PATCH-DP: a single-arm phase II trial of intra-operative application of HEMOPATCH™ to the pancreatic stump to prevent post-operative pancreatic fistula following distal pancreatectomy.

BACKGROUND: Post-operative pancreatic fistula (POPF) is the most significant cause of morbidity following distal pancreatectomy. Hemopatch™ is a thin, bovine collagen-based hemostatic sealant. We hypothesized that application of Hemopatch™ to the pancreatic stump following distal pancreatectomy would decrease the incidence of clinically-significant POPF. METHODS: We conducted a prospective, single-arm, multicentre phase II study of application of Hemopatch™ to the pancreatic stump following distal pancreatectomy. The primary outcome was clinically-significant POPF within 90 days of surgery. A sample size of 52 patients was required to demonstrate a 50% relative reduction in Grade B/C POPF from a baseline incidence of 20%, with a type I error of 0.2 and power of 0.75. Secondary outcomes included incidence of POPF (all grades), 90-day mortality, 90-day morbidity, re-interventions, and length of stay. RESULTS: Adequate fixation Hemopatch™ to the pancreatic stump was successful in all cases. The rate of grade B/C POPF was 25% (95%CI: 14.0-39.0%). There was no significant difference in the incidence of grade B/C POPF compared to the historical baseline (p = 0.46). The 90-day incidence of Clavien-Dindo grade ≥3 complications was 26.9% (95%CI: 15.6-41.0%). CONCLUSION: The use of Hemopatch™ was not associated with a decreased incidence of clinically-significant POPF compared to historical rates. (NCT03410914).

Treatment Planning Optimization in Irreversible Electroporation for Complete Ablation of Variously Sized Cervical Tumors: A Numerical Study.

Irreversible electroporation (IRE), a relatively new energy-based tumor ablation technology, has shown itself in the last decade to be able to safely ablate tumors with favorable clinical outcomes, yet little work has been done on optimizing the IRE protocol to variously sized tumors. Incomplete tumor ablation has been shown to be the main reason leading to the local recurrence and thus treatment failure. The goal of this study was to develop a general optimization approach to optimize the IRE protocol for cervical tumors in different sizes, while minimizing the damage to normal tissues. This kind of approach can lay a foundation for future personalized treatment of IRE. First, a statistical IRE cervical tumor death model was built using previous data in our group. Then, a multi-objective optimization problem model was built, in which the decision variables are five IRE-setting parameters, namely, the pulse strength (U), the length of active tip (H), the number of pulses delivered in one round between a pair of electrodes (A), the distance between electrodes (D), and the number of electrodes (N). The domains of the decision variables were determined based on the clinical experience. Finally, the problem model was solved by using nondominated sorting genetic algorithms II (NSGA-II) algorithm to give respective optimal protocol for three sizes of cervical tumors. Every protocol was assessed by the evaluation criterion established in the study to show the efficacy in a more straightforward way. The results of the study demonstrate this approach can theoretically provide the optimal IRE protocol for different sizes of tumors and may be generalizable to other types, sizes, and locations of tumors.

Early experience with hypothermic machine perfusion of living donor kidneys - a retrospective study.

Although hypothermic machine perfusion (HMP) has been shown to be beneficial to deceased donor kidneys, the effect of HMP on living donor kidneys (LDK) is unknown. LDK are subjected to minutes of normothermic ischemia at the time of recovery. Comparison of 16 LDK preserved by HMP with 16 LDK preserved by static cold storage (SCS). Outcomes of interest are resistive indices (RI), both while on HMP and postoperatively, and creatinine clearance (CrCl). Injury markers NGAL and LDH were seen in the perfusate of LDK in amounts similar to what is found for donation after neurological determination of death kidneys. Compared to SCS kidneys, CrCl was significantly higher in the HMP group from days 2 through 7 post-transplant [ie: day 7 (78.8 ± 5.4 vs. 54.0 ± 4.6 ml/min, P = 0.005)]. CrCl at 1 year was higher in the HMP group (81.2 ± 5.8 vs. 70.0 ± 5.3 ml/min, P = 0.03). Early post-transplant RI was significantly lower in the HMP group (0.61 ± 0.02 vs. 0.71 ± 0.02, P < 0.0001). Our data support the assertion that injury does occur during LDK procurement and suggest that some of this injury may be reversed with HMP, resulting in more favorable early RI and graft function compared to SCS kidneys.

A new approach to feedback control of radiofrequency ablation systems for large coagulation zones.

AIM: The aim of this study was to investigate the feasibility of achieving relatively large coagulation zones (i.e. ≥3 cm in diameter) with radiofrequency ablation (RFA) by using a broad control system. MATERIALS AND METHODS: A broad control system consists of information such as (i) the area of the tumour tissue for feedback control, (ii) the set-point temperature and (iii) the control law. The proposed approach has advanced knowledge in (i) and (ii) in particular. RFA is known to be limited by tissue dehydration that occurs around the electrode, which results in impedance such that no further energy can be delivered to the tissues. We proposed the notion of "energy gate", an area on the electrode, which is not covered by the dehydrated tissue and through which energy can still be delivered to the surrounding tissues. Given a specific size of energy gate, both (i) the area of the tissue in which the temperature is monitored and (ii) the set-point temperature were determined. A reliable finite element model or simulator for a commercially available electrode was used and the tissue surrounding the RFA electrode was divided into three areas for a comprehensive study of the issues (i) and (ii). Porcine liver tissue (30 specimens in total) and a custom-made RFA device with a RF power generator (100 W and 460 ± 30 kHz) and a Covidien cool-tip electrode (17 gauge and 30 mm exposure) were used to validate the findings regarding the area of the tissue for feedback control and the set-point temperature. RESULTS: The size of coagulation zone achieved was maximised when the area of tissue surrounding the middle part of the active tip (i.e. Point 7) was used for feedback control and when the set-point temperature was set to 90 ^ C (this temperature is determined based on the energy gate through a trial-and-error procedure). At both 80 and 90 ^ C, the coagulation zones generated using Area II were significantly larger than that generated using Area I (p = 0.0028 and 0.0003, respectively) and Area III (P = 0.0010 and < 0.0001, respectively). A similar finding regarding the control area and set-point temperature was confirmed by the in-vitro experiment. When compared with Point a (p < 0.0001) and Point c (p < 0.0001), the largest coagulation zone (1066.7 ± 36.1 mm2) was achieved by controlling the temperature of the tissue area surrounding the middle part of the active tip (i.e. Point b) at 90 ^ C. CONCLUSION: The judicious selection of the control area within the biological tissue for temperature monitoring and the set-point temperature for feedback control is critical in increasing the size of the coagulation zone in the treatment of RFA.

Numerical analysis of the relationship between the area of target tissue necrosis and the size of target tissue in liver tumours with pulsed radiofrequency ablation.

PURPOSE: Radiofrequency ablation (RFA) is currently restricted to the treatment of target tissues with a small size (<3 cm in diameter). To overcome this problem with RFA, some phenomena need to be understood first. The study presented in this paper investigated the relationship between the area of target tissue necrosis (TTN) and the size of target tissue in pulsed radiofrequency ablation (PRFA). MATERIALS AND METHODS: Liver tumour, one of the common targets of RFA in clinical practice, was used as the target tissue in this study. Two types of pulsed RF power supply methods (half-square and half-sine) and three target tissues with different sizes (25 mm, 30 mm and 35 mm in diameter) were studied using finite element modelling. The finite element model (FEM) was validated by using an in vitro experiment with porcine liver tissue. The first roll-off occurrence or 720 s, whichever occurs first, was chosen as the ablation termination criterion in this study. RESULTS: For each target tissue size, the largest TTN area was obtained using the maximum voltage applied (MVA) without roll-off occurrence. In this study, target tissues with a 25 mm diameter can be ablated cleanly but target tissues with 30-mm and 35-mm failed to be ablated. CONCLUSIONS: The half-square PRFA could achieve a larger TTN area than the half-sine PRFA. The MVA decreases with an increase in the target tissue diameter in both the half-square PRFA and the half-sine PRFA. The findings of this study are in agreement with the clinical results that lesions (≥ 3 cm in diameter) have less favourable results from RFA.

Study of the relationship between the target tissue necrosis volume and the target tissue size in liver tumours using two-compartment finite element RFA modelling.

PURPOSE: The aim of this study was to investigate the relationship between the target tissue necrosis volume and the target tissue size during the radiofrequency ablation (RFA) procedure. MATERIALS AND METHODS: The target tissues with four different sizes (dxy = 20, 25, 30 and 35 mm) were modelled using a two-compartment radiofrequency ablation model. Different voltages were applied to seek the maximum target tissue necrosis volume for each target tissue size. The first roll-off occurrence or the standard ablation time (12 min) was taken as the sign for the termination of the RFA procedure. RESULTS: Four different maximum voltages without the roll-off occurrence were found for the four different sizes of target tissues (dxy = 20, 25, 30 and 35 mm), and they were 36.6, 35.4, 33.9 and 32.5 V, respectively. The target tissues with diameters of 20, 25 mm can be cleanly ablated at their own maximum voltages applied (MVA) but the same finding was not found for the 35-mm target tissue. For the target tissue with diameter of 30 mm, the 50 °C isothermal contour (IT50) result showed that the target tissue can be cleanly ablated, but the same result did not show in the Arrhenius damage model result. Furthermore, two optimal RFA protocols with a minimal thermal damage to the healthy tissues were found for the target tissues with diameters of 20 and 25 mm, respectively. CONCLUSIONS: The study suggests that target tissues of different sizes should be treated with different RFA protocols. The maximum target tissue volume was achieved with the MVA without the roll-off occurrence for each target tissue size when a constant RF power supply was used.

A multi-modal deep neural network for multi-class liver cancer diagnosis.

Liver disease is a potentially asymptomatic clinical entity that may progress to patient death. This study proposes a multi-modal deep neural network for multi-class malignant liver diagnosis. In parallel with the portal venous computed tomography (CT) scans, pathology data is utilized to prognosticate primary liver cancer variants and metastasis. The processed CT scans are fed to the deep dilated convolution neural network to explore salient features. The residual connections are further added to address vanishing gradient problems. Correspondingly, five pathological features are learned using a wide and deep network that gives a benefit of memorization with generalization. The down-scaled hierarchical features from CT scan and pathology data are concatenated to pass through fully connected layers for classification between liver cancer variants. In addition, the transfer learning of pre-trained deep dilated convolution layers assists in handling insufficient and imbalanced dataset issues. The fine-tuned network can predict three-class liver cancer variants with an average accuracy of 96.06% and an Area Under Curve (AUC) of 0.832. To the best of our knowledge, this is the first study to classify liver cancer variants by integrating pathology and image data, hence following the medical perspective of malignant liver diagnosis. The comparative analysis on the benchmark dataset shows that the proposed multi-modal neural network outperformed most of the liver diagnostic studies and is comparable to others.

RMS-UNet: Residual multi-scale UNet for liver and lesion segmentation.

Precise segmentation is in demand for hepatocellular carcinoma or metastasis clinical diagnosis due to the heterogeneous appearance and diverse anatomy of the liver on scanned abdominal computed tomography (CT) images. In this study, we present an automatic unified registration-free deep-learning-based model with residual block and dilated convolution for training end-to-end liver and lesion segmentation. A multi-scale approach has also been utilized to explore novel inter-slice features with multi-channel input images. A novel objective function is introduced to deal with fore- and background pixels imbalance based on the joint metric of dice coefficient and absolute volumetric difference. Further, batch normalization is used to improve the learning without any loss of useful information. The proposed methodology is extensively validated and tested on 30% of the publicly available Dircadb, LiTS, Sliver07, and Chaos datasets. A comparative analysis is conducted based on multiple evaluation metrics frequently used in segmentation competitions. The results show substantial improvement, with mean dice scores of 97.31, 97.38, 97.39 and 95.49% for the Dircadb, LiTS, Sliver07, and Chaos liver test sets, and 91.92 and 86.70% for Dircadb and LiTS lesion segmentation. It should be noted that we achieve the best lesion segmentation performance on common datasets. The obtained qualitative and quantitative results demonstrate that our proposed model outperform other state-of-the-art methods for liver and lesion segmentation, with competitive performance on additional datasets. Henceforth, it is envisaged as being applicable to pertinent medical segmentation applications.

Early discontinuation of adjuvant chemotherapy in patients with early-stage pancreatic cancer correlates with inferior survival: A multicenter population-based cohort study.

BACKGROUND: The current study aimed to determine the association between timing and completion of adjuvant chemotherapy and outcomes in real-world patients with early-stage pancreatic cancer. METHODS: In this multi-center cohort study patients with early-stage pancreatic cancer who were diagnosed from 2007-2017 and underwent complete resection in the province of Saskatchewan were examined. Cox proportional multivariate analyses were performed for correlation with recurrence and survival. RESULTS: Of 168 patients, 71 eligible patients with median age of 69 years and M:F of 37:34 were identified. Median time to the start of adjuvant therapy from surgery was 73 days. Of all patients, 49 (69%) patients completed adjuvant chemotherapy and 22 (31%) required early treatment discontinuation. Median recurrence-free survival of patients who completed treatment was 22 months (95%CI:15.8-28.2) vs. 9 months (3.3-14.7) if treatment was discontinued early (P<0.001). Median overall survival of those who completed treatment was 33 (17.5-48.5) vs. 16 months (17.5-48.5) with early treatment discontinuation (P<0.001). In the multivariate analysis, treatment discontinuation was significantly correlated with recurrent disease, hazard ratio (HR), 2.57 (1.41-4.68), P = 0.002 and inferior survival, HR, 2.55 (1.39-4.68), P = 0.003. No correlation between treatment timing and survival was noted. CONCLUSIONS: Early discontinuation but not the timing of adjuvant chemotherapy correlates with inferior outcomes.

Early Single-Center Experience With Irreversible Electroporation for Stage 2, 3, and 4 Pancreatic Adenocarcinomas.

OBJECTIVES: Irreversible electroporation (IRE) is an ablation technology that uses electrical energy delivered between electrodes. If the electrodes are placed atraumatically, there is little to no risk of collateral injury, making IRE appealing for the treatment of pancreatic tumors. METHODS: We report on 20 patients with pancreatic adenocarcinoma (PAC) who underwent 21 IRE in our center. There were 6 IRE for stage 2 PAC, 11 for stage 3 PAC, 1 for stage 4 PAC, and 2 patients treated with IRE for recurrence after pancreaticoduodenectomy. One patient had local progression 18 months after IRE and received a second IRE treatment. Using propensity score matching (age, sex, stage, tumor size, and chemotherapy), cases were matched 2 to 1 with patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 7 cases experienced 8 complications; 4 complications were mild, and 4 were severe. Significant survival benefit was seen for patients with stage 3 PAC (27.5 vs 14.6 months for the matched group, P = 0.003); for stage 2, median survival was 15 months, and the single stage 4 patient survived 9 months after IRE treatment. CONCLUSIONS: Pancreatic cancers were safely and effectively treated with image-guided IRE in our medium-sized center.

Prognosticating Outcome in Pancreatic Head Cancer With the use of a Machine Learning Algorithm.

Background: The purpose of this project is to identify prognostic features in resectable pancreatic head adenocarcinoma and use these features to develop a machine learning algorithm that prognosticates survival for patients pursuing pancreaticoduodenectomy. Methods: A retrospective cohort study of 93 patients who underwent a pancreaticoduodenectomy was performed. The patients were analyzed in 2 groups: Group 1 (n = 38) comprised of patients who survived < 2 years, and Group 2 (n = 55) comprised of patients who survived > 2 years. After comparing the two groups, 9 categorical features and 2 continuous features (11 total) were selected to be statistically significant (p < .05) in predicting outcome after surgery. These 11 features were used to train a machine learning algorithm that prognosticates survival. Results: The algorithm obtained 75% accuracy, 41.9% sensitivity, and 97.5% specificity in predicting whether survival is less than 2 years after surgery. Conclusion: A supervised machine learning algorithm that prognosticates survival can be a useful tool to personalize treatment plans for patients with pancreatic cancer.

Chemical Enhancement of Irreversible Electroporation: A Review and Future Suggestions.

Irreversible electroporation has raised great interest in the past decade as a means of destroying cancers in a way that does not involve heat. Irreversible electroporation is a novel ablation technology that uses short high-voltage electrical pulses to enhance the permeability of tumor cell membranes and generate irreversible nano-sized structural defects or pores, thus leading to cell death. Irreversible electroporation has many advantages over thermal therapies due to its nonthermal mechanism: (1) reduced risk of injury to surrounding organs and (2) no "heat-sink" effect due to nearby blood vessels. However, so far, it has been difficult for irreversible electroporation to completely ablate large tumors (eg, >3 cm in diameter). In order to overcome this problem, many preclinical and clinical studies have been performed to improve the efficacy of IRE in the treatment of large size of tumors through a chemical perspective. Due to the distribution of electric field, irreversible electroporation region, reversible electroporation region, and intact region can be found in the treatment of irreversible electroporation. Thus, 2 types of chemical enhancements of irreversible electroporation were discussed in the article, such as the reversible electroporation region enhanced and the irreversible electroporation region enhanced. Specifically, the state-of-the-art results regarding the following approaches that have the potential to be used in the enhancement of irreversible electroporation were systematically reviewed in the article, including (1) combination with cytotoxic drugs, (2) calcium electroporation, (3) modification of cell membrane, and (4) modification of the tumor cell microenvironment. In the end, we concluded with 4 issues that should be addressed in the future for improving irreversible electroporation further in a chemical way.

Steerable catheters for minimally invasive surgery: a review and future directions.

The steerable catheter refers to the catheter that is manipulated by a mechanism which may be driven by operators or by actuators. The steerable catheter for minimally invasive surgery has rapidly become a rich and diverse area of research. Many important achievements in design, application and analysis of the steerable catheter have been made in the past decade. This paper aims to provide an overview of the state of arts of steerable catheters. Steerable catheters are classified into four main groups based on the actuation principle: (1) tendon driven catheters, (2) magnetic navigation catheters, (3) soft material driven catheters (shape memory effect catheters, steerable needles, concentric tubes, conducting polymer driven catheters and hydraulic pressure driven catheters), and (4) hybrid actuation catheters. The advantages and limitations of each of them are commented and discussed in this paper. The future directions of research are summarized.

The role of anti-non-Gal antibodies in the development of acute humoral xenograft rejection of hDAF transgenic porcine kidneys in baboons receiving anti-Gal antibody neutralization therapy.

BACKGROUND: The present study was undertaken to determine the role of preformed and induced anti-non-Gal antibodies in the rejection of hDAF pig-to-baboon kidney xenotransplants after anti-Gal antibody neutralization therapy. METHODS: Seven baboons received life-supporting kidney transplants from hDAF transgenic pigs. Anti-Gal antibodies were neutralized by GAS914 or TPC (a Gal PEG glycoconjugate polymer). Group 1 (n=5) underwent a conventional immunosuppressive therapy with FK506, rabbit anti-thymocyte serum/immunoglobulin, mycophenolate mofetil, and steroids. Group 2 (n=2) received an anti-humoral immunity regimen with LF15-0195, Rituxan and cobra venom factor in addition to ATG, FK506 and steroids. Levels of anti-non-Gal antibodies and their mediated complement-dependent cytotoxic activities (CDC) were detected by flow cytometry using Gal knockout (k/o) pig lymphocytes (LC) or endothelial cells (EC) as targets. RESULTS: Continuous infusion of GAS914/TPC significantly reduced anti-Gal antibodies. In Group 1, four of five baboons developed severe acute humoral xenograft rejection (AHXR) and the rejection was associated with either a high level of preformed anti-non-Gal IgG or a marked elevation in induced anti-non-Gal IgG and IgM. Sera collected at the time of AHXR had a high level of CDC to porcine LC/EC from Gal k/o animals. The intensive anti-humoral therapy in Group 2 completely inhibited both anti-Gal and non-Gal antibody production and prevented AHXR. However, this therapy was not well tolerated by the baboons. CONCLUSION: In a pig-to-baboon kidney transplant model, both preformed and induced anti-non-Gal antibodies are strongly associated with the pathogenesis of AHXR when anti-Gal antibodies are neutralized.

A review of radiofrequency ablation: Large target tissue necrosis and mathematical modelling.

Radiofrequency ablation (RFA) is an effective clinical method for tumour ablation with minimum intrusiveness. However, the use of RFA is mostly restricted to small tumours, especially those <3cm in diameter. This paper discusses the state-of-the-art of RFA, drawn from experimental and clinical results, for large tumours (i.e. ⩾3cm in diameter). In particular, the paper analyses clinical results related to target tissue necrosis (TTN) and mathematical modelling of the RFA procedure to understand the mechanism whereby the TTN is limited to under 3cm with RFA. This paper also discusses a strategy of controlling of the temperature of target tissue in the RFA procedure with the state-of-art device, which has the potential to increase the size of TTN. This paper ends with a discussion of some future ideas to solve the so-called 3-cm problem with RFA.

Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases.

BACKGROUND: Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion. METHODS: Human kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD). RESULTS: Markers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers. CONCLUSIONS: Based on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.

Monotherapy with LF 15-0195, an analogue of 15-deoxyspergualin, significantly prolongs renal allograft survival in monkeys.

BACKGROUND: LF 15-0195 is a novel, more potent, and less toxic analogue of 15-deoxyspergualin, an antibiotic used as an immunosuppressive agent to prevent rejection of organ transplants. This study was undertaken to determine whether LF 15-0195 monotherapy would prevent renal allograft rejection in a nonhuman primate model. METHODS: In the study groups, recipients received LF 15-0195 monotherapy at doses of 0.065 mg/kg per day (group 2, n=4), 0.13 mg/kg per day (group 3, n=4), or 0.2 mg/kg per day (group 4, n=4), administered subcutaneously, on postoperative days 0 to 14. RESULTS: Group 1 consisted of untreated control recipients, all of which developed advanced graft rejection after surviving for an average of 6.5+/-0.6 days. LF 15-0195 treatment significantly prolonged graft survival in groups 2, 3, and 4, to 20+/-20 days, 49+/-5 days, and 39+/-4 days, respectively. Animals in groups 3 and 4 demonstrated no evidence of rejection during LF 15-0195 treatments. The animals maintained stable renal function for 2 weeks after LF 15-0195 withdrawal but gradually developed rejection at 5 to 6 weeks. Pathologic studies demonstrated that vascular graft rejection was attenuated in LF 15-0195-treated allografts, compared with control specimens. These groups also demonstrated transient reductions in lymphocyte counts during treatment, which returned to normal levels 2 weeks after LF 15-0195 withdrawal. Total serum concentrations of IgM and IgG decreased by a mean of 20.4% and a mean of 31.4%, respectively, at the end of LF 15-0195 treatment (postoperative day 14). LF 15-0195 did not significantly alter thrombocyte counts or hemoglobin levels. Necropsy studies showed no evidence of drug toxicity in the heart, liver, spleen, intestines, stomach, or colon. CONCLUSIONS: LF 15-0195 monotherapy significantly prolonged renal allograft survival in monkeys. These encouraging data suggest that this novel agent may be of future value in clinical transplantation.

Improvement in human decay accelerating factor transgenic porcine kidney xenograft rejection with intravenous administration of gas914, a polymeric form of alphaGAL.

BACKGROUND: The present study was undertaken to determine whether intravenous administration of GAS914, a polymeric form of alphaGal, would minimize porcine kidney xenograft rejection in baboons. Human decay accelerating factor renal xenografts were transplanted into 16 baboon recipients. METHODS: Baseline immunosuppression for all groups included cyclosporine A, cyclophosphamide, SDZ-RAD, and methylprednisolone. Group 1 received only baseline immunosuppression; group 2 animals received low-dose GAS914 with baseline immunosuppression; group 3 animals received high dose GAS914 with high-dose baseline immunosuppression; and animals from group 4 received high-dose GAS914 and low-dose baseline immunosuppression. RESULTS: None of the animals in this study developed hyperacute rejection. Intravenous administration of GAS914 significantly reduced xenoreactive antibodies as measured by antiporcine hemolytic assays and anti-Gal (immunoglobulin [Ig] G and IgM) antibody assays. Rejection was less severe in the GAS914-treated group. Only 25% (3 of 12) of GAS914-treated animals were killed as a result of rejection, whereas 75% (three of four) of non-GAS914-treated animals were killed because of terminal rejection (P<0.01). Protocol biopsies demonstrated that the degree of acute humoral xenograft rejection (AHXR) was reduced in the GAS914-treated animals compared with non-GAS914-treated animals. CONCLUSION: The intravenous administration of GAS914 reduces xenoreactive antibody levels and reduces the degree of porcine kidney xenograft rejection, but does not improve survival. AHXR and drug toxicity remain major barriers to the long-term success of xenotransplantation.

Improvement in rejection of human decay accelerating factor transgenic pig-to-primate renal xenografts with administration of rabbit antithymocyte serum.

BACKGROUND: Survival in pig-to-baboon kidney xenotransplantation is currently limited by acute humoral xenograft rejection (AHXR). We hypothesized that the administration of rabbit antithymocyte serum (RATS) would delay or prevent AHXR as compared with a cyclophosphamide (CyP)-based immunosuppressive regimen. METHODS: Nine baboons received life-supporting heterotopic single-kidney transplants from human decay accelerating factor transgenic pigs. Immunosuppression consisted of GAS (a galactosyl alpha-1,3-galactose analog), cyclosporine, and steroids. Group 1 (n=2) was also treated with CyP and a rapamycin derivative (RAD), group 2 (n=4) received RATS and RAD, and group 3 (n=3) received only RATS. Animals were maintained until death or sacrifice because of uncontrollable rejection or other complications. Graft histopathology was assessed at the study endpoint. RESULTS: Mean survival was 28+/-11.3 days, 23+/-2.5 days, and 20+/-2.5 days for groups 1, 2, and 3 (not significant). Graft rejection was the cause of death in both CyP-treated animals. One RATS-treated animal died of rejection; the others died of infections or bleeding. Two RATS-treated animals developed posttransplant lymphoproliferative disorder, and one died of cytomegalovirus pneumonitis. Histopathology revealed severe AHXR in group 1 kidneys, involving 100+/-0% of the tissue examined. In contrast, AHXR was reduced in groups 2 and 3, involving 21+/-14% and 18+/-28%, respectively, of the tissue examined (P<0.01). CONCLUSIONS: Substitution of RATS for CyP was well tolerated and resulted in reduced severity of AHXR in this model. Complications seen in RATS-treated animals may be preventable through the use of standard prophylaxis for infections. Our data suggest that further studies are warranted to explore the use of antilymphocyte agents in xenotransplantation.

Evaluation of the current radiofrequency ablation systems using axiomatic design theory.

This article evaluates current radiofrequency ablation systems using axiomatic design theory. Due to its minimally invasive procedure, short-time hospital stay, low cost, and tumour metastasis treatment, the radiofrequency ablation technique has been playing an important role in tumour treatment in recent decades. Although the radiofrequency ablation technique has many advantages, some issues still need to be addressed. Among these issues, the two most important are as follows: (1) the size of tumours to be removed (has to be larger than 3 cm in diameter) and (2) cleanness of the removal. Many device solutions have been proposed to address the two issues. However, there is a lack of knowledge regarding the systematic evaluation of these solutions. This article evaluates these systems in terms of their solution principles (or simply called conceptual design in general product design theory) using a design theory called axiomatic design theory. In addition, with the axiomatic design theory, a better conceptual design in terms of its feasibility to cope with incomplete target tissue necrosis from the large size of tumours has been found. The detailed analysis and simulation of the new conceptual design are conducted using finite element approach. The results in this article are proved by the information of animal experiments and clinical practices obtained from the literature. This study thus contributes to the current knowledge to further developments in radiofrequency ablation systems and procedure guidelines for physicians to perform the radiofrequency ablation operation more effectively.