001), QoL score = 0.7 ± 0.5 (P < .0001), PVR = 91 ± 99mL (P = 0.17), and PGV = 30 ± 5mL (P = .11). Improvements were independent of PGV, MLE, age, and CCI. Two grade II urinary infections occurred.ConclusionsPAE with 100–300-μm microspheres produced sustained substantial improvements in LUTS, PGV, and PVR, which were independent of baseline PGV, MLE, age, or CCI.     

Preoperative Arterial Embolization for Heterotopic Ossification of the Hip

PurposeTo investigate the efficacy and safety of preoperative arterial embolization for neurogenic heterotopic ossification (NHO) of the hip.Materials and MethodsThis single-center retrospective study reviewed outcomes in 16 consecutive patients who had surgical resection of NHO of the hip: 8 of whom underwent preoperative arterial embolization and 8 of whom did not. Both patient cohorts had similar baseline characteristics. A mean of 2.62 ± 1.9 arteries per patient, including the gluteal, lateral circumflex femoral, and deep circumflex iliac branches, were embolized using an n-butyl cyanoacrylate (NBCA)–ethiodized oil mixture. Data from both cohorts regarding intraoperative blood loss, volume of blood transfused, complications, and duration of hospitalization were compared.ResultsA mean of 2.6 ± 1.9 arteries were embolized with NBCA–ethiodized oil, mainly the gluteal arteries, lateral circumflex femoral artery, and deep circumflex iliac artery. In the embolization group, mean intraoperative blood loss was 875 mL ± 320, mean number of units of blood used was 0.5 ± 0.7, and mean number of days of hospitalization was 6.4 days ± 1.6. In the control group, mean intraoperative blood loss was 1,350 mL ± 120, mean number of units of blood used was 2 ± 1.1, and average number of days of hospitalization was 11.5 days ± 1.4. The embolization group had a mean reduction in blood loss of 40.7% (P = 0.035), reduction in units of blood administered of 75% (P = 0.021), and reduction in days of hospitalization of 44.7% (P = 0.014). No procedural complications were recorded.ConclusionsPreoperative arterial embolization is effective and safe in reducing intraoperative blood loss, number of hospitalization days, and need for blood transfusions in surgical resection of NHO of the hip.     

Transarterial Chemoembolization in a Woodchuck Model of Hepatocellular Carcinoma

PurposeTo assess the feasibility of transarterial chemoembolization with drug-eluting embolic (DEE) microspheres in a woodchuck model of hepatocellular carcinoma (HCC).Materials and MethodsNine woodchucks were studied: 4 normal animals and 5 animals infected with woodchuck hepatitis virus in which HCC had developed. Three animals with HCC underwent multidetector CT. A 3-F sheath was introduced into the femoral artery, and the hepatic arteries were selectively catheterized with 2.0–2.4-F microcatheters. Normal animals underwent diagnostic angiography and bland embolization. Animals with HCC underwent DEE transarterial chemoembolization with 70–150-μm radiopaque microspheres loaded with 37.5 mg doxorubicin per milliliter. Cone-beam CT and multidetector CT were performed. Following euthanasia, explanted livers underwent micro-CT, histopathologic examination, and fluorescence imaging of doxorubicin.ResultsThe tumors were hypervascular and supplied by large-caliber tortuous vessels, with arteriovenous shunts present in 2 animals. There was heterogeneous enhancement on multidetector CT with areas of necrosis. Six tumors were identified. The most common location was the right medial lobe (n = 3). Mean tumor volume was 30.7 cm³ ± 12.3. DEE chemoembolization of tumors was achieved. Excluding the 2 animals with arteriovenous shunts, the mean volume of DEE microspheres injected was 0.49 mL ± 0.17. Fluorescence imaging showed diffusion of doxorubicin from the DEE microspheres into the tumor.ConclusionsWoodchuck HCC shares imaging appearances and biologic characteristics with human HCC. Selective catheterization and DEE chemoembolization may similarly be performed. Woodchucks may be used to model interventional therapies and possibly characterize radiologic–pathologic correlations.     

Postmortem examination and toxicological analysis for acute metonitazene intoxication in Japan: A case report

Benzoimidazole analgesics (Nitazenes, NZs) are opioid receptor agonists that exhibit very strong pharmacological effects at minute doses, and their abuse has recently become a concern worldwide. Although no deaths involving NZs had been reported in Japan to date, we recently experienced an autopsy case of a middle-aged man who was determined to have died from poisoning by metonitazene (MNZ), a type of NZs. There were traces of suspected illegal drug use around the body. Autopsy findings were consistent with acute drug intoxication as the cause of death, but it was difficult to identify the causative drugs by simple qualitative drug screening. Analysis of compounds recovered from the scene where the body was found identified MNZ, and its abuse was suspected. Quantitative toxicological analysis of urine and blood was performed using a liquid chromatography high-resolution tandem mass spectrometer (LC-HR-MS/MS). Results showed that MNZ concentrations in blood and urine were 6.0 and 5.2 ng/mL, respectively. Other drugs detected in blood were within therapeutic ranges. Quantitated blood MNZ concentration in the present case was in the similar range as those reported in overseas NZs-related deaths. There were no other findings that could have contributed to the cause of death, and the decedent was judged to have died of acute MNZ intoxication. Emergence of NZs distribution has been recognized in Japan similarly to overseas; early investigation of their pharmacological effects as well as crackdown on their distribution is strongly desired.     

Preoperative Transarterial Embolization of Advanced Juvenile Nasopharyngeal Angiofibroma Using n-Butyl Cyanoacrylate: Case-Control Comparison with Microspheres

PurposeTo evaluate the efficacy and safety of transarterial embolization (TAE) with n-butyl cyanoacrylate (nBCA) for juvenile nasopharyngeal angiofibroma (JNA).Materials and MethodsA retrospective review was performed on patients with JNA who underwent TAE and endoscopic resection between 2020 and 2022. Patients embolized with nBCA were identified, and those embolized with microspheres were set as the control group. Data on demographics, symptoms, tumor characteristics, blood loss, adverse events, residual disease, and recurrence were collected, and case-control analysis was performed for the 2 groups. Differences in characteristics between the groups were tested using the Fisher exact and Wilcoxon tests. A generalized linear model (GLM) was used to analyze the univariate and multivariate influences on blood loss.ResultsTwenty patients were included in this study: 13 in the microsphere group and 7 in the nBCA group. The median blood loss was 400 mL (interquartile range [IQR], 200–520 mL) in the nBCA group and 1,000 mL (IQR, 500–1,000 mL) in the microsphere group (P = .028). The GLM confirmed lower blood loss in the nBCA group (relative risk, 0.58 [0.41–0.83]; P = .01). A residual tumor was found in 1 patient in each group (7.7% vs 14.3%; P = 1.000). Recurrence was not observed in any patient. None of the patients experienced adverse events during embolization.ConclusionsTAE of advanced JNA with nBCA glue is safe and effective and can significantly reduce intraoperative blood loss compared with microspheres.     

Idarubicin-Loaded ONCOZENE Drug-Eluting Bead Chemoembolization in a Rabbit Liver Tumor Model: Investigating Safety,Therapeutic Efficacy,and Effects on Tumor Microenvironment

PurposeTo investigate toxicity, efficacy, and microenvironmental effects of idarubicin-loaded 40-μm and 100-μm drug-eluting embolic (DEE) transarterial chemoembolization in a rabbit liver tumor model.Materials and MethodsTwelve male New Zealand White rabbits with orthotopically implanted VX2 liver tumors were assigned to DEE chemoembolization with 40-μm (n = 5) or 100-μm (n = 4) ONCOZENE microspheres or no treatment (control; n = 3). At 24–72 hours postprocedurally, multiparametric magnetic resonance (MR) imaging including dynamic contrast-enhanced (DCE), diffusion-weighted imaging (DWI), and biosensor imaging of redundant deviation in shifts (BIRDS) was performed to assess extracellular pH (pHe), followed by immediate euthanasia. Laboratory parameters and histopathologic ex vivo analysis included fluorescence confocal microscopy and immunohistochemistry.ResultsDCE MR imaging demonstrated a similar degree of devascularization of embolized tumors for both microsphere sizes (mean arterial enhancement, 8% ± 12 vs 36% ± 51 in controls; P = .07). Similarly, DWI showed postprocedural increases in diffusion across the entire lesion (apparent diffusion coefficient, 1.89 × 10⁻³ mm²/s ± 0.18 vs 2.34 × 10⁻³ mm²/s ± 0.18 in liver; P = .002). BIRDS demonstrated profound tumor acidosis at baseline (mean pHe, 6.79 ± 0.08 in tumor vs 7.13 ± 0.08 in liver; P = .02) and after chemoembolization (6.8 ± 0.06 in tumor vs 7.1 ± 0.04 in liver; P = .007). Laboratory and ex vivo analyses showed central tumor core penetration and greater increase in liver enzymes for 40-μm vs 100-μm microspheres. Inhibition of cell proliferation, intratumoral hypoxia, and limited idarubicin elution were equally observed with both sphere sizes.ConclusionsNoninvasive multiparametric MR imaging visualized chemoembolic effects in tumor and tumor microenvironment following DEE chemoembolization. Devascularization, increased hypoxia, coagulative necrosis, tumor acidosis, and limited idarubicin elution suggest ischemia as the predominant therapeutic mechanism. Substantial size-dependent differences indicate greater toxicity with the smaller microsphere diameter.     

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model

PurposeTo investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model.Materials and MethodsVX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry.ResultsThe median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 μg/mL (interquartile range [IQR], 7.42–33.5 μg/mL), and its maximal plasma concentration (C_max) was 0.164 μg/mL (IQR, 0.0798–0.528 μg/mL). The intratumoral concentration and C_max of doxorubicin were similar between the groups: 4.08 μg/mL (IQR, 3.18–4.79 μg/mL) and 0.677 μg/mL (IQR, 0.315–1.23 μg/mL), respectively, in the DOX-TACE group and 1.68 μg/mL (IQR, 0.795–4.08 μg/mL) and 0.298 μg/mL (IQR, 0.241–0.64 μg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups.ConclusionsThe addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.     

Safety of High-Dose 3% Sodium Tetradecyl Sulfate for Sclerotherapy of Renal Cysts in Patients with Autosomal Dominant Polycystic Kidney Disease

This study assessed the safety profile of high-volume (>10 mL) 3% sodium tetradecyl sulfate (STS) sclerotherapy for the treatment of renal cysts in patients with autosomal dominant polycystic kidney disease. A total of 211 sclerotherapy treatments were performed in 169 patients over a 5-year period, with a comparison of 2 patient cohorts based on the STS volumes used. The first cohort (n = 112) received a high volume (greater than 10 mL) of STS, and the second cohort (n = 57) received a low volume (less than 10 mL). The minor adverse event rate for the cohorts was 14.5% and 9.6%, respectively (P = .310), with postprocedure pain being the most common event. One major adverse event occurred, for which the patient required hospitalization for infection after low-volume STS treatment. Doses of STS higher than those currently recommended by the Food and Drug Administration for intravascular use allow large renal cysts to be treated safely in the setting of autosomal dominant polycystic kidney disease.     

A Real-Time Blood Flow Measurement Device for Patients with Peripheral Artery Disease

PurposeTo evaluate the feasibility of a new optical device that measures peripheral blood flow as a diagnostic and monitoring tool for patients with peripheral artery disease (PAD).Materials and MethodsIn this prospective study, 167 limbs of 90 patients (mean age, 76 y; 53% men) with suspected PAD were evaluated with the FlowMet device, which uses a new type of dynamic light-scattering technology to assess blood flow in real time. Measurements of magnitude and phasicity of blood flow were combined into a single-value flow–waveform score and compared vs ankle–brachial index (ABI), toe–brachial index (TBI), and clinical presentation of patients per Rutherford category (RC). Receiver operating characteristic curves were constructed to predict RC. Area under the curve (AUC), sensitivity, and specificity were compared among flow–waveform score, ABI, and TBI.ResultsQualitatively, the FlowMet waveforms were analogous to Doppler velocity measurements, and degradation of waveform phasicity and amplitude were observed with increasing PAD severity. Quantitatively, the flow, waveform, and composite flow–waveform scores decreased significantly with decreasing TBI. In predicting RC ≥ 4, the flow–waveform score (AUC = 0.83) showed a linear decrease with worsening patient symptoms and power comparable to that of TBI (AUC = 0.82) and better than that of ABI (AUC = 0.71). Optimal sensitivity and specificity pairs were found to be 56%/83%, 72%/81%, and 89%/74% for ABI, TBI, and flow–waveform score, respectively.ConclusionsThe technology tested in this pilot study showed a high predictive value for diagnosis of critical limb ischemia. The device showed promise as a diagnostic tool capable of providing clinical feedback in real time.     

The Effect of Preoperative Renal Failure on Outcomes Following Infrainguinal Endovascular Interventions for Peripheral Arterial Disease

PurposeTo analyze the effect of a patient’s renal failure status on acute outcomes after lower extremity endovascular interventions for peripheral artery disease.Materials and MethodsA retrospective analysis of the American College of Surgery National Surgical Quality Improvement Program database from 2014 to 2017 was conducted. Patients were included based on current procedural terminology codes. They were divided into renal failure cohorts. Six thousand seven hundred and sixty-five patients were included in the analysis, 11.0% of whom had renal failure. A univariate analysis was performed using chi-squared test or Fischer’s exact test as appropriate. Multivariate logistic regression models were constructed, while controlling for relevant patient factors, to identify the effect of renal failure on several outcomes of interest after the intervention. A sensitivity analysis was performed with a propensity score-matched cohort.ResultsPatients with renal failure were more likely to have infrapopliteal interventions (38.0% vs 20.9%), critical limb ischemia with tissue loss (73.5% vs 38.9%), diabetes (70.9% vs 52.3%), preoperative wound infection (59.2% vs 30.7%), mortality (5.1% vs 1.3%), prolonged hospital stay (68.5% vs 46.5%), transfusion after the intervention (13.3% vs 9.1%), reoperation (18.3% vs 9.5%), and readmission (24.9% vs 12.6%), compared to patients without renal failure. The multivariate analysis found renal failure to be significant for mortality (odds ratio [OR] = 4.11, 95% confidence interval [CI] = 2.71–6.24), any complication (OR = 2.03, 95% CI = 1.72–2.39), extended length of stay (OR = 1.53, 95% CI = 1.28–1.83), sepsis (OR = 2.37, 95% CI = 1.60–3.51), readmission (OR = 1.89, 95% CI = 1.57–2.29), reoperation (OR = 1.84, 95% CI = 1.48–2.27), major adverse cardiovascular event (OR = 3.50, 95% CI = 2.54–4.84), and major adverse limb event (OR = 1.97, 95% CI = 1.55–2.51). P value was <.001 unless otherwise noted.ConclusionsRenal failure before the intervention places patients at a significantly elevated risk of morbidity and mortality following endovascular revascularization procedures for peripheral artery disease.     

Screening of Polymer-Based Drug Delivery Vehicles Targeting Folate Receptors in Triple-Negative Breast Cancer

PurposeTo compare cellular uptake and cytotoxicity of fluorescein (FL)-labeled polyethylene glycols (PEGs) carrying 2 folate groups (targeted delivery vehicles [TDVs]) to non-PEGylated molecules with 1 or 2 folate groups.Materials and MethodsThree PEGylated TDVs and 2 non-PEGylated folic acid (FA)–fluorescein (FL) conjugates (FA-FL and FA-FL-FA) were synthesized. Two triple-negative breast cancer cell lines (MDA-MB-231and MDA-MB-468) were cultured to 70% confluency and incubated for 2 h in a folate-depleted medium. Folate receptor (FR) expression was confirmed by immunocytochemistry. Cellular uptake and cytotoxicity of compounds were measured by flow cytometry. Intracellular localization was confirmed using confocal microscopy.ResultsMDA-MB-231 demonstrated 40% more FR staining than MD-MB-468. Intracellular localization of the 2 non-PEGylated molecules (FA-FL and FA-FL-FA) and the 3 PEGylated TDVs was confirmed with confocal microscopy. Cellular uptake was independent of concentration for FA-FL, but there was 26.8% more cytotoxicity at 30 μg/mL compared with no treatment (P ≤ .05). Uptake was > 90% for FA-FL-FA at 10 μg/mL and 30 μg/mL without significant cytotoxicity (P ≤ .005). Cellular uptake was > 80% for all TDVs. The molecule containing monodispersed PEG with M_n = 1,000 g/mol had the highest uptake in both cell lines without cytotoxicity. Maximum toxicity was demonstrated by the molecule containing PEG_2,000 only at the highest dose of 30 μg/mL (8.66% ± 3.94% cytotoxicity; cut-off was 20%).ConclusionsThe molecule containing monodispersed PEG with M_n = 1,000 g/mol and 2 FA targeting groups demonstrated better targetability and cellular uptake as a TDV.     

Uterine Artery Embolization following Cesarean Delivery but prior to Hysterectomy in the Management of Patients with Invasive Placenta

PurposeTo evaluate outcomes of patients with placenta accreta spectrum (PAS) disorders who underwent uterine artery embolization (UAE) following cesarean delivery but before hysterectomy.Materials and MethodsA retrospective review of patients with PAS treated with cesarean-hysterectomy (C-hyst) was performed. Patients in the UAE group underwent UAE after cesarean delivery but before hysterectomy; patients in the control group underwent C-hyst alone. Estimated blood loss (EBL), transfusion requirements, length of intensive care unit (ICU) stay, and adverse events were evaluated.ResultsThe study included 31 patients, 7 in the UAE group and 24 in the control group. Median EBL, transfusion requirements, and length of ICU stay in the UAE group compared with control group were 1,500 mL (range, 500–2,000 mL) vs 2,000 mL (range, 1,000–4,500 mL) (P = .04), 150 mL (range, 0–650 mL) vs 550 mL (range, 0–3,125 mL) (P = .10), and 0 d (range, 0–1 d) vs 0.5 d (range, 0–2 d) (P = .07). All patients in the UAE group had placenta increta; patients in the control group had placenta accreta (29%), increta (54%), and percreta (17%) (P = .10). Subgroup analysis of patients with placenta increta demonstrated that the UAE group had a significant decrease in median EBL (P = .004), transfusion requirements (P = .009), and length of ICU stay (P = .04). No adverse events following UAE were noted.ConclusionsUAE following cesarean delivery but before hysterectomy in patients with placenta increta appears to be safe and effective in decreasing EBL, transfusion requirements, and length of ICU stay compared with C-hyst alone.     

Effect of FURIN SNP rs17514846 on coronary atherosclerosis in human cardiac specimens: An autopsy study of 106 cases

BackgroundCoronary artery disease (CAD), including coronary atherosclerosis (CAS), is one of the most common causes of death. The FURIN SNP rs17514846 is assumed to be a risk factor for CAD. We evaluated this relationship using autopsy specimens and autopsy data, such as the histopathological degree of CAS.Materials and methodsA total of 106 samples were genotyped from obtained blood samples. Myocardial and coronary arterial FURIN levels were quantified by ELISA. The degree of CAS was classified histopathologically according to the Stary classification, and the localization of FURIN was examined by immunostaining. The obtained data were analyzed statistically.ResultsFURIN expression was widely observed in the myocardium, vascular smooth muscle cells, endothelial cells, adipocytes, and macrophages. FURIN level in the myocardium of cases with the AA genotype at the FURIN SNP rs17514846 was higher than that in CC cases. Additionally, FURIN levels in both coronary arteries and myocardium were higher at the early stage of CAS than at the late stage microscopically.ConclusionOur study suggested that the A allele of rs17514846 is associated with higher FURIN level in the heart and that FURIN exhibits a higher level in the early stage of CAS. These findings deepen our understanding of the mechanism of CAS.     

Fatal anaphylaxis due to alpha-gal syndrome after initial cetuximab administration: The first forensic case report

Cetuximab is mainly used for the treatment of advanced and metastatic colorectal cancer. Owing to the oligosaccharide galactose-α-1,3-galactose (α-gal) in its heavy chain, cetuximab can induce severe IgE-dependent anaphylaxis. α-Gal is also the antigen responsible for α-gal syndrome, known as mammalian meat allergy. Patients with α-gal syndrome may suffer from cetuximab-induced anaphylaxis at the first administration because of developed α-gal-specific IgE antibodies. A male patient in his 50 s with metastatic colon cancer was receiving chemotherapy involving scheduled cetuximab administration. However, he died soon after the first administration. Forensic autopsy confirmed rectal cancer, metastatic rectal cancer in the liver, and renal cancer. Laboratory blood tests revealed the presence of cetuximab- and beef-specific IgE antibodies before cetuximab administration and an extremely high level of tryptase after administration. Thus, we determined that the death was caused by cetuximab-induced anaphylaxis due to the preexisting α-gal syndrome. To the best of our knowledge, this is the first autopsy case report in forensic medicine of fatal anaphylaxis after initial cetuximab administration.     

Safety and Effectiveness of Ethylene Vinyl Alcohol Copolymer Embolization of Peripheral High-Flow Arteriovenous Malformations: Results of a Prospective Study

PurposeTo prospectively evaluate the efficacy and safety of a new ethylene vinyl alcohol (EVOH) copolymer–based embolic agent in the treatment of symptomatic peripheral arteriovenous malformations (AVMs).Materials and MethodsThis prospective single-center study evaluated EVOH embolization with 3 different formulations of EVOH (Squid Peri 12 cP, 18 cP, and 34 cP; BALT Germany GmbH, Düsseldorf, Germany) in patients with symptomatic AVMs. Between April 2018 and October 2019, 36 embolization procedures in 21 patients (3 males and 18 females; mean age, 34.7 years) were performed (inclusion criteria: symptomatic peripheral AVM, ≥14 years of age, and elective embolization). Symptoms, technical aspects (transarterial, transvenous, or percutaneous approach; plug or balloon occlusion), clinical and technical success (defined as the improvement of symptoms and complete angiographic eradication of the AVM nidus), adverse events, and short-term outcomes were assessed.ResultsThe mean volume of the embolic agent used per session was 3.4 mL of EVOH 34 cP (standard deviation [SD], ± 5.4), 6.2 mL ± 8.1 of EVOH 18 cP, and 4.6 mL ± 10.1 of EVOH 12 cP. Angiographic success was achieved in 18 patients (85.7%). The mean follow-up was 190 days (range, 90–538 days; median, 182 days). In the follow-up assessment, findings of magnetic resonance imaging showed that 19 patients (90.5%) had a persistent state of devascularization compared with postinterventional angiography. Amelioration or complete elimination of pain was achieved in 90.0% of the patients. One patient experienced a major adverse event; minor adverse events developed in 2 patients.ConclusionsIn this study, EVOH appeared to be a safe and effective embolic agent in peripheral AVMs and had a low rate of adverse events in a limited number of patients.     

Percutaneous Lymphatic Embolization as Primary Management of Pelvic and Retroperitoneal Iatrogenic Lymphoceles

PurposeTo evaluate the efficacy of lymphatic embolization (LE) in decreasing catheter output and dwell time in iatrogenic lymphoceles after percutaneous catheter drainage.Materials and MethodsRetrospective review of patients who underwent intranodal lymphangiography (INL) with or without LE for management of iatrogenic lymphoceles between January 2017 and November 2020 was performed. Twenty consecutive patients (16 men and 4 women; median age, 60.5 years) underwent a total of 22 INLs and 18 LEs for 15 pelvic and 5 retroperitoneal lymphoceles. Lymphatic leaks were identified in 19/22 (86.4%) of the INLs. Three patients underwent INL only because a leak was not identified or was identified into an asymptomatic lymphocele. One patient underwent repeat INL and LE after persistent high catheter output, and 1 patient underwent repeat INL with LE after the initial INL did not identify a leak. Catheter output was assessed until catheter removal, and changes in output before and after the procedure were reported. The patients were followed up for 2–30 months, and procedural complications were reported.ResultsThe median catheter output before the procedure was 210 mL/day (50–1,200 mL/day), which decreased to a median of 20 mL/day (0–520 mL/day) 3 days after the procedure, with a median output decrease of 160 mL (0–900 mL). The median time between INL with LE and catheter removal was 6 days, with no recurrence requiring redrainage. Four patients experienced minor complications of low-grade fever (n = 2) and lower limb edema (n = 2).ConclusionsLymphangiogram and LE are safe and effective methods for the management of lymphoceles.     

Risk Factors for Early Port Infections in Adult Oncologic Patients

PurposeThe purpose of this study was to retrospectively investigate risk factors for chest port (port) infections within 30 days of placement (early port infections) in adult oncologic patients.Materials and MethodsThis single-institution, three-center retrospective study identified 1,714 patients (868 males, 846 females; median age 60.0 years old) who underwent port placement between January 2013 and August 2017. All patients received an intravenous antibiotic prior to port placement. The median absolute neutrophil count was 5,260 cells/μL, the median white blood cell (WBC) count was 7,700 cells/μL, and the median serum albumin was 4.00 g/dL at the time of port placement. Double-lumen ports were most commonly implanted (74.85%) more frequently in an outpatient setting (72.69%). Risk factors for early port infections were elucidated using univariate and multivariate proportional subdistribution hazard regression analyses.ResultsA total of 20 patients (1.2%) had early port infections; 15 patients (0.9%) had positive blood cultures. The mean time to infection was 20 days (range, 9–30 days). The port-related 30-day mortality rate was 0.2% (4 of 1,714 patients). Most bloodstream infections were attributed to Staphylococcus spp. (n = 11). In multivariate analysis, hematologic malignancy (hazard ratio [HR], 2.61; 95% confidence interval (CI), 1.15–5.92.; P = .02), hypoalbuminemia (albumin <3.5 g/dL; HR, 3.52; 95% CI: 1.48–8.36; P = .004), leukopenia (WBC <3,500 cells/μL; HR, 3.00; 95% CI: 1.11–8.09; P = .03), and diabetes mellitus (HR, 3.71; 95% CI: 1.57–8.83) remained statistically significant risk factors for early port infection.ConclusionsHematologic malignancy, hypoalbuminemia, leukopenia, and diabetes mellitus at the time of port placement were independent risk factors for early port infections.