A precise and sustainable doxycycline-inducible cell line development platform for reliable mammalian cell engineering with gain-of-function mutations.

For mammalian synthetic biology research, multiple orthogonal and tunable gene expression systems have been developed, among which the tetracycline (Tet)-inducible system is a key tool for gain-of-function mutations. Precise and long-lasting regulation of genetic circuits is necessary for the effective use of these systems in genetically engineered stable cell lines. However, current cell line development strategies, which depend on either random or site-specific integration along with antibiotic selection, are unpredictable and unsustainable, limiting their widespread use. To overcome these issues, we aimed to establish a Robust Overexpression via Site-specific integration of Effector (ROSE) system, a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9-mediated streamlined Tet-On3G-inducible master cell line (MCL) development platform. ROSE MCLs equipped with a landing pad facilitated the transcriptional regulation of various effector genes via recombinase-mediated cassette exchange. Long-term investigation revealed that the modular design of genetic payloads and integration sites significantly affected the induction capacity and stability, with ROSE MCLs exhibiting exceptional induction performance. To demonstrate the versatility of our platform, we explored its efficiency for the precise regulation of selection stringency, manufacturing of therapeutic antibodies with tunable expression levels and timing, and transcription factor engineering. Overall, this study demonstrated the effectiveness and reliability of the ROSE platform, highlighting its potential for various biological and biotechnological applications.

Factors Contributing to Successful Transvenous Retrograde Thoracic Duct Cannulation.

PURPOSE: To identify key factors for successful transvenous retrograde cannulation (TVRC) of the thoracic duct. MATERIALS AND METHODS: A total of 47 consecutive patients (62.1 ± 13.2 years; 32 men) who underwent attempted TVRC between July 2016 and July 2021 were included. Reasons for interventions were chylous leakage from the chest (n = 36), abdomen (n = 6), and other sites (n = 5). Patient age, sex, access vein (femoral vs brachial), anatomic classification (presence of dominant channel vs plexiform) of the terminal thoracic duct, and engagement of a diagnostic catheter into the jugulovenous junction were included in the analyses. Anatomic details were evaluated according to catheter-based high-pressure lymphangiography and conventional intranodal lymphangiography. The Firth bias-reduced penalized-likelihood logistic regression model was used to analyze prognostic factors. RESULTS: TVRC was successful in 33 of the 47 patients (70%). In univariate analysis, femoral access, diagnostic catheter engagement, and presence of dominant channel were significant positive prognostic factors (P <.05). In multivariate analysis, diagnostic catheter engagement and presence of dominant channel were significant prognostic factors (P <.05). Diagnostic catheter engagement showed the highest prognostic performance (accuracy = 0.872), followed by presence of a dominant channel. High-pressure catheter-based lymphangiographic findings showed better performance (accuracy, 0.844 vs 0.727) than intranodal lymphangiography to delineate the anatomy of the terminal thoracic duct. CONCLUSIONS: A secure selection of the jugulovenous junction and the presence of a dominant channel in the terminal portion of the thoracic duct were significant prognostic factors for successful TVRC.

Therapeutic outcomes of embolotherapy of extremity bone intraosseous arteriovenous malformation with ethanol, coils, and n-butyl cyanoacrylate.

OBJECTIVE: We evaluated the therapeutic outcomes of embolotherapy for bone arteriovenous malformations (AVMs) affecting the extremities using ethanol, coils, and n-butyl cyanoacrylate (NBCA). METHODS: We reviewed the data from 36 patients (18 males, 18 females; mean age 25 years; age range, 1-64 years) with bone AVMs affecting their extremities who had undergone embolotherapy using ethanol, coils, and NBCA from December 1996 to July 2019. Of the 36 patients, 19 had had pure bone AVMs and 17 mixed bone and soft tissue (MBS) AVMs. Embolotherapy was performed using direct puncture or a transvenous or an intra-arterial approach (range, 1-18 procedures; mean, 5 procedures). During the 178 embolotherapy procedures, ethanol was used in all 36 patients, except for 1. Coils were used in 14 patients, and NBCA and a lipiodol mixture in 9 patients. The therapeutic outcomes were evaluated by the clinical symptom response and the degree of devascularization on follow-up angiography or computed tomography. The major and minor complications were also evaluated. RESULTS: The clinical success (cure or markedly improvement) rate of embolotherapy for pure bone AVMs was significantly better than that for the MBS AVMs (88% vs 18%; P < .001). The complete devascularization rate of the bone AVM component of the MBS AVMs was 71%; however, the cure rate of the MBS AVMs was 0% owing to the remaining soft tissue AVMs. Of the 36 patients, 12 experienced complications, including 11 minor (2 skin bullae formation and 10 transient peripheral nerve injury) and 1 major (longstanding nerve palsy). CONCLUSIONS: Embolotherapy for bone AVMs affecting the extremities using ethanol, coils, and an NBCA mixture is effective and safe for the resolution or improvement of symptoms, especially in those with pure bone AVMs.

Radiologic and clinical results of transarterial ethanol embolization for renal angiomyolipoma.

OBJECTIVE: We sought to determine the efficacy and safety of selective arterial embolization for renal angiomyolipoma (AML) using ethanol alone or ethanol with additional embolic materials and to analyze the factors influencing safety and efficacy. METHODS: One hundred nineteen AMLs treated with embolization were included retrospectively during a 15-year period. Technical, radiologic, and clinical success were recorded and risk factor analysis was performed. Complications on follow-up images, post-embolization syndrome (PES), major complications, and changes in renal function were also evaluated. RESULTS: Technical success was achieved in 106 of 119 tumors. Tumor size significantly decreased after treatment (reduction rate: 55%). Significant risk factors for tumor reduction included tumor enhancement on preprocedural CT and residual tumor staining. Radiologic success was achieved in 114 of 119 tumors (risk factor: residual tumor staining), and clinical success was achieved in 22 of 23 patients. Complications on follow-up images occurred in 40 of 119 tumors, and PES occurred in 53 of 104 patients. No major complications occurred. There were no cases of renal function impairment. CONCLUSION: Selective transarterial embolization using ethanol alone or ethanol with additional embolic materials reduced AML size, alleviated symptoms, and can be performed safely without permanent impairment. KEY POINTS: • Percutaneous transarterial ethanol embolization reduces AML size and alleviates symptoms. • Embolization can be performed safely without permanent impairment of renal function.

Percutaneous radiologic gastrostomy with single gastropexy: outcomes in 636 patients.

OBJECTIVES: This study aimed to assess the technical success and overall complication rate of percutaneous radiologic gastrostomy (PRG) with single gastropexy using a separate tract from that used for tube placement. METHODS: From January 2014 to December 2018, 636 patients (469 men, 167 women; mean age 66.8 years; age range, 22-98 years) underwent PRG using single gastropexy at a tertiary center. Preprocedural computed tomography (CT) was recommended if there were no data on the location of the stomach on previous CT. After a single anchor was applied, the PRG tube was inserted through a separate tract from that used for tube placement. The technical success rate and major and minor complications were retrospectively reviewed. The number of patients and percentages were used as descriptive statistics for evaluating the complication rate. RESULTS: The technical success rate of PRG with single gastropexy was 99.2% (631/636). There were 32 complications among the 631 procedures. There were 19 (3.0%) major complications, including peritonitis (n = 7), migration (n = 5), infection (n=4), malposition (n = 2), and bleeding (n = 1). There were 13 (2.1%) minor complications, including local infection (n = 11), malfunction (n = 1), and pneumoperitoneum (n = 1). The overall complication rate within 30 days of PRG placement was 4.1% (26/631). CONCLUSIONS: PRG with single gastropexy using a separate tract from that used for tube placement is technically feasible with a low complication rate. KEY POINTS: • Percutaneous radiologic gastrostomy with single gastropexy using a separate tract from that used for tube placement is technically feasible. • Complications including peritonitis and bleeding were comparatively low with the conventional technique.

Combined therapy with bronchial artery embolization and tranexamic acid for hemoptysis.

BACKGROUND: While most previous studies have viewed tranexamic acid as a bridging or temporary therapy, our preliminary study offers insights into the combined therapy of antifibrinolytic agent with endovascular treatment for hemoptysis. PURPOSE: To investigate the feasibility and safety of combined therapy, to analyze factors affecting the outcomes of combined therapy, and to compare the effectiveness of combined therapy between groups with different etiologies. MATERIAL AND METHODS: Between January 2011 and December 2014, 64 patients (33 men, mean age 64.6 years) underwent combined therapy for hemoptysis. The median follow-up time was 14.7 months (range 174-2435 days). Patients were divided into a tuberculosis group (GroupTB, n=37) and a non-tuberculosis group (Groupnon-TB, n=27). RESULTS: Embolotherapy was technically successful in 62/64 (96.9%) cases. The immediate clinical success rate was 96.8% (60/62). The short-term and long-term recurrence rates were 12.9% (n=8) and 19.4% (n=12), respectively. The one-, two-, and four-year recurrence-free survival rates were 61%, 49%, and 32%, respectively. There was no significant survival difference between the two groups. Suboptimal embolization was a significant risk factor for immediate clinical failure (odds ratio 29.624, P = 0.023). Optimal embolization (hazard ratio [HR] 0.199, P = 0.023) and older age (HR 0.956, P = 0.013) were significantly associated with lower recurrence risk. CONCLUSION: Combined therapy is an effective and safe treatment modality for hemoptysis of various etiologies, with potential benefits for short-term recurrence vis-a-vis current literature evidence. Suboptimal embolization was the most important modifiable risk factor for treatment failure and recurrence after combined therapy.

Controlling Ratios of Plasmid-Based Double Cut Donor and CRISPR/Cas9 Components to Enhance Targeted Integration of Transgenes in Chinese Hamster Ovary Cells.

Chinese hamster ovary (CHO) cells are the most valuable expression host for the commercial production of biotherapeutics. Recent trends in recombinant CHO cell-line development have focused on the site-specific integration of transgenes encoding recombinant proteins over random integration. However, the low efficiency of homology-directed repair upon transfection of Cas9, single-guide RNA (sgRNA), and the donor template has limited its feasibility. Previously, we demonstrated that a double-cut donor (DCD) system enables highly efficient CRISPR/Cas9-mediated targeted integration (TI) in CHO cells. Here, we describe several CRISPR/Cas9 vector systems based on DCD templates using a promoter trap-based TI monitoring cell line. Among them, a multi-component (MC) system consisting of an sgRNA/DCD vector and Cas9 expression vector showed an approximate 1.5-fold increase in knock-in (KI) efficiency compared to the previous DCD system, when a systematically optimized relative ratio of sgRNA/DCD and Cas9 vector was applied. Our optimization efforts revealed that concurrently increasing sgRNA and DCD components relative to Cas9 correlated positively with KI efficiency at a single KI site. Furthermore, we explored component bottlenecks, such as effects of sgRNA components and applicability of the MC system on simultaneous double KI. Taken together, we improved the DCD vector design by tailoring plasmid constructs and relative component ratios, and this system can be widely used in the TI strategy of transgenes, particularly in CHO cell line development and engineering.

Optimized CRISPR/Cas9 strategy for homology-directed multiple targeted integration of transgenes in CHO cells.

Site-specific integration has emerged as a promising strategy for precise Chinese hamster ovary (CHO) cell line engineering and predictable cell line development (CLD). CRISPR/Cas9 with the homology-directed repair (HDR) pathway enables precise integration of transgenes into target genomic sites. However, inherent recalcitrance to HDR-mediated targeted integration (TI) of transgenes results in low targeting efficiency, thus requiring a selection process to find a targeted integrant in CHO cells. Here, we explored several parameters that influence the targeting efficiency using a promoter-trap-based single- or double-knock-in (KI) monitoring system. A simple change in the donor template design by the addition of single-guide RNA recognition sequences strongly increased KI efficiency (2.9-36.0 fold), depending on integration sites and cell culture mode, compared to conventional circular donor plasmids. Furthermore, sequential and simultaneous KI strategies enabled us to obtain populations with ~1-4% of double-KI cells without additional enrichment procedures. Thus, this simple optimized strategy not only allows efficient CRISPR/Cas9-mediated TI in CHO cells but also paves the way for the applicability of multiplexed KIs in one experimental step without the need for sequential and independent CHO-CLD procedures.

Endovascular treatment results and risk factors for complications of body and extremity arteriovenous malformations.

OBJECTIVE: The objective of this study was to investigate the factors associated with the complication rate and treatment outcomes of arteriovenous malformations (AVMs) during a 20-year period. METHODS: This was a retrospective study of 306 patients (135 men, 171 women; mean age, 30.8 years) with body and extremity AVMs who were treated between 1996 and 2017. A total of 913 sessions of endovascular treatment were performed. Patients were divided into two decades of the study period to compare complications and clinical results. Group 1 comprised 107 patients treated in the first decade of the study period, and group 2 comprised 199 patients treated in the last decade. AVMs were classified according to the angiographic findings. Complication rates, number of treatment sessions, and treatment results were compared between the two groups. RESULTS: Minor complication (group 1, 20.1%; group 2, 18.5%) and major complication (group 1, 3.1%; group 2, 4.1%) rates were similar between groups (P = .79). The mean number of treatment sessions in group 1 and group 2 was 4.2 and 2.3, respectively, indicating a 45% reduction in treatment sessions (P < .0001). The treatment failure rate decreased from 9.3% in group 1 to 1.5% in group 2 (P = .04). The clinical success rate was 54.2% in group 1 and 64.3% in group 2 (P = .10). CONCLUSIONS: With an accumulation of AVM treatment experience, the number of treatment sessions and the rate of treatment failures were significantly reduced.

Subclassification and Treatment Results of Ethanol Embolotherapy of Type II Arteriovenous Malformations of the Extremity and Body.

PURPOSE: To evaluate the safety and efficacy of ethanol and coil embolization of type II arteriovenous malformation (AVM) according to a new subtype classification. MATERIALS AND METHODS: Eighty-four type II AVMs in the body or extremity of 79 patients who underwent AVM treatment from 1996 to 2017 were retrospectively subclassified according to the angiographic morphology of the draining vein as type IIa (arterioles shunt to focal segment of single draining vein), type IIb (arterioles shunt to venous sac with multiple draining veins), and type IIc (arterioles shunt along long segment of draining vein). Coil and ethanol embolization of the focal or long segment of the draining vein or the venous sac was performed with direct puncture or transvenous approach according to subtype. Treatment outcomes, number of treatment sessions, and complications were analyzed. RESULTS: AVM cure (ie, complete embolization) rates were 95%, 76%, and 65% in types IIa, IIb, and IIc AVMs, respectively. The cure rate of type IIa AVMs was significantly better than that of type IIc AVMs (P = .015). Median numbers of treatment sessions were 1 in types IIa and IIb AVMs and 2.5 in type IIc AVMs, with a significant difference between type IIc and the other 2 types (P < .05). Minor complications occurred in 20% of patents and major complications occurred in 7%. CONCLUSIONS: The cure rate of type IIa AVMs was significantly better than that of type IIc AVMs, which also required significantly more treatment sessions than the other 2 types.

Effect of Hyperbilirubinemia on Hepatic Hypertrophy after Portal Vein Embolization and Liver Failure after Hepatectomy in Primary Biliary Malignancy.

PURPOSE: To retrospectively investigate the impact of hyperbilirubinemia on future liver remnant (FLR) volume after percutaneous transhepatic portal vein embolization (PVE) and incidence of post-hepatectomy liver failure in primary biliary malignancy. MATERIALS AND METHODS: Eighty-seven patients (62 men, overall mean age 66.9 y) who underwent PVE, using Gelfoam and coils before major hepatectomy between January 2004 and June 2016, were included in this study and divided into a hyperbilirubinemia (serum total bilirubin level at PVE 5.80 ± 2.44 mg/dL; n = 41) group and a control group (1.09 ± 0.73 mg/dL; n = 46). Liver volume was measured from computerized tomographic data before and 18.5 days, on average, after PVE. Correlation between FLR hypertrophy (degree of hypertrophy and percentage increase in future liver remnant [%FLR]) and total bilirubin were analyzed. FLR hypertrophy and incidence of post-hepatectomy liver failure were compared. Simple and multiple regressions were used for univariable and multivariable analyses, respectively. RESULTS: Mean FLR volumes before and after PVE were 529.1 cm3 and 640.5 cm3, respectively. Degree of hypertrophy and %FLR were 7.64 ± 4.22 and 21.77 ± 13.34, respectively. There was no significant correlation between FLR hypertrophy and total bilirubin (P > .5). FLR hypertrophy was not significantly different between the 2 groups. Planned major hepatectomy was performed in 73 patients (83.9%). Grade 3 post-hepatectomy liver failure occurred in 6 patients (8.2%; 2 in the hyperbilirubinemia group and 4 in the control group), and its incidence was not significantly different between the groups (P = .354). CONCLUSIONS: Hyperbilirubinemia at the time of PVE seems to have no effect on FLR hypertrophy. The incidence of grade 3 post-hepatectomy liver failure is not likely to be influenced, either.

Novel Albumin-Bilirubin Grade-Based Risk Prediction Model for Patients with Hepatocellular Carcinoma Undergoing Chemoembolization.

BACKGROUND: Recently, albumin-bilirubin (ALBI) grade has been suggested as a better surrogate for hepatic functional reserve for patients with hepatocellular carcinoma (HCC). AIMS: We developed and validated a novel prediction model to predict outcome for HCC patients who underwent transcatheter arterial chemoembolization (TACE) as a first-line therapy. METHODS: From a multivariate Cox regression model for overall survival, five objective variables (ALBI grade), the Barcelona clinic liver cancer (BCLC) stage, response after the first TACE session, Alpha-fetoprotein level, and sex were chosen and the ABRAS score was developed from the derivation cohort (n = 476) and scored to generate an 8-point risk prediction model. The model's prognostic performance was assessed in the randomly assigned internal validation set (n = 475) and external validation set (n = 243). RESULTS: The ALBI grade was able to stratify patient survival within the same Child-Pugh class. The time-dependent area under receiver operating characteristics curves (AUROCs) for overall survival at 1 and 3 years were 0.78 and 0.73 in the training set, 0.78 and 0.71 in the internal validation set, and 0.70 and 0.65 in the external validation set, respectively. When stratified by BCLC stage, ABRAS score at a cutoff point of more than 3, 4, and 5 for BCLC stage 0/A, B, and C could identify subset of patients with dismal prognosis. CONCLUSION: ABRAS score was useful in estimating prognosis for patients who underwent TACE as a first-line therapy. This score can be useful in planning and guiding treatment strategies with TACE, which warrants prospective validation.

Combined transarterial chemoembolization and radiofrequency ablation for small treatment-naïve hepatocellular carcinoma infeasible for ultrasound-guided radiofrequency ablation: long-term outcomes.

Background Ultrasound (US)-guided radiofrequency ablation (RFA) for small hepatocellular carcinoma (HCC) is often infeasible due to unfavorable location and poor conspicuity. Those small HCCs can be treated with combined transarterial chemoembolization (TACE) and RFA. Purpose To evaluate long-term outcomes of combined TACE and RFA for small treatment-naïve HCC infeasible for US-guided RFA. Material and Methods Between February 2009 and January 2014, 69 patients with small (≤3 cm) HCC infeasible for US-guided RFA received TACE and subsequent RFA in one session as a first-line treatment. Local tumor progression (LTP), overall survival (OS), and event-free survival rates were evaluated. Univariate and multivariate analyses were conducted to identify prognostic factors. Results Cumulative rates of LTP were 4.4%, 6.8%, 8.2%, 9.5%, and 9.5% at one, two, three, five, and seven years, respectively. Cumulative one-, two-, three-, five-, and seven-year OS rates were 100%, 95%, 89%, 80%, and 80%, respectively. Cumulative one-, two-, three-, five-, and seven-year event-free survival rates were 81%, 63%, 54%, 31%, and 20%, respectively. No significant prognostic factors for LTP, OS, and event-free survival were identified in univariate analysis. Conclusion Combined TACE and RFA appears to be an effective treatment for small treatment-naïve HCC infeasible for US-guided RFA in terms of LTP and OS.

Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma After Combined Transarterial Chemoembolization and Radiofrequency Ablation.

OBJECTIVE: The goal of this study is to evaluate the outcomes of combined transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) in terms of the frequency of aggressive intrasegmental recurrence. MATERIALS AND METHODS: Sixty-one patients (43 men and 18 women; mean [± SD] age, 65.8 ± 8.6 years; age range, 44-82 years) with 71 HCCs (mean [± SD] size, 2.8 ± 0.9 cm; range, 0.7-4.2 cm) underwent combined TACE and RFA. Aggressive intrasegmental recurrence was defined as initial tumor recurrence at least 6 months after treatment and the simultaneous development of recurrence of multiple (at least three) nodular or infiltrative tumors in the treated segment. Tumor contact with a thick (diameter, ≥ 3 mm) portal vein (i.e., periportal HCC) was evaluated. The frequency of aggressive intrasegmental recurrence, the local tumor progression (LTP) rate, and the complication rate were assessed. RESULTS: The median follow-up period was 25.6 months (range, 6.1-75.5 months). Twenty-two HCCs (31%) were in contact with a thick portal vein. Aggressive intrasegmental recurrence was observed in one patient (representing 1.4% of all treated HCCs and 4.5% of periportal HCCs) after treatment of a 4.0-cm periportal HCC. The cumulative LTP rates at 1, 3, and 5 years were 6.7%, 21.0%, and 30.5%, respectively. The rate of major complications was 6.6%. CONCLUSION: The frequency of aggressive intrasegmental recurrence after combined TACE and RFA for HCCs was very low.

Combination treatment of trans-arterial chemo-embolisation, radiotherapy and hyperthermia (CERT) for hepatocellular carcinoma with portal vein tumour thrombosis: Interim analysis of prospective phase II trial.

Objectives This study evaluated the objective response to and toxicity of trans-arterial chemo-embolisation (TACE) followed by radiotherapy and hyperthermia (CERT) in hepatocellular carcinoma patients with portal vein tumour thrombosis. Methods The study design was a single-centre prospective phase II trial. Patients were first treated with TACE, with the first hyperthermia session 1 week later. Respiration-gated radiotherapy (RT) was delivered in 10 fractions of 3-5 Gy after another week. Six sessions of hyperthermia were delivered twice a week according to an energy escalation protocol. Response evaluation was planned at 1 month after RT completion using the modified Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Interim analysis was conducted on patients enrolled from October 2013 to November 2014. During this period, 46 patients (90.2%) who received at least one hyperthermia session were eligible and enrolled. Median follow-up was 6.7 months (range 2.0-15.0 months). Complete response was observed in 10 (21.7%) patients and partial response in 27 (47.8%). Most toxicities were grade I or II. One death was related to severe pneumonia of unknown cause in the left lung and one patient could not complete planned treatment because of continuous elevation of bilirubin after TACE. Late, asymptomatic gastroduodenal toxicities were noticed in 13 (28.3%) patients. Conclusion Preliminary evaluation of CERT showed a promising response rate with acceptable toxicities.

Feasibility and efficacy of primary tractography during percutaneous catheter drainage.

BACKGROUND: The indication of percutaneous catheter drainage (PCD) has expanded with the development of guiding modalities. Since serious complications still occur, efforts and new techniques have been continuously searched for safer PCD. PURPOSE: To evaluate the feasibility and efficacy of primary tractography for establishing a safe needle pathway during PCD. MATERIAL AND METHODS: A total of 42 patients (20 men, 22 women; mean age, 50.7 years) who underwent primary tractography during PCD were prospectively enrolled between April 2009 and August 2013. The locations of fluid collection included sub-phrenic (n = 8), between bowel loops (n = 21), pelvic cavity (n = 8), within solid organ (n = 2), and others (n = 3). The interposed anatomic structures were analyzed on the basis of primary tractography findings. Complications related to PCD or primary tractography were evaluated. RESULTS: Interposition of any significant anatomic structure was confirmed in 10 of 42 patients (23.8%). The entrapped anatomic structures were the omental vessel (n = 4), bowel (n = 2), pleura (n = 2), bile duct (n = 2), and a branch of the left inferior epigastric artery (n = 1). In one patient, both the pleura and bile duct were interposed simultaneously. The technical and clinical success rates of PCD were 97.6% and 97.6%, respectively. No complications related to PCD or primary tractography occurred during the follow-up period. CONCLUSION: Primary tractography is a simple and feasible method to evaluate the entrapment of normal anatomic structure during PCD. This method may aid in preventing possible serious PCD-related complications, such as bleeding and fistula.

A novel, ring-connected stent versus conventional GI stents: comparative study of physical properties and migration rates in a canine colon obstruction model.

BACKGROUND: Migration of stents is one of the most common adverse events in covered stent placement in GI tract obstruction. OBJECTIVE: To compare physical property and migration rates in a canine colon obstruction model among a novel stent and conventional stents. DESIGN: Comparative physical test and animal study. SETTING: Medical device testing laboratory and animal laboratory. SUBJECTS: Mongrel dogs (N=26). INTERVENTIONS: Surgical colon obstruction followed by placement of a novel (n=13) or conventional (n=13) stent. MAIN OUTCOME MEASUREMENTS: Physical properties, migration, and adverse events. RESULTS: The novel stent showed better flexibility, as in a physical test of longitudinal compressibility and axial force, than did conventional stents, and it withstood the fatigue test for 10 days. In terms of radial force and tensile strength, the novel stent showed the same or better results than conventional stents. In a canine colon obstruction model, the migration rate of a novel stent was significantly lower than that of a conventional stent (2/13, 15.4% vs 8/13, 61.5%; P=.008). LIMITATIONS: Animal study of limited size. CONCLUSION: The novel, ring-connected stent is more flexible and more resistant to migration than the conventional stents.

Transarterial chemoembolization as first-line therapy for hepatocellular carcinomas infeasible for ultrasound-guided radiofrequency ablation: a retrospective cohort study of 116 patients.

BACKGROUND: Ultrasound (US)-guided radiofrequency ablation (RFA) is frequently infeasible even for very early or early stage hepatocellular carcinoma (HCC) due to various reasons such as inconspicuous tumors or absence of a safe electrode path and the infeasibility rate is reportedly as high as 45%. In such cases, transarterial chemoembolization (TACE) is a commonly practiced alternative. PURPOSE: To analyze long-term outcomes including tumor progression patterns and factors contributing to survival of patients who received TACE as the first line of therapy for very early or early stage HCC infeasible for US-guided RFA. MATERIAL AND METHODS: From October 2006 through October 2009, 116 patients with very early or early stage HCCs underwent the first-line therapy TACE after their tumors were deemed infeasible for RFA. Long-term survival rates were calculated and prognostic factors were assessed by univariate and multivariate analyses. The patterns and rates of tumor progression or recurrence were also evaluated. RESULTS: The 1, 3, and 5-year survival rates of the whole cohort were 94.7%, 68.4%, and 47.2% with a mean overall survival of 53.1 months (95% CI: 48.2-58.0). Preserved liver function with Child-Pugh class A was the only independent factor associated with longer survival. The most common first tumor progression pattern was intrahepatic distant recurrence. The cumulative rates of local tumor progression and intrahepatic distant recurrence at 1, 3, and 5 years were 33% and 22%, 52% and 49%, and 73% and 75%, respectively. CONCLUSION: TACE is a viable first-line treatment of HCC infeasible for RFA, especially when liver function was preserved.

Efficacy of RECIST and mRECIST criteria as prognostic factors in patients undergoing repeated iodized oil chemoembolization of intermediate stage hepatocellular carcinoma.

BACKGROUND: Given that transarterial chemoembolization (TACE) is usually a repeated procedure for treatment of hepatocellular carcinoma (HCC), repeated radiologic response assessments rather than a single time point assessment may have different clinical implications through the repeated course of TACE. PURPOSE: To evaluate the efficacy of RECIST and mRECIST criteria as a survival predictor across early time points after repeated TACE of HCC. MATERIAL AND METHODS: Ninety-eight patients with intermediate stage HCC received repeated iodized oil TACE. Treatment response was assessed according to RECIST and mRECIST criteria at 1, 3, and 6 months after initial TACE. Cox proportional model was used for survival analysis and the predicting power of each time point response was evaluated with C-statistics and time-dependent area under the receiver operating characteristic curve (AUC). Inter-method agreement was assessed with the κ coefficient. RESULTS: mRECIST was not applicable in 15 patients because of patchy uptake of iodized oil after TACE. On multivariate analysis, responders at 6 months by RECIST, responders at 3 months, and 6 months by mRECIST showed better survival than non-responders (P < 0.05). Predicting power of response criteria improved over time and mRECIST at 6 months showed the best performance. The degree of agreements was poor or fair between RECIST and mRECIST. CONCLUSION: mRECIST predicted long-term survival as early as 3 months after TACE of intermediate stage HCC. The predicting power of the uni-dimensional response criteria tended to be stronger over time.

A novel animal model of gastrointestinal obstruction for the development of stent.

BACKGROUND: The need for newer gastrointestinal (GI) stents has been continuously raised. Newly developed stents are generally tested for physical properties in vitro and directly introduced to clinical practice because there is no reliable animal model of GI obstruction. The aim of this study was to establish an animal model both that can represent obstruction of the GI tract and be used to develop new stents. MATERIAL AND METHODS: Surgical obstruction of the descending colon by wrapping with a nonabsorbable synthetic mesh and rubber bands was made in 17 healthy mongrel dogs. Four days later, a covered self-expanding metallic stent was placed for the obstructed segment in each dog under fluoroscopic guidance. Patency and migration of the inserted stents were evaluated clinically on a daily basis and fluoroscopically on a weekly basis. After sacrifice of the dogs, the degree and extent of residual colonic obstruction were assessed fluoroscopically. The specimen of the colonic obstructed segment was examined microscopically. RESULTS: In all 17 mongrel dogs, segmental obstruction in the descending colon was successfully created and confirmed with fluoroscopic examination using a contrast medium. The percentage of luminal narrowing ranged from 99%-100%. Stent placement was technically successful in all 17 dogs. During the follow-up period, stent migration occurred in 12 dogs and indwelling time of a stent ranged from 0-95 d (mean 29.2 ± 38.8 d). On postmortem pathologic examination, it was found that fibrosis had newly formed outside the colonic longitudinal muscle layer in all dogs. CONCLUSIONS: Our canine colonic obstruction model is the first animal model that can be feasible for developing a new design of stent and provide in vivo data on complications, particularly stent migration.