The "double-fired" gastro-jejunostomy as a form of improved efficiency during Whipple procedure.

BACKGROUND: Gastro-jejunostomy (GJ) after pylorus-resecting pancreatoduodenectomy (PD) is most commonly performed in a hand-sewn fashion. Intestinal stapled anastomosis are reported to be as effective as hand-sewn in terms of patency and risk of leakage in other indications. However, the use of a stapled gastro-jejunostomy hasn't been fully assessed in PD. The aim of the present technical report is to evaluate functional outcomes of stapled GJ during PD, its associated effect on operative time and related complications. METHODS: The institutional database for pancreatic duct adenocarcinoma (PDAC) was retrospectically reviewed. Pylorus resecting open PD without vascular or multivisceral resections were considered for the analysis. The incidence of clinically significant delayed gastric emptying (DGE from the International Stufy Group of Pancreatic Surgery (ISGPS) grade B and C), other complications, operative time and overall hospitalization were evaluated. RESULTS: Over a 10-years study period, 1182 PD for adenocarcinoma were performed and recorded in the database. 243 open Whipple procedures with no vascular and with no associated multivisceral resections were available and constituted the study population. Hand-sewn (HS) anastomosis was performed in 175 (72 %), stapled anastomosis (St) in 68 (28 %). No significant differences in baseline characteristics were observed between the two groups, with the exception of a higher rate of neoadjuvant chemotherapy in the HS group (74 % St vs. 86 % HS, p = 0.025). Intraoperatively, a significantly reduced median operative time in the St group was observed (248 min St vs. 370 mins HS, p < 0.001). Post-operatively, rates of clinically relevant delayed gastric emptying (7 % St vs. 14 % HS, p = 0.140), clinically relevant pancreatic fistula (10 % St, 15 % HS, p = 0.300), median length of stay (7 days for each group, p = 0.289), post-pancreatectomy hemorrhage (4.4 % St vs. 6.3 % HS, p = 0.415) and complication rate (22 % St vs. 34 % HS, p = 0.064) were similar between groups. However, readmission rates were significantly lower after St GJ (13.2 % St vs 29.7 % HS, p = 0.008). CONCLUSION: Our results indicate that a stapled GJ anastomosis during a standard Whipple procedure is non-inferior to a hand-sewn GJ, with a comparable rate of DGE and no increase of gastrointestinal related long term complications. Further, a stapled GJ anastomosis might be associated with reduced operative times.

Priority setting in the German healthcare system: results from a discrete choice experiment.

Worldwide, social healthcare systems must face the challenges of a growing scarcity of resources and of its inevitable distributional effects. Explicit criteria are needed to define the boundaries of public reimbursement decisions. As Germany stands at the beginning of such a discussion, more formalised priority setting procedures seem in order. Recent research identified multi-criteria decision analysis (MCDA) as a promising approach to inform and to guide decision-making in healthcare systems. In that regard, this paper aims to analyse the relative weight assigned to various criteria in setting priority interventions in Germany. A discrete choice experiment (DCE) was employed in 2015 to elicit equity and efficiency preferences of 263 decision makers, through six attributes. The experiment allowed us to rate different policy interventions based on their features in a composite league table (CLT). As number of potential beneficiaries, severity of disease, individual health benefits and cost-effectiveness are the most relevant criteria for German decision makers within the sample population, the results display an overall higher preference towards efficiency criteria. Specific high priority interventions are mental disorders and cardiovascular diseases.

The SMART-ALPPS Protocol: Strategy to Minimize ALPPS Risks by Targeting Invasiveness.

BACKGROUND: The range of procedures with documented feasibility by laparoscopic approach is widening in the setting of liver resections. Many technical limits have been overcome in the attempt to reduce the biological impact of major procedures [1-8]. Similarly, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS)-which could be assumed as the paradigm of maxi-invasiveness-has recently been proposed in a minimally invasive fashion to reduce the impact of this procedure [9-12]. Technical insights to perform laparoscopic ALPPS are provided. METHODS: Perioperative and intraoperative tips for laparoscopic ALPPS are provided within a SMART (Strategy to Minimize ALPPS Risks by Targeting invasiveness) protocol. Stage 1: After volumetric and functional assessment, partial liver transection is performed, keeping intact both the hilum and the caval plane (to prevent adhesions), therefore avoiding portal ligation. No inert material is left inside the abdominal cavity at the end of procedure to keep the liver surfaces apart. Radiologic portography with portal vein embolization is scheduled on postoperative day (POD) 1. Liver volume (pre-PVE: 29%; post-PVE: 52%) and liver function measured through a Technetium-99 hepatobiliary scintigraphy [13] (pre-PVE: 2.15%/min/sqm; post-PVE: 3.67%/min/sqm) of the future remnant liver are reassessed within 10 days to verify whether size and function are adequate. Stage 2: After 2 weeks from the first stage, laparoscopic right hepatectomy is performed following an anterior approach. RESULTS: No conversion to open was required. Operative time was 100 and 300 minutes for stage 1 and 2, respectively. Intraoperative blood loss was 50 and 300 ml for the two procedures. Postoperative course was uneventful; patient was discharged on POD 6 of the second operation. CONCLUSIONS: The implementation of a perioperative protocol to prevent the risk of liver failure by both assessing volume and function of FLR and targeting the invasiveness of the surgical procedure may allow to minimize and control risks of a maximally invasive procedure, such as ALPPS.

Metronomic chemotherapy for advanced breast cancer patients in the real world practice: Final results of the VICTOR-6 study.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3-10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8-11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3-15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Propensity Score-Matched Analysis of Pure Laparoscopic Versus Hand-Assisted/Hybrid Major Hepatectomy at Two Western Centers.

BACKGROUND: Laparoscopic major hepatectomy is expanding, but little data exist comparing surgical approaches. The aim of this study was to test the hypothesis that pure laparoscopic liver resection (PLAP) has advantages over hand-assisted (HALS) or hybrid (HYB) resection for major hemi-hepatectomy at two western centers. METHODS: Using propensity score matching, 65 cases of HALS + HYB (18 hand-assisted and 47 hybrid) were matched to 65 cases of PLAP. Baseline characteristics were well matched for gender, age, ASA score, Childs A cirrhosis, right/left hepatectomy, malignancy, tumor size, and type between the groups. RESULTS: The HALS + HYB group had 27 right and 38 left major hepatectomies (n = 65) versus 29 right and 36 left (n = 65) in the PLAP group (p = NS). The median number of lesions resected was 1 in each group, with median size 5.6 cm (HALS + HYB) versus 6.0 cm (PLAP), (p = NS). The HALS + HYB group had shorter OR time (240 versus 330 min, p < 0.01), and less blood loss (EBL 150 ml vs. 300 ml, p < 0.01) versus the PLAP group, respectively. Median length of stay (LOS) was 4 days with HALS + HYB versus 5 days in the PLAP group (p = 0.02). There were no significant differences in use of the Pringle maneuver, transfusion rate, ICU stay, post-op morbidity, liver-specific complications, or R0 resection. Pain regimen/usage in each group is provided. There were no 30/90-day deaths in either group. CONCLUSION: This is the first reported series of propensity score matching of HALS + HYB versus PLAP for major hepatectomy. The HALS + HYB group had non-inferior OR time, blood loss, and LOS versus the PLAP group, while the other perioperative parameters were comparable. We conclude that minimally invasive liver resection with either PLAP or HALS + HYB technique yields excellent results.

Theory of Relativity for Posterosuperior Segments of the Liver.

BACKGROUND: The accessibility to posterosuperior segments of the liver has traditionally constituted a restrain to adopt the laparoscopic approach in this setting. To overcome this challenge, multiple approaches have been reported in literature. Total transabdominal approach has been previously described for this purpose, even though the rationale to standardly adopt it and a technical depiction of how to achieve an optimal mobilization has never been specifically addressed. METHODS: Total transabdominal purely laparoscopic approach to posterosuperior segments of the liver is presented, with detailed emphasis to the rotational motions targeted in laparoscopy. A literature review is presented to summarize all other possible accesses to posterosuperior area of the liver. The institutional series for the laparoscopic approach to Sg 7, Sg 6+7, and Sg8 is retrospectively described. RESULTS: Three rotational motions of the liver are specifically addressed in a video presentation and described for the laparoscopic total-transabdominal approach; the local institutional series using this approach is presented. Other miscellaneous approaches identified from literature encompassing variations in operative position, transabdominal, transthoracic, and combined approaches are described. CONCLUSIONS: Complete mobilization of the ligaments of the liver leads to a rotation of the transection line in front of the operator's view, allowing to achieve a safe total trans-abdominal laparoscopic approach to the posterosuperior ligaments of the liver, without compromising the vascular inflow control, the possibility to convert to open approach, nor requiring potentially harmful decubitus.

Tips and Tricks for a Laparoscopic Approach to Paracaval Liver Segments.

BACKGROUND: A dramatic spread of laparoscopic liver surgery has been experienced over the last years. The approach to paracaval liver segments 1 and 9 is still poorly described in literature, mainly due to its technical demands. OBJECTIVE: The aim of this article was to introduce a safe and effective approach to paracaval liver segments through laparoscopy. METHODS: A minimally invasive approach to resection of Segments 1 and 9 is presented, and an operative set-up is depicted. A step-by-step technique describing the inferior vena cava (IVC) with left and right hepatic venous junction exposure, segmental pedicle isolation, and parenchymal transection is shown through a video document. RESULTS: Postoperative courses were uneventful, and patients were discharged on postoperative day 3. DISCUSSION: The approach to paracaval liver segments requires accurate preoperative case selection, technical, surgical, and anesthesiological expertise in laparoscopic liver surgery, and adequate instrumentary. CONCLUSION: Paracaval segments of the liver can be approached safely through laparoscopy by teams with extensive expertise in the field of laparoscopic liver surgery; however, suspected malignant infiltration of the IVC or unclear preoperative anatomy still contraindicate this approach.

Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Impact of ground soybean and starch levels on the quality of meat from feedlot young Nellore bulls.

Twenty-eight young Nellore bulls (395±32kg initial body weight) were assigned to a completely randomized design (2×2 factorial design with 7 animals per treatment) to evaluate effects on the quality of meat. Diet treatments consisted of high (about 25%) or low (about 16%) starch levels, with or without ground soybean addition. Shear force was decreased in the meat from animals fed a low-starch diet (P=0.0016). Meat from animals fed a high-starch diet had increased total concentrations of unsaturated (P=0.0029) and monounsaturated fatty acids (P=0.0253). Polyunsaturated fatty acid content increased in the meat from animals fed a diet containing soybean (P=0.0121). High starch diets (>25%) decreased the concentration of saturated fatty acids and increased the amount of unsaturated fatty acids in the meat from young Nellore bulls.

Measurement of ratios of νµ charged-current cross sections on C, Fe, and Pb to CH at neutrino energies 2-20 GeV.

We present measurements of ν(µ) charged-current cross section ratios on carbon, iron, and lead relative to a scintillator (CH) using the fine-grained MINERvA detector exposed to the NuMI neutrino beam at Fermilab. The measurements utilize events of energies 2

Clinical impact of the HGF/MET pathway activation in patients with advanced gastric cancer treated with palliative chemotherapy.

In gastric cancer, available clinical studies focusing on the activated hepatocyte growth factor (HGF)/MET pathway are limited to surgical and often heterogeneous series. MET copy number gain (CNG) and an activating truncation in the HGF promoter (deoxyadenosine tract element, DATE+) were studied in tumors of 95 patients with advanced gastric cancer treated with palliative chemotherapy. Associations with overall survival (OS) and the pattern of metastatic disease were studied. Median OS was 9.7 months in 80 MET CNG <5 copies cases (MET-), and 6.4 months in 15 MET CNG was ⩾5 copies cases (MET+) (P=0.001). MET+ status confirmed the adverse prognostic effect in the multivariate model. A significantly different distribution of MET+/DATE+ and MET-/DATE- cases was observed between patients with and without peritoneal carcinomatosis (PC). MET+ status confirms its adverse prognostic role in advanced gastric cancer patients. The activated MET/HGF axis seems to be associated with PC. These findings are relevant to the development of anti-MET/HGF compounds.

Effect of lipid sources with different fatty acid profiles on the intake, performance, and methane emissions of feedlot Nellore steers.

The present study was conducted to evaluate the effect of lipids with different fatty acid profiles on the intake, performance, and enteric CH4 emission of Nellore steers. A total of 45 Nellore animals with an average initial BW of 419 ± 11 kg (at 15 ± 2 mo) were distributed in a completely randomized design consisting of 5 treatments and 9 replicates. The roughage feed was maize silage (600 g/kg on a DM basis) plus concentrate (400 g/kg on a DM basis). The dietary treatments were as follows: without additional fat (WF), palm oil (PO), linseed oil (LO), protected fat (PF; Lactoplus), and whole soybeans (WS). The lipid source significantly affected (P < 0.05) nutrient intake. The greatest intakes of DM, OM, and CP were observed in the animals that were fed the WF or PF diets, and the lowest intakes were observed in the animals that were fed the PO diet. Intake of NDF decreased (P < 0.05) with the addition of PO. Enteric methane emission (g/kg DMI) was reduced by an average of 30% when the animals were fed diets containing WS, LO, and PO (P < 0.05), and these diets caused a larger reduction in the energy loss in the form of methane compared to those without added fat and with added PF (3.3 vs. 4.7%). The different fatty acid profiles did not affect the backfat thickness or the loin eye area of the animals (P > 0.05). However, animals fed PO displayed lower daily weight gain (0.36 kg/d), feed efficiency (0.08 kg ADG/kg DM), HCW (245 kg), and hot yield percentage (52.6%) compared to animals that were fed the other diets. Therefore, PO compared to the other lipid sources used in this study reduces intake, performance, feed efficiency, and carcass yield. Therefore, PO is not suggested for feedlot-finished animals.

Measurement of coherent production of π(±) in neutrino and antineutrino beams on carbon from Eν of 1.5 to 20 GeV.

Neutrino-induced coherent charged pion production on nuclei νµA→µ(±)π(∓)A is a rare, inelastic interaction in which a small squared four-momentum |t| is transferred to the recoil nucleus, leaving it intact in the reaction. In the scintillator tracker of MINERvA, we remove events with evidence of particles from nuclear breakup and reconstruct |t| from the final-state pion and muon. We select low |t| events to isolate a sample rich in coherent candidates. By selecting low |t| events, we produce a model-independent measurement of the differential cross section for coherent scattering of neutrinos and antineutrinos on carbon. We find poor agreement with the predicted kinematics in neutrino generators used by current oscillation experiments.

Measurement of muon antineutrino quasielastic scattering on a hydrocarbon target at Eν ~ 3.5 GeV.

We have isolated ν(µ) charged-current quasielastic (QE) interactions occurring in the segmented scintillator tracking region of the MINERvA detector running in the NuMI neutrino beam at Fermilab. We measure the flux-averaged differential cross section, dσ/dQ², and compare to several theoretical models of QE scattering. Good agreement is obtained with a model where the nucleon axial mass, M(A), is set to 0.99 GeV/c² but the nucleon vector form factors are modified to account for the observed enhancement, relative to the free nucleon case, of the cross section for the exchange of transversely polarized photons in electron-nucleus scattering. Our data at higher Q² favor this interpretation over an alternative in which the axial mass is increased.

Measurement of muon neutrino quasielastic scattering on a hydrocarbon target at Eν ~ 3.5 GeV.

We report a study of ν(µ) charged-current quasielastic events in the segmented scintillator inner tracker of the MINERvA experiment running in the NuMI neutrino beam at Fermilab. The events were selected by requiring a µ- and low calorimetric recoil energy separated from the interaction vertex. We measure the flux-averaged differential cross section, dσ/dQ², and study the low energy particle content of the final state. Deviations are found between the measured dσ/dQ² and the expectations of a model of independent nucleons in a relativistic Fermi gas. We also observe an excess of energy near the vertex consistent with multiple protons in the final state.

First characterisation of natural radioactivity in building materials manufactured in Albania.

This study focuses on the radiological characterisation of building materials manufactured in Albania by using a high-resolution gamma-ray spectrometer. The average activity concentrations of (40)K, (226)Ra and (232)Th were, respectively, 644.1±64.2, 33.4 ± 6.4 and 42.2 ± 7.6 Bq kg(-1) in the clay brick samples and 179.7 ± 48.9, 55.0 ± 5.8 and 17.0 ± 3.3 Bq kg(-1) in the cement samples. The calculated activity concentration index (ACI), varied from 0.48±0.02 to 0.63±0.04 in the clay brick samples and from 0.29±0.03 to 0.37±0.02 in the cement samples. Based on the ACI, all of the clay brick and cement samples were categorised as A1 materials. The authors can exclude (at 3σ level) any restriction of their use as bulk materials.

A new FSA approach for in situ γ ray spectroscopy.

An increasing demand of environmental radioactivity monitoring comes both from the scientific community and from the society. This requires accurate, reliable and fast response preferably from portable radiation detectors. Thanks to recent improvements in the technology, γ spectroscopy with sodium iodide scintillators has been proved to be an excellent tool for in-situ measurements for the identification and quantitative determination of γ ray emitting radioisotopes, reducing time and costs. Both for geological and civil purposes not only (40)K, (238)U, and (232)Th have to be measured, but there is also a growing interest to determine the abundances of anthropic elements, like (137)Cs and (131)I, which are used to monitor the effect of nuclear accidents or other human activities. The Full Spectrum Analysis (FSA) approach has been chosen to analyze the γ spectra. The Non Negative Least Square (NNLS) and the energy calibration adjustment have been implemented in this method for the first time in order to correct the intrinsic problem related with the χ(2) minimization which could lead to artifacts and non physical results in the analysis. A new calibration procedure has been developed for the FSA method by using in situ γ spectra instead of calibration pad spectra. Finally, the new method has been validated by acquiring γ spectra with a 10.16 cm × 10.16 cm sodium iodide detector in 80 different sites in the Ombrone basin, in Tuscany. The results from the FSA method have been compared with the laboratory measurements by using HPGe detectors on soil samples collected particular, the (137)Cs isotopes has been implemented in the analysis since it has been found not negligible during the in-situ measurements.

Selective arterial embolisation for bone tumours: experience of 454 cases.

PURPOSE: The authors present the experience of a single institution with selective arterial embolisation for primary and metastatic bone tumours. MATERIALS AND METHODS: A total of 365 patients were treated with 454 embolisation procedures from December 2002 to April 2010. Embolisation was the primary treatment for benign bone tumours, adjuvant treatment to surgery for benign and malignant bone tumours and palliative treatment for bone sarcomas and metastases. Indications for repeat embolisation included pain or imaging evidence of progressive disease: 105 patients had repeat embolisation at the same location at an interval of 1-3 months; 260 patients had one embolisation, 78 had two and 29 had three or more. In all patients, N-2-butyl cyanoacrylate (NBCA) in 33% lipiodol was the embolic agent used. RESULTS: A total of 419 of the 454 embolisations (93%) were technically successful. In 35 cases, embolisation was not feasible because of poor lesion vascularisation (21 patients with bone metastases and two with aneurysmal bone cysts), origin of the Adamkiewicz artery in the embolisation field (four patients with bone metastases and one with aneurysmal bone cyst), atheromatosis and arteriosclerosis (five patients with bone metastases) and anatomical and technical problems such as small-calibre vessels, many branches and acute vessel angles (two patients with bone metastases). A clinical response was achieved in 406 of the 419 procedures (97%), and no response in 13 procedures in patients with pelvis and sacrum tumours. Complications included postembolisation syndrome in 81 patients (22%), transient paraesthesias in 41 (11%), skin breakdown and subcutaneous necrosis at the shoulder and pelvis in five (1.4%) and paresis of the sciatic nerve in one (0.3%). CONCLUSIONS: We recommend embolisation as primary or palliative treatment or an adjunct to surgery for tumours of variable histology. Strict adherence to the principles of transcatheter embolisation is important. Arteries feeding the tumour and collaterals must be evaluated carefully and catheterised superselectively to protect the normal tissues. NBCA is considered the most appropriate embolic agent for small-vessel occlusion without major complications.