Value of diffusion weighted MR imaging as an early surrogate parameter for evaluation of tumor response to high-dose-rate brachytherapy of colorectal liver metastases

<p>Abstract</p> <p>Background</p> <p>To assess the value of diffusion weighted imaging (DWI) as an early surrogate parameter for treatment response of colorectal liver metastases to image-guided single-fraction ¹⁹²Ir-high-dose-rate brachytherapy (HDR-BT).</p> <p>Methods</p> <p>Thirty patients with a total of 43 metastases underwent CT- or MRI-guided HDR-BT. In 13 of these patients a total of 15 additional lesions were identified, which were not treated at the initial session and served for comparison. Magnetic resonance imaging (MRI) including breathhold echoplanar DWI sequences was performed prior to therapy (baseline MRI), 2 days after HDR-BT (early MRI) as well as after 3 months (follow-up MRI). Tumor volume (TV) and intratumoral apparent diffusion coefficient (ADC) were measured independently by two radiologists. Statistical analysis was performed using univariate comparison, ANOVA and paired t test as well as Pearson's correlation.</p> <p>Results</p> <p>At early MRI no changes of TV and ADC were found for non-treated colorectal liver metastases. In contrast, mean TV of liver lesions treated with HDR-BT increased by 8.8% (<it>p </it>= 0.054) while mean tumor ADC decreased significantly by 11.4% (<it>p </it>< 0.001). At follow-up MRI mean TV of non-treated metastases increased by 50.8% (<it>p </it>= 0.027) without significant change of mean ADC values. In contrast, mean TV of treated lesions decreased by 47.0% (<it>p </it>= 0.026) while the mean ADC increased inversely by 28.6% compared to baseline values (<it>p </it>< 0.001; Pearson's correlation coefficient of r = -0.257; p < 0.001).</p> <p>Conclusions</p> <p>DWI is a promising imaging biomarker for early prediction of tumor response in patients with colorectal liver metastases treated with HDR-BT, yet the optimal interval between therapy and early follow-up needs to be elucidated.</p

Modified transarterial chemoembolization with locoregional administration of sorafenib for treating hepatocellular carcinoma: feasibility, efficacy, and safety in the VX-2 rabbit liver tumor model

PURPOSE:We aimed to assess the feasibility, efficacy and safety of a local application of sorafenib within a conventional transarterial chemoembolization in the VX-2 tumor-bearing rabbit model.METHODS:VX-2 tumors were induced in the left liver lobe of 10 New Zealand White rabbits. After two weeks, growth was verified by contrast-enhanced computed tomography (CT). Five rabbits were treated by transarterial chemoembolization using an emulsion of sorafenib and ethiodized oil (referred to as SORATACE; n=5). Rabbits receiving oral sorafenib for two weeks (n=2) and untreated rabbits (n=3) served as controls. After two weeks, contrast-enhanced CT was performed, followed by animal necropsy.RESULTS:The change in tumor diameter between baseline and follow-up was significantly different in the SORATACE group compared with the other groups; tumor shrinkage was observed in the SORATACE group only (P = 0.016). In both control groups, preserved hypervascularity was seen in the follow-up CT in all but one tumor. All tumors in the SORATACE group were devascularized in the follow-up CT. Importantly, substantial parenchymal damage in nontargeted areas of the tumor-bearing liver lobe was seen in rabbits treated with SORATACE.CONCLUSION:SORATACE demonstrated high efficacy in the treatment of experimental VX-2 liver tumors but was also associated with substantial liver parenchymal toxicity

Precipitating liquid embolics

GesamthabilitationsschriftPräzipitierende Flüssigembolisate zur Embolisation von zerebralen Aneurysmen und arteriovenösen Malformationen basieren auf einer Mixtur aus biokompatiblen Polymeren gelöst in organischen, wasserlöslichen Lösungsmitteln. Nach intravaskulärer Injektion präzipitiert das Flüssigembolisat und bildet einen nicht adhäsiven Ausguss infolge eines raschen Austauschs des Lösungsmittels durch umgebende physiologische Flüssigkeiten. In der vorliegenden Arbeit wurde die Entwicklung neuartiger präzipitierender Flüssigembolisate, welche sich aus biokompatiblen Polymeren und darin gelösten organischen Lösungsmitteln zusammensetzen, und der Einsatz der CT-Angiographie (CTA) zur Volumetrie von embolisierten Aneurysmen dargestellt. Folgende Ergebnisse konnten hierbei erzielt werden: 1\. Jodierter Polyvinyl Alkohol (I-PVAL) stellt einen in der Arbeitsgruppe entwickelten Polymer-Bestandteil für präzipitierende Flüssigembolisate dar. Wesentliche Innovation dieses Polymers gegenüber bekannten Embolisaten ist die intrinsische Röntgensichtbarkeit ohne Zusatz weiterer röntgendichter Substanzen. Eine Vorbereitung vor der Applikation ist dadurch nicht notwendig. Wir konnten zeigen, dass mit einer zähflüssigen Mixtur aus I-PVAL gelöst in Dimethylsulfoxid (DMSO), der meistverwendeten Trägersubstanz präzipitierender Flüssigembolisate, die Embolisation experimenteller breitbasiger Seitwandaneurysmen der Arteria carotis des Schweins mit einer hohen initialen Okklusionsrate technisch möglich ist. Darüber hinaus ist I-PVAL das erste neuroendovaskuläre Embolisationsmaterial mit dem eine artefaktfreie Darstellung embolisierter Aneurysmen mittels CT und MRT möglich ist. 2\. Aus toxikologischer Sicht bestehen Bedenken bezüglich der Verwendung von DMSO als Lösungsmittel-Bestandteil präzipitierender Flüssigembolisate. Anlass für Besorgnis ist insbesondere ein nach zu rascher intraarterieller Injektion auftretender Vasospasmus, welcher in Untersuchungen am Rete mirabile des Schweins regelhaft fatale klinische Folgen hatte. In einer vergleichenden tierexperimentellen Studie am Rete mirabile konnten wir andere organische Lösungsmittel identifizieren, welche eine wesentlich geringere Angiotoxizität nach intraarterieller Injektion als DMSO aufwiesen. Die Substanzen mit den günstigsten angiotoxischen Profilen waren hierbei Dimethylsulfoxid (DMI) und N-Methyl Pyrrolidon (NMP). 3\. In der Arbeitsgruppe wurde ein weiteres Flüssigembolisat synthetisiert, welches die aufgezeigten Vorzüge des intrinsisch röntgendichten Polymers I-PVAL mit jenen des gering angiotoxischen Lösungsmittels NMP verbindet. Aufgrund der guten und homogenen Röntgensichtbarkeit auch unter Fluoroskopie sowie günstiger Präzipitationseigenschaften war auch mit dieser Polymer-Lösungsmittel-Mixtur die Embolisation experimenteller breitbasiger Seitwandaneurysmen der Arteria carotis des Schweins mit einer hohen initialen Okklusionsrate technisch möglich. 4\. In einer in vitro Studie mit verschiedenen Phantomen intrakranieller Aneurysmen zeigte sich die moderne Mehrzeilen CTA geeignet zur exakten Volumenbestimmung auch solcher komplexer dreidimensionaler Strukturen. Die geringsten Abweichungen fanden sich hierbei für Volumen Rendering Rekonstruktionen unter Verwendung einer automatisierten Analysesoftware. 5\. Bei der Volumetrie mittels CTA von experimentellen Aneurysmen, welche direkt im Anschluss an deren chirurgische Konstruktion mit I-PVAL embolisiert wurden, zeigte sich eine deutliche Volumenzunahme von durchschnittlich über 60%. Diese Beobachtung war jedoch am ehesten durch eine Unzulänglichkeit des Aneurysmamodells bedingt. Bedenken einer Druckerhöhung im Aneurysma durch die Embolisatinjektion während der temporären Ballonokklusion des Trägergefäßes konnten durch weitere in vitro Versuche mit intraaneurysmatischer Druckmessung ausgeräumt werden. Ursache hierfür sind trotz maximal inflatiertem Ballon stets verbleibende Öffnungen entlang des Mikrokatheters, welche auf der anderen Seite jedoch die bevorzugte Austrittsstelle von Embolisat in das Trägergefäß darstellen.Precipitating liquid embolics used for embolization of cerebral aneurysms or arteriovenous malformations are based on solutions of preformed polymers dissolved in organic, water-miscible solvents. Following intravascular injection, the liquid embolic precipitates and forms a nonadhesive solid cast due to a rapid exchange of the solvent with surrounding physiological fluids. We have developed a new precipitating liquid embolic, composed of a biocompatible polymer dissolved in organic solvents. In addition, we have evaluated CT-angiography (CTA) for volumetry of such embolized aneurysms. The following results were achieved: 1\. Iodinated polyvinyl alcohol (I-PVAL) resembles a newly developed polymer proportion of precipitating liquid embolics. The main innovation of this polymer in comparison to known embolics is the intrinsic radiopacity without the need of radiopaque admixtures. Thus, no preparation before use is necessary. We have demonstrated that embolisation of porcine carotid artery sidewall aneurysms with a highly viscous mixture of I-PVAL dissolved in dimethylsulfoxide (DMSO), the most commonly used organic solvent for precipitating liquid embolics, was feasible with a high initial occlusion rate. Moreover, I-PVAL is the first neuroendovascular embolisation material not to produce artifacts on CT or MRI of embolized aneurysms. 2\. Concerns exist for the use of DMSO as a solvent proportion of precipitating liquid embolics from a toxicological standpoint. Especially worrisome is the observation that rapid intraarterial injection in swine rete mirabile regularly lead to vasospasm with fatal clinic consequences. In a comparative study in swine rete mirabile we were able to identify other organic solvents, which were far less angiotoxic than DMSO after intraarterial injection. The substances with the most promising angiotoxic profiles were dimethylsulfoxide (DMI) and n-methyl pyrrolidone (NMP). 3\. We have synthesized another liquid embolic, which combines the advantages of the intrinsically radiopaque polymer I-PVAL with those of the low angiotoxic solvent NMP. We have demonstrated that embolisation of porcine carotid artery sidewall aneurysms was feasible with a high initial occlusion rate due to the good and homogeneous radiopacity and favourable precipitation pattern of this liquid embolic. 4\. A systematic in vitro analysis of different reconstruction methods for volume determination of phantoms of intracranial aneurysms using 16-row multislice CTA was performed. This was the first investigation to show that volumetric assessment of such complex three dimensional structures is feasible with CTA. The lowest deviations were found for an automated volume analysis tool on volume-rendered reconstructions. 5\. A considerable volume increase of over 60% of experimental aneurysms, which were embolized with I-PVAL immediately after their surgical construction, was found by CTA volumetry. This observation was most likely the result of a shortcoming of this aneurysm model. The concern of an intraaneurysmal pressure increase during injection of liquid embolics and temporary balloon occlusion of the parent artery was ruled out by in-vitro experiments with assessment of intraaneurysmal pressure. On the other hand, open spaces along the microcatheter remain despite maximal inflation of a compliant balloon, which constitute the preferred route of liquid embolic migration into the parent artery

CT-assisted transfemoral intrahepatic portosystemic shunt in a long duration follow-up : a case report

Background: Transjugular intrahepatic portosystemic shunt (TIPS) in patients with portal hypertension may be considered as a rescue therapy in case of recurrent variceal bleeding or failure of endoscopic management. Case Reports: We present a case of a patient with massive gastroesophageal variceal bleeding refractory to numerous endoscopic treatments in which TIPS was considered in an attempt to decrease the risk of potentially fatal rebleeding. Standard TIPS procedure was not feasible due to altered anatomy of the liver resulting from right hemidiaphragmatic paresis. Computed Tomography (CT) fluoroscopic guidance was utilized for direct percutaneous puncture of the left hepatic and left portal vein with subsequent guidewire snaring to perform portosystemic shunting via femoral access. Since the procedure, no recurrent variceal bleeding was reported and the shunt remained patent at a 3-year follow-up. Although stent fracture with fragment migration was observed. Conclusions: Significant variation in liver anatomy does not preclude the creation of nonsurgical portosystemic shunt. In these cases, combined percutaneous and endovascular technique may be utilized

Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro

As there is currently no superior hepatocellular carcinoma (HCC) model with percutaneous vascular access for transarterial treatments available, the VX2 rabbit model is frequently used for in vivo investigations on liver carcinoma. However, the VX2 cell line was derived from a virus-induced skin papilloma that can form carcinosarcoma in liver of rabbits and the transferability of obtained results to HCC treatment remains open. Here we compared the most frequently investigated human HCC model cell line, HepG2, with VX2 cells in vitro in terms of sensitivity towards the broad specificity kinase inhibitor sorafenib and responsiveness to the addition of platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF), as well as insulin and interleukin-1 beta (IL1 beta). Phosphorylation of protein kinase B (AKT) the mitogen-activated protein kinases (MAPKs) p38 and p42/44 (extracellular signal-regulated kinase, ERK1/2) and inhibitor of kappa light chain gene enhancer alpha (I kappa B alpha) was determined by western blotting as these events are associated with early signaling cascades. Additionally, the inhibition of phosphorylation under sorafenib treatment was investigated. Sorafenib was equally toxic to both cell lines, but only in HepG2 was activation of caspase 3/7 activity, as a sign of apoptosis, observed. VX2 cells exhibited generally more intense phosphorylation signals in response to the growth factors and also serum. In contrast to VX2, HepG2 cells showed no response to PDGF-AB or VEGF as determined by kinase phosphorylation. In both cell lines, sorafenib inhibited growth factor-induced phosphorylation of ERK and p38-MAPK. AKT phosphorylation was only inhibited in VX2 cells and I kappa B alpha phosphorylation was not influenced by this kinase inhibitor in either cell type. Taken together, the two cellular models for HCC share several features related to sorafenib application, but differed in their responsiveness towards growth factors. Therefore, results obtained with the VX2 model cannot be extended to human HCC without appropriate caution

Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans’ cell sarcoma: evidence for hematopoietic plasticity

Background. The hierarchical organization of the hematopoiesis with unidirectional lineage determination has become a questionable tenet in view of the experimental evidence for reprogramming and transdifferentiation of lineage determined cells. Clinical examples of hematopoietic lineage plasticity are rare. Here we report on a patient who presented with an acute B-lymphoblastic leukemia (B-ALL) and developed a Langerhans cell sarcoma (LCS) nine years later. We provide evidence that the second neoplasm is the result of a transdifferentiation. Design and Methods. B-ALL was diagnosed in an 11 year old boy in 1996. Treatment according to the ALL-BFM-1995 protocol resulted in a complete remission. Nine years later, in 2005, LCS was diagnosed in a supraclavicular lymph node. Despite treatment with different chemotherapy protocols the patient had progressive disease. Finally, he received an allogeneic peripheral blood stem cell transplantation and achieved a continuous remission. Molecular studies of IgH- and TCRgamma- gene rearrangements were performed with DNA from the LCS and the cryopreserved cells from the B-ALL. The expression of PAX5 and Id2 was analyzed with real-time RT-PCR. Results. Identical IgH-rearrangements in the B-ALL and the LCS were demonstrated. The key factors required for B-cell and dendritic cell development PAX5 and Id2 were differentially expressed, with a strong PAX5 signal in the B-ALL and only a weak expression in the LCS, whereas Id2 showed an opposite pattern. Conclusions. The identical IgH-rearrangement in both neoplasms indicates a transdifferentiation of the B-ALL into a LCS. Loss of PAX5 and the acquisition of Id2 suggest that these key factors are involved in the transdifferentiation from a B-cell phenotype into a Langerhans/dendritic cell phenotype