Hepatobiliary-phase gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid MRI for pretreatment prediction of efficacy-to-standard-therapies based on Barcelona Clinic Liver Cancer algorithm: an up-to-date review.

Recent advances in systemic therapy have had major impacts on treatment strategies for hepatocellular carcinoma (HCC). The 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines incorporate a new section on clinical decision-making for personalized medicine, although the first treatment suggested by the BCLC guidelines is based on solid scientific evidence. More than ever before, the appropriate treatment strategy must be selected prior to the initiation of therapy for HCC. Gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid magnetic resonance imaging (Gd-EOB-DTPA-MRI) is essential for liver imaging and the hepatobiliary phase (HBP) of EOB-MRI reflects the expression of organic anion transporting polypeptide (OATP) transporters. Molecules associated with OATP expression are relevant in the molecular classification of HCC subclasses, and EOB-MRI is becoming increasingly important with advances in the molecular and genetic understanding of HCC. In this review, we describe imaging findings for the pretreatment prediction of response to standard therapies for HCC based on the BCLC algorithm using the HBP of EOB-MRI, with specific attention to the molecular background of OATPs. A more complete understanding of these findings will help radiologists suggest appropriate treatments and clinical follow-ups and could lead to the development of more personalized treatment strategies in the future. CLINICAL RELEVANCE STATEMENT: In the coming era of personalized medicine, HBP of EOB-MRI reflecting molecular and pathological factors could play a predictive role in the therapeutic efficacy of HCC and contribute to treatment selection. KEY POINTS: • Imaging features of hepatobiliary phase predict treatment efficacy prior to therapy and contribute to treatment choice. • Wnt/ß-catenin activation associated with organic anion transporting polypeptide expression is involved in the tumor immune microenvironment and chemo-responsiveness. • Peritumoral hypointensity of hepatobiliary phase reflecting microvascular invasion affects the therapeutic efficacy of locoregional to systemic therapy.

Transarterial Embolization of Neovascularity for Refractory Nighttime Shoulder Pain: A Multicenter, Open-Label, Feasibility Trial.

PURPOSE: To assess the feasibility of transarterial embolization (TAE) for recalcitrant nighttime shoulder pain in a multicentric study. MATERIALS AND METHODS: This prospective, open-label, feasibility trial included 100 patients treated at 5 institutions. TAE was performed in 76 patients with adhesive capsulitis (AC) and 24 patients with symptomatic rotator cuff tears (sRCTs). The ipsilateral radial artery was punctured, and imipenem/cilastatin sodium was infused as an embolic agent. Adverse events, 10 point pain numerical rating scale (NRS), range of motion (ROM) of the shoulder joint, and quality of life (via the EuroQol-5D [EQ-5D]) were evaluated. RESULTS: All patients exhibited neovascularity on baseline angiography, and all TAE procedures were performed successfully. No patient experienced a major adverse event. The mean nighttime pain NRS scores at baseline and 1, 3, and 6 months after TAE were 6.4 ± 2.2, 3.4 ± 2.6, 2.3 ± 2.5, and 1.6 ± 2.2, respectively (for all, P < .001). The mean ROM of anterior elevation at baseline and 1, 3, and 6 months after TAE were 97° ± 29°, 119° ± 28°, 135° ± 27°, and 151° ± 17°, respectively (for all, P < .001). The mean EQ-5D scores at baseline and 1, 3, and 6 months after TAE were 0.63 ± 0.17, 0.73 ± 0.16, 0.80 ± 0.17, and 0.84 ± 0.17, respectively (for all, P < .001). There was no significant difference in the clinical success rate between the AC and sRCT groups. CONCLUSIONS: TAE for nighttime shoulder pain caused by AC and sRCTs was feasible with sufficient safety and efficacy.

Effect of bead size and doxorubicin loading on tumor cellular injury after transarterial embolization and chemoembolization in a rat model of hepatocellular carcinoma.

Embolic agents used in transarterial embolization for intermediate stage hepatocellular carcinoma reduce blood flow into tumors and can deliver anticancer drugs. Tumor blood supply can be interrupted using doxorubicin-eluting beads (DEB-TACE) or non-loaded beads (TAE) of different calibers. In this preclinical study, we characterized the extent of remaining stressed tumor cells after treatment, hypoxia within the surviving tumor regions, and inflammatory immune cell infiltrates after embolization with 40-60 or 70-150 µm with non-loaded or doxorubicin-loaded beads at 3 and 7 days after treatment. TAE-treated tumors had more stressed and surviving tumor cells after 3 days, irrespective of bead size, compared with DEB-TACE-treated tumors. Hypoxic stress of residual cells increased after treatment with 70-150 µm beads without or with doxorubicin. Treatment with DEB-TACE of 70-150 µm resulted in increased inflammation and proliferation in the adjacent parenchyma. Inflammatory cell infiltrates were reduced at the periphery of tumors treated with 40-60 µm DEB-TACE.

A Rat Model of Frozen Shoulder Demonstrating the Effect of Transcatheter Arterial Embolization on Angiography, Histopathology, and Physical Activity.

PURPOSE: To assess the angiographic findings and the effects of transcatheter arterial embolization on physical activity and histopathology using a frozen shoulder rat model. MATERIALS AND METHODS: First, the angiographic and histopathologic findings of rats in which the shoulder was immobilized with molding plaster for 6 weeks (n = 4) were compared to control rats with normal non-immobilized shoulders (n = 4). Next, a total of 16 frozen shoulder rats were divided into 2 groups. In the transcatheter arterial embolization group (n = 8), imipenem/cilastatin was injected into the left thoracoacromial artery. The changes of physical activity before and after procedures were evaluated and compared with a saline-injected control group (n = 8). Histopathologic findings were also compared between the 2 groups. RESULTS: Angiography revealed abnormal shoulder staining in all of the rats with a frozen shoulder. On histopathology, the numbers of microvessels and mononuclear inflammatory cells in the synovial membrane of the joint capsule were significantly higher compared with the control rats (both P = .03). In the transcatheter arterial embolization group, the running distance and speed were improved (P = .03 and P = .01, respectively), whereas there were no significant differences in the control group. The number of microvessels and mononuclear inflammatory cells in the transcatheter arterial embolization group were significantly lower than the control group (P = .002 and P = .001, respectively). CONCLUSIONS: The rat frozen shoulder model revealed the development of neovascularization. Transcatheter arterial embolization decreased the number of blood vessels and inflammatory changes in the frozen shoulder and increased the moving distance and speed of the rats.

Efficacy of combined bland embolization and chemoembolization for huge (≥10 cm) hepatocellular carcinoma.

INTRODUCTION: To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). MATERIAL AND METHODS: Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. RESULTS: The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. CONCLUSION: Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

Hepatic Arterial Infusion Chemotherapy of 5-Fluorouracil for Patients with Unresectable Liver Metastases from Colorectal Cancer Refractory to Standard Systemic Chemotherapy: A Multicenter Retrospective Study.

INTRODUCTION: Hepatic arterial infusion chemotherapy (HAIC) is a feasible treatment for patients with colorectal cancer (CRC) with unresectable liver metastases. OBJECTIVE: The aim of this retrospective study was to assess HAIC of 5-fluorouracil (5FU) in patients with unresectable liver metastases from CRC refractory to standard systemic chemotherapy. METHODS: A total of 137 patients (85 men, 52 women; median age, 62 years; with KRAS mutation, n = 57) were recruited from seven institutions from September 2008 to December 2015. These patients were refractory to systemic chemotherapy including three cytotoxic agents (fluoropyrimidine, oxaliplatin, and irinotecan) with two molecular-targeted agents (bevacizumab and epidermal growth factor receptor antibody [cetuximab or panitumumab]). All patients underwent HAIC of continuous 5FU for unresectable liver metastases. Overall survival time, time to treatment failure, objective response rate, disease control rate, and incidence of adverse events to HAIC were assessed retrospectively. RESULTS: The median overall survival time was 4.8 months (95% confidence interval [CI], 4.0-5.7 months), whereas time to treatment failure was 2.4 months (95% CI, 2.0-2.8 months). The objective overall response rate and disease control rate were 12.4 and 64%, respectively. Grade 3 or 4 adverse events were observed in 2.9% of the patients (hyperbilirubinemia in 2, liver abscess in 1, and myelosuppression in 1). CONCLUSIONS: There were few incidences of severe adverse events to HAIC of 5FU for liver metastases from CRC refractory to standard systemic chemotherapy. Therefore, it might present as a treatment option as last-line chemotherapy.

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

PURPOSE: To 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 METHODS: Epirubicin 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. RESULTS: The 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). CONCLUSIONS: Conventional transarterial chemoembolization using the pumping emulsification device significantly improved the pharmacokinetics of epirubicin compared to the current standard technique using a 3-way stopcock.

Comparison of embolic effect between water-in-oil emulsion and microspheres in transarterial embolization for rat hepatocellular carcinoma model.

AIM: To compare two different embolic materials, water-in-oil (W/O) emulsion followed by gelatin particles and microspheres in transarterial embolization (TAE), using a rat hepatocellular carcinoma model. METHODS: Twenty rats bearing N1S1 cells were divided into the W/O emulsion group and Microsphere group. Water-in-oil emulsion was created by a glass membrane emulsification device. The tumor vascularity was measured by contrast-enhanced ultrasonography 24 h before and 10 min and 48 h after TAE. Tumor necrosis, hepatic infarction ratio surrounding the tumor, and locations of the embolic materials 48 h after TAE were assessed. The changes of serum liver enzymes were also evaluated. Statistical significance was determined by using either the Mann-Whitney U-test or Fisher's exact test. RESULTS: The tumor vascularity 48 h after TAE was significantly higher in the Microsphere group (20.1 vs. 3.76%, P = 0.016). The overflow of Lipiodol into the portal veins surrounding the tumor was seen, whereas microspheres were seen only in the artery. The percentage of necrotic area and complete response ratio in the W/O emulsion group was significantly higher (99.9 vs. 87.6%, P = 0.029 and 87.5 vs. 28.6%, P = 0.041, respectively). Serum aspartate aminotransferase and serum alanine aminotransferase levels 48 h after TAE were significantly higher in the W/O emulsion group (P < 0.01). CONCLUSIONS: The embolization using W/O emulsion followed by gelatin particles showed stronger antitumor effects with the occlusion of both the tumor feeding artery and the portal vein compared with microspheres, which occluded only the arteries.

Selective TACE with irinotecan-loaded 40 µm microspheres and FOLFIRI for colorectal liver metastases: phase I dose escalation pharmacokinetic study.

BACKGROUND: Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 µm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. METHODS: The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. RESULTS: Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and Cmax of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P <  0.001, respectively). CONCLUSION: Selective TACE using 40 µm irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, Registration number; UMIN000015367 ; Registered date; 08,10,2014.

Significance of the inflammation-based prognostic score in recurrent pancreatic cancer.

BACKGROUND: Although the prognosis of recurrent pancreatic cancer (RPC) is improving with the appearance of new anticancer drugs, prognostic indicators for RPC are still poorly understood. The aim of this study was to evaluate significance of the inflammation-based prognostic score, including modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Prognostic Nutritional Index (PNI), in patients with RPC. METHODS: This study reviewed 263 patients of pancreatic ductal adenocarcinoma at our institution between 2006 and 2015. A receiver operating characteristics curve analysis was performed to determine the cut-off values. The prognostic significance of the inflammation-based prognostic scores were evaluated by a multivariate analysis. RESULTS: 172 patients (65.4%) who had recurrence was included in this study. The optimal PNI for predicting 1-year survival after recurrence was 40 with higher area under receiver operating characteristics curve value (0.704) in comparison with other inflammation-based prognostic scores. A univariate and multivariate analysis revealed that liver metastasis (P < 0.001) and PNI < 40 (P < 0.001) were independently associated with the survival time after recurrence. When each of the two predictors was counted as one point and the points were calculated for all cases, a good stratified survival curve was obtained, showing the shorter survival in the higher points: median survival times of 2, 1, and 0 points were 4.3, 11.1, and 21.2 months, respectively (P < 0.001). CONCLUSIONS: Inflammation-based prognostic scores, especially PNI is useful clinical biomarker for predicting the survival time after recurrence in patients with pancreatic adenocarcinoma.

Angiographic Atlas of the Visceral Vascular Anatomy in Translational Rat Models.

PURPOSE: To characterize angiographic and cross-sectional imaging anatomy of the rat visceral vasculature in 2 translational models. MATERIALS AND METHODS: Animal studies were conducted in accordance with institutional guidelines and approval of the Institutional Animal Care and Use Committees. Retrospective review of digital subtraction arteriography was performed in 65 Wistar and 50 Sprague-Dawley male rats through a left common carotid artery or right common femoral artery approach. MR imaging of the abdomen was performed on the rats to correlate imaging modalities. RESULTS: Aortography was performed in 3 locations, including cranial to the celiac artery, cranial to the renal arteries, and cranial to the caudal (inferior) mesenteric artery, enabling characterization of the visceral branch arteries in all 65 Wistar rats. Selective arteriography of first-, second-, and third-order branch vessels of the aorta was performed allowing characterization of normal and variant anatomy. Dedicated selective arteriography was performed of the celiac artery in 65 Wistar and 10 Sprague-Dawley rats, of the common hepatic artery in 65 Wistar and 50 Sprague-Dawley rats, and of the cranial mesenteric artery in 43 Wistar rats. MR imaging enabled correlation with the lobar and portal venous anatomy. CONCLUSIONS: Analysis of arteriography and MR imaging in these rat models will provide translational researchers with anatomic details needed to develop new endovascular protocols for small animal research in interventional radiology.

Risk Factors for Late-Onset Gastrointestinal Hemorrhage After Pancreatoduodenectomy for Pancreatic Cancer.

BACKGROUND: Late-onset gastrointestinal hemorrhage after pancreatoduodenectomy (PD) occasionally occurs repeatedly or leads to a serious condition. This retrospective study aimed to clarify its frequency and pathogenesis. METHODS: A total of 147 consecutive patients who underwent PD for pancreatic cancer between 2006 and 2014 were evaluated. Patients were divided into two groups according to the occurrence of late-onset gastrointestinal hemorrhage on postoperative day 100 or later. Furthermore, recurrence and portal vein (PV) hemodynamics were thoroughly reevaluated by computed tomography. RESULTS: Eleven patients experienced late-onset gastrointestinal hemorrhage. The bleeding sites were gastrojejunostomy in four patients, choledochojejunostomy in two, transverse colic marginal vein in one, and unknown in four. The median occurrence time of late-onset gastrointestinal hemorrhage was 13.3 months after PD. PV occlusion (63.6 vs. 8.9%; p < 0.001), no patency of PV-splenic vein (SPV) confluence (54.5 vs. 12.7%; p = 0.002), and SPV ligation (36.4 vs. 9.6%; p = 0.025) were found to be significant risk factors for late-onset gastrointestinal hemorrhage. Among 11 patients who experienced late-onset gastrointestinal hemorrhage, 7 had PV occlusion and 6 had local recurrence. CONCLUSIONS: Our data suggested for the first time that both oncologic and non-oncologic factors might contribute to late-onset gastrointestinal hemorrhage after PD for pancreatic cancer. Furthermore, PV occlusion, no PV-SPV patency, and SPV ligation were found to be significant risk factors for late-onset gastrointestinal hemorrhage. Therefore, to prevent late-onset gastrointestinal hemorrhage, we must consider various approaches to maintain the patency of the PV and SPV.

Development of pumping emulsification device with glass membrane to form ideal lipiodol emulsion in transarterial chemoembolization.

PURPOSE: To evaluate a pumping emulsification device that can improve the physiochemical properties and stability of lipiodol emulsion for conventional transarterial chemoembolization. MATERIALS AND METHODS: A pumping emulsification device constructed of a glass membrane with a hydrophobic surface with pore size of 50 µm in diameter was placed between two syringe adaptors. Epirubicin solutions were mixed with lipiodol with pumping exchanges using the emulsification device or a three-way cock. The ratios of epirubicin solution to lipiodol were 1:2 or 1:1. A total of 120 emulsions were created. RESULTS: The emulsification device showed significantly higher percentages of water-in-oil when compared with the three-way cock (97.9 % vs. 68.9 % in 1:2 ratio, and 82.1 % vs. 17.8 % in 1:1 ratio, p < .001). Droplet sizes in the emulsification device were more homogenous. Mean droplet sizes and viscosities in the emulsification device did not show any significant changes for 30 min after pumping, whereas in the three-way cock, the droplet sizes significantly enlarged and viscosities significantly decreased (p=.023 and p=.002). CONCLUSION: The emulsification device can form a high percentage of water-in-oil emulsion with stable droplets sizes and viscosities. This developed device is promising to increase therapeutic effects in conventional transarterial chemoembolization. KEY POINTS: • We developed new device for transarterial chemoembolization for liver cancer. • The device can improve the physiochemical properties of lipiodol emulsion. • The device can increase the therapeutic effects in conventional transarterial chemoembolization.

Multicenter Phase II Clinical Trial of Sorafenib Combined with Transarterial Chemoembolization for Advanced Stage Hepatocellular Carcinomas (Barcelona Clinic Liver Cancer Stage C): STAB Study.

PURPOSE: To evaluate safety and efficacy of combining sorafenib with transarterial chemoembolization in patients with advanced stage hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Systemic chemotherapy-naïve patients with a Child-Pugh class A liver profile and advanced stage HCCs were enrolled. Sorafenib therapy (daily dose 800 mg) was initiated within 4 weeks after initial conventional transarterial chemoembolization with an allowance of subsequent on-demand conventional chemoembolization. The primary endpoint was rate of protocol treatment completion, which was defined as sorafenib administration for at least 2 months. Secondary endpoints included objective response rate, disease control rate, overall survival, progression-free survival, and incidence of adverse events. Thirty-one patients (24 men, 7 women; median age, 75 years; vascular invasion, n = 19; extrahepatic metastases, n = 18; both, n = 6) who met the inclusion criteria were enrolled. RESULTS: Protocol treatment was completed in 28 patients (90.3%, 28/31) with median protocol treatment duration of 7.0 months (range, 0.5-30 months) and median of 2 (range, 1-4) transarterial chemoembolization sessions. Objective response rate was 77.4% with median overall and progression-free survival of 17.3 months (95% confidence interval, 11.9-22.6 months) and 5.4 months (95% confidence interval, 4.6-6.2 months), respectively. The most common grade 3 or 4 adverse events were self-limiting elevation of aspartate aminotransferase (54.8%, 17/31) and alanine aminotransferase (45.2%, 14/31). CONCLUSIONS: This combination therapy is feasible and promising in patients with advanced stage HCCs.

Techniques to Form a Suitable Lipiodol-Epirubicin Emulsion by Using 3-Way Stopcock Methods in Transarterial Chemoembolization for Liver Tumor.

PURPOSE: To compare physicochemical properties of emulsions of ethiodized oil (Lipiodol; Guerbet, Villepinte, France) and epirubicin prepared using different techniques for conventional transarterial chemoembolization. MATERIALS AND METHODS: Lipiodol was mixed with epirubicin solution (8.33 mg/mL) by using a 3-way stopcock. The following technical parameters were compared: ratio of epirubicin solution to Lipiodol (1:2 vs 1:1), number of pumping exchanges through the stopcock (20 exchanges vs 10 exchanges), pumping speed (1 s/push vs 2 s/push), and first push syringe (epirubicin solution vs Lipiodol). RESULTS: The mean percentage of water-in-oil was 70.45 ± 1.51 in the 1:2 epirubicin-Lipiodol ratio and 16.03 ± 2.95 in the 1:1 ratio (P < .001). The first push syringe did not influence emulsion type. Median droplet sizes were significantly larger in the slower pumping speed (52.0 µm in 2 s vs 33.7 µm in 1 s; P < .001), whereas there was no significant difference in number of pumping exchanges. Droplet sizes enlarged during 30 minutes after pumping. Viscosity was lower in the 1:1 ratio and the slower pumping speed. Viscosity decreased during 30 minutes after pumping. CONCLUSIONS: The ratio of epirubicin to Lipiodol is a significant factor to form water-in-oil emulsions with higher viscosity. The percentage of water-in-oil is limited to 70% using current pumping techniques. The pumping speed strongly influences droplet size and viscosity.

Intraarterial Therapy Using Micellar Nanoparticles Incorporating SN-38 in a Rabbit Liver Tumor Model.

PURPOSE: To evaluate the pharmacokinetics of intraarterial (IA) administration of micellar nanoparticles incorporating SN-38 injection compared with intravenous (IV) administration in a rabbit liver tumor model. MATERIALS AND METHODS: In this animal care committee-approved study, 18 rabbits (mean weight, 3.89 kg; range, 3.20-4.70 kg) with VX2 liver tumors were divided into two groups (IA and IV). Micellar nanoparticles incorporating SN-38 (30 mg/kg) were injected through the left hepatic artery in the IA group and the right femoral vein in the IV group. NK012 and free SN-38 in the plasma, liver parenchyma, and tumors were measured within 24 hours. Histologic examinations were conducted at 2 and 24 hours. RESULTS: There were no significant differences in the serum area under the concentration-time curve (0-24 h) for free SN-38, at 1,500 and 1,310 µg∙min/mL in the IA and IV groups, respectively (P = .152). The IA group showed significantly higher free SN-38 concentrations in tumor tissues at all time points compared with the IV group (P = .002 at 3 min, P = .011 at 2 h, and P = .047 at 24 h). Histologic findings showed that significantly higher tumor necrosis ratios were observed in the IA group compared with the IV group at 24 hours (P = .028). CONCLUSIONS: Micellar nanoparticles could be a promising IA drug delivery system to achieve high tumor tissue concentrations of SN-38.

Increased tumour ADC value during chemotherapy predicts improved survival in unresectable pancreatic cancer.

OBJECTIVES: To investigate whether changes to the apparent diffusion coefficient (ADC) of primary tumour in the early period after starting chemotherapy can predict progression-free survival (PFS) or overall survival (OS) in patients with unresectable pancreatic adenocarcinoma. METHODS: Subjects comprised 43 patients with histologically confirmed unresectable pancreatic cancer treated with first-line chemotherapy. Minimum ADC values in primary tumour were measured using the selected area ADC (sADC), which excluded cystic and necrotic areas and vessels, and the whole tumour ADC (wADC), which included whole tumour components. Relative changes in ADC were calculated from baseline to 4 weeks after initiation of chemotherapy. Relationships between ADC and both PFS and OS were modelled by Cox proportional hazards regression. RESULTS: Median PFS and OS were 6.1 and 11.0 months, respectively. In multivariate analysis, sADC change was the strongest predictor of PFS (hazard ratio (HR), 4.5; 95 % confidence interval (CI), 1.7-11.9; p = 0.002). Multivariate Cox regression analysis for OS revealed sADC change and CRP as independent predictive markers, with sADC change as the strongest predictive biomarker (HR, 6.7; 95 % CI, 2.7-16.6; p = 0.001). CONCLUSION: Relative changes in sADC could provide a useful imaging biomarker to predict PFS and OS with chemotherapy for unresectable pancreatic adenocarcinoma. KEY POINTS: • Relative change in ADC value can predict survival in unresectable pancreatic cancer. • ADC change could determine a chemosensitivity of pancreatic cancer. • ADC values should be measured by excluding cystic, necrotic areas and vessels.

Optimal indication of neoadjuvant chemoradiotherapy for pancreatic cancer.

PURPOSE: Much attention has been paid to preoperative treatment as a new strategy especially for borderline resectable pancreatic cancer (BRPC). The purpose of this study was to define the optimal indication of neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer. METHODS: We analyzed consecutive 184 patients who had undergone pancreatic resection in Nara Medical University Hospital. Resectability status was classified by NCCN guidelines. Full-dose gemcitabine with concurrent radiation was used as NACRT. We evaluated 85 patients treated with NACRT in comparison with 99 patients without NACRT as control. RESULTS: The regimen of NACRT was well tolerated and feasible. The perioperative outcomes were almost comparable. The postoperative complications were significantly less frequent in NACRT group than non-NACRT group. The pathological effects on both resectable and borderline tumors were favorable in NACRT group compared to non-NACRT group. The overall survival of resectable pancreatic cancer was significantly better than that of BRPC regardless of whether the patients were treated with or without NACRT. The prognosis of the patients with NACRT in resectable tumors was significantly better than without, while there was no significant difference in BRPC. Furthermore, multivariate analysis of various factors in the patients with NACRT identified resectability status and completion of adjuvant chemotherapy as independent prognostic factors. CONCLUSIONS: NACRT did not improve the prognosis of the patients with BRPC, although it induced substantial pathological antitumor effect. In contrast, the prognosis of resectable pancreatic cancer treated with NACRT was favorable. Therefore, resectable pancreatic cancer may be good indication for multimodal treatment including NACRT.

Coils versus gelatin particles with or without intraarterial antibiotics for partial splenic embolization: a comparative evaluation.

PURPOSE: To compare the efficacy, complications, and inflammatory levels in partial splenic embolization (PSE) with coils or gelatin sponge (GS) particles with or without intraarterial antibiotic agents. MATERIALS AND METHODS: Forty-four patients with hypersplenism treated by PSE were assessed. GS particles were used in 31 patients, and coils were used in 13 patients. In 17 of the 31 patients who received GS, GS suspended in antibiotic solution was injected via the splenic artery. In the other 14 patients, antibiotic agents were not used. In all 13 coil group patients, an antibiotic solution was intraarterially injected before embolization. Platelet counts were compared between the GS and coil groups. Complications and serum C-reactive protein (CRP) levels were compared among the three groups. RESULTS: There were no significant differences in platelet counts and platelet increased ratios at 6 months (10.0 × 10(4)/µL and 193% in the GS group vs 9.0 × 10(4)/µL and 221% in the coil group), and no significant differences in frequencies of complications. However, one splenic abscess occurred in a patient treated with GS without antibiotics, resulting in death. The mean serum CRP level in the GS with antibiotic group at 2 weeks was significantly lower than in the other two groups. CONCLUSIONS: The efficacy of PSE is similar with the use of coils versus GS particles. Prophylactic intraarterial antibiotic treatment could be useful in preventing inflammatory reactions after PSE.

Pharmacokinetics and antitumor efficacy of chemoembolization using 40 µm irinotecan-loaded microspheres in a rabbit liver tumor model.

PURPOSE: To evaluate the pharmacokinetics and antitumor efficacy of 40 µm irinotecan-loaded drug-eluting microspheres (Embozene TANDEM Microspheres; CeloNova BioSciences, Inc, San Antonio, Texas) (TANDEM-IRI). MATERIALS AND METHODS: The following three groups included eight VX2 rabbits each: group 1, full-loaded (50 mg irinotecan/1 mL TANDEM)/high-dose injection (1 mg irinotecan/kg); group 2, full-loaded (50 mg irinotecan/1 mL TANDEM)/low-dose injection (0.5 mg irinotecan/kg); and group 3, half-loaded (25 mg irinotecan/1 mL TANDEM)/low-dose injection (0.5 mg irinotecan/kg). Irinotecan and SN-38 in the plasma and tumors were measured within 72 hours. Histologic examinations were conducted on days 1, 3, and 7. RESULTS: Serum irinotecan levels remained near the maximum concentration for 180 minutes after transarterial chemoembolization; in group 1, levels were 351.4 ng/mL at 30 minutes, 329.0 ng/mL at 60 minutes, and 333.5 ng/mL at 180 minutes. The area under the curve for 0-24 hours of irinotecan in group 1 was approximately two times higher than the same value in groups 2 and 3. High irinotecan and SN-38 concentrations in the tumors were measured at 24 hours and 72 hours. After transarterial chemoembolization, levels of liver enzymes aspartate aminotransferase and alkaline phosphatase were significantly higher in group 1 compared with groups 2 and 3. Histologic findings showed microspheres had deeply penetrated into tumors. Significantly higher tumor necrosis ratios were observed in groups 1 (86.6%-90.0%) and 3 (90.0%-100%) compared with group 2 (63.3%-70%) (P = .031 and P = .016). CONCLUSIONS: Slow drug release with high drug concentration in tumors can be provided with 40 µm TANDEM-IRI. When complete arterial embolization is performed, the dose of irinotecan loaded on 40 µm TANDEM microspheres can be reduced while maintaining efficacy.