Intraarterial contrast-enhanced ultrasound to predict the short-term tumour response of hepatocellular carcinoma to Transarterial chemoembolization with Lipiodol.

BACKGROUND: Transarterial chemoembolization (TACE) is an effective locoregional therapy in hepatocellular carcinoma (HCC). However, it is difficult to predict the tumour response (TR) of TACE intraprocedurally. The aim of this study was to predict the TR after TACE (1-3 months) in HCC patients using intraprocedural intraarterial contrast enhanced ultrasound (IA-CEUS). METHODS: In this case-control study, consecutive patients who received TACE in our hospital from September 2018 to May 2019 were enrolled. IA-CEUS was performed before and after TACE. Postoperative contrast-enhanced liver MRI was performed 1-3 months after TACE as the gold standard. According to the modified Response Evaluation Criteria in Solid Tumours (mRECIST), ultrasonic manifestations were compared between the complete remission (CR) group and non-CR group by univariate and multivariate analyses. A logistic predictive model was established and validated, and its diagnostic efficiency was evaluated. RESULTS: Forty-four patients with sixty-one lesions were enrolled in the study. Multivariate analysis identified, the risk factors as a large lesion diameter (OR: 1.84; 95% confidence interval [CI]: 1.009, 3.080; P = 0.020), a larger dimension of non-enhancing area in superior mesenteric artery (SMA)-CEUS than the size in B-mode ultrasound preoperatively (OR: 3.379; 95% CI: 1.346,8.484; P = 0.010), presence of corona enhancement in hepatic artery (HA)-CEUS postoperatively (OR: 6.642; 95% CI: 1.214, 36.331; P = 0.029), and decreased corona enhancement thickness (per centimetre) postoperatively (OR: 0.025; 95% CI: 0.006,0.718; P = 0.025). The area under the receiver operating characteristic curve (AUROC) of the predictive model was 0.904 (95% CI: 0.804, 0.966; P < 0.001). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 81.08, 91.67, 85.25, 93.75, and 75.86%, respectively. Leave-one-out cross-validation (LOOCV) showed that the accuracy was 77.05%. CONCLUSIONS: Intraprocedural IA-CEUS can be used to predict the TR in HCC patients after TACE.

Selective Ophthalmic Artery Chemotherapy with Melphalan in the Management of Unilateral Retinoblastoma: A Prospective Study.

PURPOSE: To determine prospectively the efficacy and to assess potential side effects of melphalan selective ophthalmic artery chemotherapy (SOAC) as first-line treatment for unilateral retinoblastoma. DESIGN: Phase 2 nonrandomized, prospective study. PARTICIPANTS: Patients with unilateral retinoblastoma group B, C, or D of the International Classification for Intraocular Retinoblastoma (IRC). Group D eyes with massive vitreous seeding were not eligible. METHODS: Melphalan SOAC associated with diode laser thermotherapy, cryotherapy, or both at 4-week intervals (3-6 cycles). For persistent vitreous seeding, intravitreal melphalan chemotherapy also was used. MAIN OUTCOME MEASURES: The primary outcome was globe preservation rate. Secondary outcomes were tumor relapse rate, occurrence of ocular or systemic adverse events, and measurement of the dose area product (DAP). RESULTS: Between 2012 and 2017, 39 patients (39 eyes) with unilateral retinoblastoma were included prospectively. Three included patients did not receive SOAC (2 catheterization failures and 1 case of viral syndrome) and were considered failures. At diagnosis, IRC groups for the 36 treated patients were: B, n = 4 (11%); C, n = 13 (36%); and D, n = 19 (53%); median age was 21.5 months (range, 3.2-61.6 months). Median number of SOAC cycles was 3.9 (range, 1-6 cycles), and median melphalan dose was 4.9 mg/procedure. The median DAP was 1.24 Gy.cm2/procedure. Median follow-up was 63 months (range, 34-93 months). SOAC was associated with local treatments for 31 patients (86%): diode laser thermotherapy for all of them and cryotherapy or intravitreal chemotherapy for 10 (32%) and 9 patients (25%), respectively. SOAC treatment was interrupted in 5 patients because of severe ophthalmic (ptosis, n = 2; retinal ischemia, n = 2) or systemic (hypotension, n = 1) adverse events. At the cutoff date analysis, all patients were alive without metastasis. The 18-month eye preservation rate was 80% (range, 68.6%-94.6%). After a follow-up of at least 30 months, the ocular preservation rate was 69% (n = 24 preservations). CONCLUSIONS: This first prospective trial demonstrated that SOAC with melphalan alone as first-line treatment for retinoblastoma is efficient and well tolerated with no metastatic events, although ocular ischemic complications were observed.

Induction of Contralateral Hepatic Hypertrophy by Unilobar Yttrium-90 Transarterial Radioembolization versus Portal Vein Embolization: An Animal Study.

PURPOSE: To compare hepatic hypertrophy in the contralateral lobe achieved by unilobar transarterial radioembolization (TARE) versus portal vein embolization (PVE) in a swine model. METHODS: After an escalation study to determine the optimum dose to achieve hypertrophy after unilobar TARE in 4 animals, 16 pigs were treated by TARE (yttrium-90 resin microspheres) or PVE (lipiodol/n-butyl cyanoacrylate). Liver volume was calculated based on CT before treatment and during 6 months of follow-up. Independent t-test (P < .05) was used to compare hypertrophy. The relationship between hypertrophy after TARE and absorbed dose was calculated using the Pearson correlation. RESULTS: At 2 and 4 weeks after treatment, a significantly higher degree of future liver remnant hypertrophy was observed in the PVE group versus the TARE group, with a median volume gain of 31% (interquartile range [IQR]: 16%-66%) for PVE versus 23% (IQR: 6%-36%) for TARE after 2 weeks and 51% (IQR: 47%-69%) for PVE versus 29% (IQR: 20%-50%) for TARE after 4 weeks. After 3 and 6 months, hypertrophy converged without a statistically significant difference, with a volume gain of 103% (IQR: 86%-119%) for PVE versus 82% (IQR: 70%-96%) for TARE after 3 months and 115% (IQR: 70%-46%) for PVE versus 86% (IQR: 58%-111%) for TARE after 6 months. A strong correlation was observed between radiation dose (median 162 Gy, IQR: 139-175) and hypertrophy. CONCLUSIONS: PVE resulted in rapid hypertrophy within 1 month of the procedure, followed by a plateau, whereas TARE resulted in comparable hypertrophy by 3-6 months. TARE-induced hypertrophy correlated with radiation absorbed dose.

Intra-articular magnesium to alleviate postoperative pain after arthroscopic knee surgery: a meta-analysis of randomized controlled trials.

OBJECTIVE: We aimed to evaluate the safety and efficacy of intra-articular (IA) magnesium (Mg) for postoperative pain relief after arthroscopic knee surgery. METHODS: We searched PubMed, Embase, Medline, Cochrane library, and Web of Science to identify randomized controlled trials that compared postoperative pain outcomes with or without IA Mg after knee arthroscopy. The primary outcomes were pain intensity at rest and with movement at different postoperative time points and cumulative opioid consumption within 24 h after surgery. Secondary outcomes included the time to first analgesic request and side effects. RESULTS: In total, 11 studies involving 677 participants met the eligibility criteria. Pain scores at rest and with movement 2, 4, 12, and 24 h after surgery were significantly lower, doses of supplementary opioid consumption were smaller, and the time to first analgesic requirement was longer in the IA Mg group compared with the control group. No significant difference was detected regarding adverse reactions between the groups. CONCLUSIONS: Intra-articular magnesium is an effective and safe coadjuvant treatment for relieving postoperative pain intensity after arthroscopic knee surgery. Protocol registration at PROSPERO: CRD42020156403.

Blue Dye Embolization of Renal Tumor: A New Technique to Improve Tumor Localization During Laparoscopic Partial Nephrectomy.

Purpose: To improve the tumor localization during laparoscopic surgery, we describe an innovative technique involving superselective intra-arterial injection of blue dye in tumoral vessels to color the tumor before surgical enucleation. Materials and Methods: The dye injection was performed at the same time as superselective embolization, immediately before laparoscopic surgery in a hybrid operating room. We used this new treatment sequence on 50 consecutive patients. Results: The selective intra-arterial injection of an emulsion of blue dye and lipiodol was feasible in 46 (92%) cases and well tolerated, followed by superselective embolization of the tumor vessels with glue or coils. The tumor was easily localized during surgery due to the blue coloration. Tumor coloration was not associated with postoperative complication, especially allergic reaction or renal failure. Pathologic analysis of the tumor was not modified by the coloration and all tumors had negative surgical margins. Conclusions: The preoperative dye localization is a feasible, safe, and accurate procedure. This combined approach reduces the difficulty of surgery and increases patient safety.

Transluminal balloon angioplasty for cerebral vasospasm after spontaneous subarachnoid hemorrhage: A single-center experience.

OBJECTIVES: After spontaneous subarachnoid hemorrhage (sSAH), cerebral vasospasm (CVS) is a common complication, potentially resulting in infarction mainly responsible for a poor outcome. Intra-arterial vasodilators lead to transient increase of brain perfusion, but only transluminal balloon angioplasty (TBA) promises longer-lasting effects, though it poses the risk of severe complications. Until now, the precise impact of TBA on the course of CVS is not yet finally clarified. Thus we aimed to identify risk factors of recurrent CVS and vasospasm-related infarction following TBA. PATIENTS AND METHODS: We analyzed 35 patients with CVS after sSAH who received TBA (41 procedures, 99 vessel segments). Gender, age, WFNS grade and Fisher scale, occurrence of intraventricular and intracerebral hemorrhage, localization of the aneurysm and the initial treatment modality were obtained. We assessed functional outcome after 3 months and in-hospital mortality. TBA was analyzed concerning time point, localization, technique, complications and angiographic response. Furthermore, recurrence of CVS and vasospasm-related infarction after TBA were described and risk factors were identified with logistic regression analyses. RESULTS: In 7 of 35 patients (20%) and in 16 of 99 vessel segments (16%) previously treated with TBA, we found recurrent CVS. Vasospasm-related infarction occurred in 18 cases (18%) in the arterial territories of the TBA-treated vessel segments. The angiographic effect after TBA was mostly classified as good (87%), good response was negatively associated with recurrent CVS (p = 0.004) and vasospasm-related infarction (p = 0.001). We identified only the male gender as a risk factor for vasospasm-related infarction after TBA (p = 0.040). In connection with TBA, only one complication occurred (intracranial dissection). CONCLUSION: Our data support TBA as a safe and effective therapy for CVS. Nevertheless, recurrent CVS and vasospasm-related infarction were common after TBA and not predictable by clinical conditions on admission or the localization of CVS. A moderate or poor angiographic response after TBA was identified as a risk factor for both, recurrent CVS and vasospasm-related infarction, while male gender was associated with a higher risk of vasospasm-related infarction. Our results augment the still sparse evidence concerning optimal patient selection for this method and provide new aspects for individual therapy decisions.

Elemene injection combined with transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: To evaluate the short-term efficacy, long-term efficacy, and adverse events (AEs) of elemene plus transcatheter arterial chemoembolization (TACE) in comparison with TACE alone for the treatment of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Full-text Database, Wanfang Data, CBM, and VIP were searched by 2 reviewers using the same search strategy for clinical studies on elemene plus TACE in the treatment of HCC. These articles were screened according to pre-established inclusion and exclusion criteria, and the qualities of the included studies were assessed using the Newcastle-Ottawa scale. The primary outcomes were the objective response rate (ORR), the 1-year survival rate and AEs. Review Manager 5.3 and Stata 15.0 were used for the meta-analysis. RESULTS: A total of 10 studies involving 543 patients (TACE + elemene = 277, TACE alone = 266) were included. The results showed that the ORR was significantly improved in the combined treatment group compared to the TACE alone group (odds ratio [OR] = 2.72, 95% confidence interval [CI]: 1.84-4.00, P < .05). TACE + elemene significantly increased the 1-year survival rate (OR = 2.79, 95% CI: 1.58-4.95, P < .05). We also found no significant difference in gastrointestinal reactions (OR = 0.97, 95% CI: 0.57-1.64, P = .90), fever (OR = 0.80, 95% CI: 0.37-1.71, P = .56), or bone marrow suppression (OR = 0.73, 95% CI: 0.44-1.22, P = .23) between the 2 groups. CONCLUSION: Based on current findings, TACE + elemene injection may improve the ORR and the 1-year survival rate for HCC patients compared to TACE alone. Arterial perfusion may be superior to intravenous guttae.

Preliminary results of the Phase 1 Lip-Re I clinical trial: biodistribution and dosimetry assessments in hepatocellular carcinoma patients treated with 188Re-SSS Lipiodol radioembolization.

PURPOSE: This study sought to provide preliminary results on the biodistribution and dosimetry following intra-arterial liver injection of 188Re-SSS Lipiodol on hepatocellular carcinoma patients included in the Phase I Lip-Re 1 study. METHODS: Results of the first six patients included are reported. Analysis of the 188Re-SSS Lipiodol biodistribution was based on planar scintigraphic and tomoscintigraphic (SPECT) studies performed at 1, 6, 24, 48, and 72 h post-administration. Quantification in blood, urine, and stool samples was performed. Determination of the tumour to non-tumour uptake ratio (T/NT) was calculated. Absorbed doses to target organs and tumours were evaluated using the MIRD formalism. RESULTS: The mean injected activity of 188Re-SSS Lipiodol was 1645 ± 361 MBq. Uptakes were seen in the liver (tumour and healthy liver) and the lungs only. All these uptakes were stable over time. A mean 1.4 ± 0.7% of 188Re-SSS Lipiodol administered was detected in serum samples at 6 h, declining rapidly thereafter. On average, 1.5 ± 1.6% of administered activity was eliminated in urine and feces over 72 h. Overall, 90.7 ± 1.6% of detected activity on SPECT studies was found in the liver (74.9 ± 1.8% in tumours and 19.1 ± 1.7% in the healthy liver) and 9.3 ± 1.6% in the lungs (5.7 ± 1.1% in right and 3.7 ± 0.5% in left lungs). Mean doses absorbed were 7.9 ± 3.7Gy to the whole liver, 42.7 ± 34.0Gy to the tumours, 10.2 ± 3.7Gy to the healthy liver, and 1.5 ± 1.2Gy to the lungs. Four patients had stable disease on CT scans at 2 months. The first patient with rapidly progressive disease died at 1 month, most probably of massive tumour progression. Due to this early death and using a conservative approach, the trial independent evaluation committee decided to consider this event as a treatment-related toxicity. CONCLUSION: 188Re-SSS Lipiodol has a favorable biodistribution profile concerning radioembolization, with the highest in-vivo stability among all radiolabeled Lipiodol compounds reported to date. These preliminary results must be further confirmed while completing this Phase I Lip Re1 study.

Multifocal Stroke From Ozone Gas Emboli.

A 34-year-old man with chronic neck pain was treated with regular cervical paravertebral ozone injections. After his last injection, he experienced a syncopal episode and, upon awakening, was found to have ataxia, aphasia, hemiparesis, and left sixth nerve palsy. Computed tomographic angiography demonstrated intra-arterial gas in the right vertebral artery; multiple posterior circulation infarcts were seen on brain MRI. This case illustrates the potential dangers of paravertebral injections of ozone.

Simultaneous hyperthermia-chemotherapy effect by arterial injection of Fe(Salen) for femur tumor.

We previously identified a novel nanomagnetic particle, N,N'-bis(salicylidene)ethylenediamine iron [Fe(Salen)]. Fe(Salen) not only shows antitumor effects but also magnetic properties. We found that Fe(Salen) can be used for magnet-guided drug delivery and visualization of accumulated drug by magnetic resonance imaging (MRI) because of its magnetism. In addition, Fe(Salen) can generate heat by itself when exposed to an alternating current magnetic field (AMF), resulting in a hyperthermia effect. Herein, we partly elucidated the antitumor mechanism of Fe(Salen) and carried out an i.v. repeated dose toxicity study to decide the therapeutic amount. Furthermore, we evaluated the antitumor effect of selective intra-arterial injection or i.v. injection of Fe(Salen) by catheter and the hyperthermia effect of Fe(Salen) when exposed to AMF in vivo. We used a rabbit model grafted with VX2 cells (rabbit squamous cell carcinoma) on the right leg. Intra-arterial injection of Fe(Salen) showed a greater antitumor effect than did i.v. injection. The combination of Fe(Salen) intra-arterial injection and AMF exposure showed a greater antitumor effect than did either Fe(Salen) or methotrexate (MTX) without AMF exposure, suggesting that AMF exposure greatly enhanced the antitumor effect of Fe(Salen) by arterial injection by catheter. This is the first report that the effectiveness of Fe(Salen) was evaluated in the point of administration route; that is, selective intra-arterial injection by catheter. Taken together, these results indicate a new administration route; that is, selective arterial injection of Fe(Salen) by catheter, and the development of a new strategy of simultaneous hyperthermia-chemotherapy in the future.

Autologous cells derived from different sources and administered using different regimens for 'no-option' critical lower limb ischaemia patients.

BACKGROUND: Revascularisation is the gold standard therapy for patients with critical limb ischaemia (CLI). In over 30% of patients who are not suitable for or have failed previous revascularisation therapy (the 'no-option' CLI patients), limb amputation is eventually unavoidable. Preliminary studies have reported encouraging outcomes with autologous cell-based therapy for the treatment of CLI in these 'no-option' patients. However, studies comparing the angiogenic potency and clinical effects of autologous cells derived from different sources have yielded limited data. Data regarding cell doses and routes of administration are also limited. OBJECTIVES: To compare the efficacy and safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients. SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and trials registries (16 May 2018). Review authors searched PubMed until February 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving 'no-option' CLI patients comparing a particular source or regimen of autologous cell-based therapy against another source or regimen of autologous cell-based therapy. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the eligibility and methodological quality of the trials. We extracted outcome data from each trial and pooled them for meta-analysis. We calculated effect estimates using a risk ratio (RR) with 95% confidence interval (CI), or a mean difference (MD) with 95% CI. MAIN RESULTS: We included seven RCTs with a total of 359 participants. These studies compared bone marrow-mononuclear cells (BM-MNCs) versus mobilised peripheral blood stem cells (mPBSCs), BM-MNCs versus bone marrow-mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose, and intramuscular (IM) versus intra-arterial (IA) routes of cell implantation. We identified no other comparisons in these studies. We considered most studies to be at low risk of bias in random sequence generation, incomplete outcome data, and selective outcome reporting; at high risk of bias in blinding of patients and personnel; and at unclear risk of bias in allocation concealment and blinding of outcome assessors. The quality of evidence was most often low to very low, with risk of bias, imprecision, and indirectness of outcomes the major downgrading factors.Three RCTs (100 participants) reported a total of nine deaths during the study follow-up period. These studies did not report deaths according to treatment group.Results show no clear difference in amputation rates between IM and IA routes (RR 0.80, 95% CI 0.54 to 1.18; three RCTs, 95 participants; low-quality evidence). Single-study data show no clear difference in amputation rates between BM-MNC- and mPBSC-treated groups (RR 1.54, 95% CI 0.45 to 5.24; 150 participants; low-quality evidence) and between high and low cell dose (RR 3.21, 95% CI 0.87 to 11.90; 16 participants; very low-quality evidence). The study comparing BM-MNCs versus BM-MSCs reported no amputations.Single-study data with low-quality evidence show similar numbers of participants with healing ulcers between BM-MNCs and mPBSCs (RR 0.89, 95% CI 0.44 to 1.83; 49 participants) and between IM and IA routes (RR 1.13, 95% CI 0.73 to 1.76; 41 participants). In contrast, more participants appeared to have healing ulcers in the BM-MSC group than in the BM-MNC group (RR 2.00, 95% CI 1.02 to 3.92; one RCT, 22 participants; moderate-quality evidence). Researchers comparing high versus low cell doses did not report ulcer healing.Single-study data show similar numbers of participants with reduction in rest pain between BM-MNCs and mPBSCs (RR 0.99, 95% CI 0.93 to 1.06; 104 participants; moderate-quality evidence) and between IM and IA routes (RR 1.22, 95% CI 0.91 to 1.64; 32 participants; low-quality evidence). One study reported no clear difference in rest pain scores between BM-MNC and BM-MSC (MD 0.00, 95% CI -0.61 to 0.61; 37 participants; moderate-quality evidence). Trials comparing high versus low cell doses did not report rest pain.Single-study data show no clear difference in the number of participants with increased ankle-brachial index (ABI; increase of > 0.1 from pretreatment), between BM-MNCs and mPBSCs (RR 1.00, 95% CI 0.71 to 1.40; 104 participants; moderate-quality evidence), and between IM and IA routes (RR 0.93, 95% CI 0.43 to 2.00; 35 participants; very low-quality evidence). In contrast, ABI scores appeared higher in BM-MSC versus BM-MNC groups (MD 0.05, 95% CI 0.01 to 0.09; one RCT, 37 participants; low-quality evidence). ABI was not reported in the high versus low cell dose comparison.Similar numbers of participants had improved transcutaneous oxygen tension (TcO2) with IM versus IA routes (RR 1.22, 95% CI 0.86 to 1.72; two RCTs, 62 participants; very low-quality evidence). Single-study data with low-quality evidence show a higher TcO2 reading in BM-MSC versus BM-MNC groups (MD 8.00, 95% CI 3.46 to 12.54; 37 participants) and in mPBSC- versus BM-MNC-treated groups (MD 1.70, 95% CI 0.41 to 2.99; 150 participants). TcO2 was not reported in the high versus low cell dose comparison.Study authors reported no significant short-term adverse effects attributed to autologous cell implantation. AUTHORS' CONCLUSIONS: Mostly low- and very low-quality evidence suggests no clear differences between different stem cell sources and different treatment regimens of autologous cell implantation for outcomes such as all-cause mortality, amputation rate, ulcer healing, and rest pain for 'no-option' CLI patients. Pooled analyses did not show a clear difference in clinical outcomes whether cells were administered via IM or IA routes. High-quality evidence is lacking; therefore the efficacy and long-term safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients, remain to be confirmed.Future RCTs with larger numbers of participants are needed to determine the efficacy of cell-based therapy for CLI patients, along with the optimal cell source, phenotype, dose, and route of implantation. Longer follow-up is needed to confirm the durability of angiogenic potential and the long-term safety of cell-based therapy.

Coadjuvant Treatment of Vasospasm in Ruptured Unsecured Cerebral Aneurysms with Aggressive Angioplasty, Intra-Arterial Nimodipine, and Aneurysm Embolization.

BACKGROUND: Vasospasm is a major cause of morbidity and mortality in patients after aneurysmal subarachnoid hemorrhage. Early treatment of ruptured aneurysms is advocated; delayed intervention complicates the treatment strategy leading to significant vasospasm and poor prognosis. We report an endovascular protocol for occlusion of the unsecured aneurysm and angioplasty for vasospasm in a single session. METHODS: Between January 2011 and May 2017, among 660 patients with aneurysmal subarachnoid hemorrhage, 24 patients with significant vasospasm and unsecured ruptured cerebral aneurysm were reviewed. Continuous nimodipine drip through a pressure line of the guiding catheter was set up. Aggressive angioplasty with a compliant balloon catheter either before or after embolization of the aneurysm in the major branches of vasospastic territory was performed. The goal was complete embolization of the aneurysm. RESULTS: Of 24 patients, 17 had ischemic symptoms at presentation, and the average delay from aneurysm rupture to presentation was 7.58 days. Angioplasty and nimodipine drip were performed on all patients. Severity of vasospasm was significantly reduced, and outcome improved in each patient. Two patients required a second angioplasty. In 20 patients, embolization of aneurysms was achieved without any aneurysmal sac or residual neck. Clinical outcome was good recovery (modified Rankin Scale score 0-2) in 23 patients (95.8%) and moderate disability in 1 patient (modified Rankin Scale score 3). CONCLUSIONS: Aggressive endovascular treatment of patients with unsecured ruptured cerebral aneurysm and associated vasospasm is safe and effective.

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

Protection from Reperfusion Injury with Intracoronary N-Acetylcysteine in Patients with STEMI Undergoing Primary Percutaneous Coronary Intervention in a Cardiac Tertiary Center.

BACKGROUND: Evidence suggests that oxidative stress plays a principal role in myocardial damage following ischemia/reperfusion events. Recent studies have shown that the antioxidant properties of N-acetylcysteine (NAC) may have cardioprotective effects in high doses, but-to the best of our knowledge-few studies have assessed this. OBJECTIVES: Our objective was to investigate the impact of high-dose NAC on ischemia/reperfusion injury. METHODS: We conducted a randomized double-blind placebo-controlled trial in which 100 consecutive patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) were randomly assigned to the case group (high-dose NAC 100 mg/kg bolus followed by intracoronary NAC 480 mg during PCI then intravenous NAC 10 mg/kg for 12 h) or the control group (5% dextrose). We measured differences in peak creatine kinase-myocardial band (CK-MB) concentration, highly sensitive troponin T (hs-TnT), thrombolysis in myocardial infarction (TIMI) flow, myocardial blush grade (MBG), and corrected thrombolysis in myocardial infarction frame count (cTFC). RESULTS: The peak CK-MB level was comparable between the two groups (P = 0.327), but patients receiving high-dose NAC demonstrated a significantly larger reduction in hs-TnT (P = 0.02). In total, 94% of the NAC group achieved TIMI flow grade 3 versus 80% of the control group (P = 0.03). No significant differences were observed between the two groups in terms of changes in the cTFC and MBG. CONCLUSIONS: In this study, NAC improved myocardial reperfusion markers and coronary blood flow, as revealed by differences in peak hs-TnT and TIMI flow grade 3 levels, respectively. Further studies with large samples are warranted to elucidate the role of NAC in this population. ClinicalTrials.gov identifier: NCT01741207, and the Iranian Registry of Clinical Trials (IRCT; http://irct.ir ) registration number: IRCT201301048698N8.

Parenteral bilirubin in healthy volunteers: a reintroduction in translational research.

AIMS: Preclinical results suggest therapeutic potential of mild hyperbilirubinemia in T2DM and cardiovascular disease. Translational data are limited, because an appropriate bilirubin formulation for parenteral human use is lacking. Considering its use in both clinical practice and medical research in the past, we explored the feasibility to reintroduce parenteral bilirubin for translational experiments. METHODS: We developed a preparation method in accordance with good manufacturing practice and evaluated the parenteral applicability in healthy volunteers (n = 8). Explorative pharmacokinetic and safety data were compared to the results from a literature study on the former parenteral use of bilirubin. Bilirubin was administered intra-arterially to raise the local plasma concentration in the forearm vascular bed (n = 4) and intravenously to raise the systemic plasma concentration (n = 4). Finally, pharmacokinetic characteristics were studied following a single bolus infusion (n = 3). RESULTS: During parenteral application, no side effects occurred. Adverse events mentioned during the two-week observation period were in general mild and self-limiting. Three more significant adverse events (appendicitis, asymptomatic cardiac arrhythmia and atopic eczema) were judged unrelated by independent physicians. A dose-concentration relationship appeared sufficiently predictable for both intra-arterial and intravenous administration. In line with existing knowledge, bilirubin pharmacokinetics could be described best according to a two-compartment model with a volume of distribution of 9.9 (±2.0) l and a total plasma clearance of 36 (±16) ml per minute. CONCLUSIONS: Supported by previous reports, our data suggest that it is both feasible and safe to perform translational experiments with parenteral albumin bound bilirubin.

Intralesional versus intracoronary administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention in patients with acute coronary syndromes: A meta-analysis of randomized controlled trials.

BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) have been regarded as an adjuvant regimen to deal with no-reflow. However, whether intralesional (IL) administration of GPIs improves myocardial reperfusion without increasing bleeding in patients with acute coronary syndrome (ACS) compared with intracoronary (IC) administration has not been well addressed. Our meta-analysis aimed to evaluate the efficacy and safety of IL versus IC administration of GPIs for patients with ACS during percutaneous coronary intervention. METHODS: We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and Cambridge Scientific Abstracts from January 2007 to May 2017. Thrombolysis in Myocardial Infarction (TIMI) 3 flow, corrected TIMI frame count (CTFC), and complete ST-segment resolution (>70%) were selected as the primary outcomes. Major adverse cardiac events (MACEs) were the secondary outcome, and major bleeding complications were the safety outcome. Data analysis was conducted using the Review Manager 5.3 software. RESULTS: Six randomized controlled trials were included in our meta-analysis. Compared with IC, IL obtained better results in terms of TIMI grade 3 flow [odds ratio (OR) 2.29; 95% confidence intervals (CIs) 1.31-4.01; P = .004], CTFC [weighted mean difference (WMD) -4.63; 95% CI -8.82 to -0.43; P = .03], and complete ST-segment resolution (OR 1.55; 95% CI 1.12-2.14; P = .008). There was a trend toward decreased MACE in the IL administration groups, which was not of statistical significance (OR 0.63; 95% CI 0.30-1.31; P = .22). No significant difference was found between the two groups in terms of in-hospital major bleeding events (OR 2.52; 95% CI .66 to 9.62; P = .18). CONCLUSION: IL administration yielded favorable outcomes in terms of myocardial tissue reperfusion as evidenced by the improved TIMI flow grade, CTFC, complete ST-segment resolution, and decreased MACE without increasing in-hospital major bleeding events. The IL administration of GPIs can be recommended as the preferred regimen to guard against no-reflow.

Intra-arterial verapamil post-thrombectomy is feasible, safe, and neuroprotective in stroke.

Large vessel ischemic stroke represents the most disabling subtype. While t-PA and endovascular thrombectomy can recanalize the occluded vessel, good clinical outcomes are not uniformly achieved. We propose that supplementing endovascular thrombectomy with superselective intra-arterial (IA) verapamil immediately following recanalization could be safe and effective. Verapamil, a calcium channel blocker, has been shown to be an effective IA adjunct in a pre-clinical mouse focal ischemia model. To demonstrate translational efficacy, mechanism, feasibility, and safety, we conducted a group of translational experiments. We performed in vivo IA dose-response evaluation in our animal stroke model with C57/Bl6 mice. We evaluated neuroprotective mechanism through in vitro primary cortical neuron (PCN) cultures. Finally, we performed a Phase I trial, SAVER-I, to evaluate feasibility and safety of administration in the human condition. IA verapamil has a likely plateau or inverted-U dose-response with a defined toxicity level in mice (LD50 16-17.5 mg/kg). Verapamil significantly prevented PCN death and deleterious ischemic effects. Finally, the SAVER-I clinical trial showed no evidence that IA verapamil increased the risk of intracranial hemorrhage or other adverse effect/procedural complication in human subjects. We conclude that superselective IA verapamil administration immediately following thrombectomy is safe and feasible, and has direct, dose-response-related benefits in ischemia.

Development of Semiautomated Module for Preparation of 131I Labeled Lipiodol for Liver Cancer Therapy.

Intra-arterial injection of 131I Lipiodol is an effective treatment option for primary hepatocellular carcinoma as it delivers high radiation dose to liver tumor tissue with minimal accumulation in adjacent normal tissue. The present article demonstrates design, fabrication, and utilization of a semiautomated radiosynthesis module for preparation of 131I labeled Lipiodol. The radiolabeling method was standardized for preparation of patient dose of 131I labeled Lipiodol radiochemical yield (RCY); radiochemical purity (RCP) and pharmaceutical purity of the product were determined using optimized procedures. Sterile and apyrogenic 131I labeled Lipiodol in >60% RCY could be prepared with >95% RCP. Preclinical evaluation in animals indicated retention of more than 90% of activity at 24 hours postportal vein injection. This is the first report demonstrating potential application of simple user friendly and safe semiautomated system for routine production of 131I labeled Lipiodol, which is adaptable at centralized hospital radiopharmacies. The described prototype module can be modified as per demand for preparation of other therapeutic radiopharmaceuticals.

Pharmacokinetic Modeling of Intra-arterial Nimodipine Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm.

PURPOSE: Intra-arterial (IA) administration of nimodipine has been shown to be an effective treatment for subarachnoid hemorrhage-related cerebral vasospasm. The concentrations achieved in cerebral arteries during this procedure, though, are unknown. Therefore, there are no clinical studies investigating dose-dependent effects of nimodipine. We aimed at providing a pharmacokinetic model for IA nimodipine therapy for this purpose. METHODS: A two-compartment pharmacokinetic model for intravenous nimodipine therapy was modified and used to assess cerebral arterial nimodipine concentration during IA nimodipine infusion into the internal carotid artery (ICA). RESULTS: According to our simulations, continuous IA nimodipine infusion at 2 mg/h and 1 mg/h resulted in steady-state cerebral arterial concentrations of about 200 ng/ml and 100 ng/ml assuming an ICA blood flow of 200 ml/min and a clearance of 70 l/h. About 85 % of the maximal concentration is achieved within the first minute of IA infusion independent on the infusion dose. Within the range of physiological and pharmacokinetic data available in the literature, ICA blood flow has more impact on cerebral arterial concentration than nimodipine clearance. CONCLUSION: The presented pharmacokinetic model is suitable for estimations of cerebral arterial nimodipine concentration during IA infusion. It may, for instance, assist in dose-dependent analyses of angiographic results.

Transarterial Alcohol-Lipiodol Therapy in Patients with Hepatocellular Carcinoma Using Low Alcohol Concentrations.

PURPOSE: To evaluate transarterial alcohol-lipiodol therapy (TAL) with low concentrations of alcohol for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: 17 patients (69.3 ±â€Š10.7a, 13 male, 4 female) with previously untreated HCC (tumor diameter: 7.7 ±â€Š5.8 cm), who underwent 20 transarterial alcohol-lipiodol injections, were evaluated retrospectively. 14 patients had HCC with coexistent cirrhosis (Child-A n = 9, Child-B n = 4, Child-C n = 1). 9 patients presented an Okuda stage I, 7 patients an Okuda stage II and 1 patient an Okuda stage III. Infiltration of the portal vein was seen in 3 patients. RESULTS: 15 patients underwent TAL with an alcohol:lipiodol ratio of 1:2, another one with a ratio of 1:3 and yet another one with a ratio of 1:5. The median survival was 23 months, and the 1-year and 2-year survival rates were 62.7 % and 31.4 %, respectively. The median survival of patients with HCC < 7.5 cm (n = 10) was 25 months and significantly (p = 0.009) higher than for patients with HCC ≥ 7.5 cm (n = 7; 3 months). Tumor diameters ≥ 7.5 cm were associated with worse lipiodol-contrasting of HCC. Intrainterventional side effects were only feelings of slight abdominal pressure in 2 of 20 interventions. Postinterventional, mild side effects were observed after 3 interventions (abdominal pain n = 1, thoracic pain n = 1, fever n = 1). Serious complications were not observed, in particular there was no decompensation of liver cirrhosis. CONCLUSION: TAL with low concentrations of alcohol was a safe and effective treatment in our cohort in spite of extensive tumors and impaired liver function. TAL could be a treatment option for patients who cannot receive other therapies (e. g. TACE, RFA) because of their advanced tumor disease, liver cirrhosis or other contraindications. KEY POINTS: • TAL can be performed safely in advanced tumor disease and liver cirrhosis Citation Format: • Mohné F, Meyer C, Kuhl CK et al. Transarterial Alcohol-Lipiodol Therapy in Patients with Hepatocellular Carcinoma Using Low Alcohol Concentrations. Fortschr Röntgenstr 2016; 188: 676 - 683.