[Establishment of a nude mouse model of highly metastatic gastric lymphoma constructed with orthotopic transplantation of surgical specimen].

PubMed

Yang, Bo; Tuo, Shuai; Tuo, Chao-wei; Zhang, Ning; Liu, Qiu-zhen

2010-06-01

To construct a mouse model of highly metastatic gastric lymphoma with orthotopic transplantation of human primary gastric lymphoma specimen. A fresh surgical specimen of primary gastric lymphoma was obtained intraoperatively and implanted into the submucosa of stomach in nude mice. Tumor formation, invasion, metastasis, morphological characteristics under light microscopy and electron microscopy, immunohistochemistry,and the karyotype of orthotopically transplanted tumor cells were studied. An orthotopic highly metastatic model of human primary gastric lymphoma in nude mice(HGBL-0305) was successfully established. Histopathology of transplanted tumors showed primary gastric diffuse large B cell lymphoma. CD19, CD20, CD22 and CD79alpha were positive, while CD3 and CD7 were negative. The number of chromosome ranged from 56 to 69. DNA index(DI) was 1.47+/-0.12(i.e. heteroploid). Until now, HGBL-0305 model has been maintained for 45 generations by orthotopic passage for almost 4 years in nude mice. A total of 156 nude mice were used for transplantation. The growth rate and resuscitation rate of liquid nitrogen cryopreservation of transplanted tumor cells were both 100%. The autonomic growth of the transplanted tumor cells invaded and destructed all the layers of the nude mice stomach. The metastasis rates of liver, spleen, lymph node, and peritoneal seeding were 69.5%, 55.6%, 45.7%, and 30.5%, respectively. An orthotopic highly metastatic model of human primary gastric lymphoma in nude mice is successfully established. HGBL-0305 model may simulate the natural course of primary gastric lymphoma in human and provides an ideal animal model for studies on pathogenesis, metastasis biology and anti-metastatic therapies of primary gastric lymphoma.

Sodium-reduced continuous venovenous hemodiafiltration (CVVHDF) for the prevention of central pontine myelinolysis (CPM) in hyponatremic patients scheduled for orthotopic liver transplantation.

PubMed

Lenk, Marcus R; Kaspar, Michael

2012-08-01

Two patients in end-stage hepatic failure presented for orthotopic liver transplantation with longstanding severe hyponatremia (121 and 122 mmol/L). Both patients underwent liver transplantation with the concomitant use of continuous venovenous hemodiafiltration. Replacement and dialysate solutions were prepared individually to contain a sodium level that was individually considered safe with regard to the development of central pontine myelinolysis. The sodium increase in both patients was within the expected and planned limits despite a situation of mass transfusion. Both patients did well postoperatively and neither patient suffered neurological deficits. Copyright © 2012 Elsevier Inc. All rights reserved.

Successful cardiac transplantation outcomes in patients with adult congenital heart disease.

PubMed

Menachem, Jonathan N; Golbus, Jessica R; Molina, Maria; Mazurek, Jeremy A; Hornsby, Nicole; Atluri, Pavan; Fuller, Stephanie; Birati, Edo Y; Kim, Yuli Y; Goldberg, Lee R; Wald, Joyce W

2017-09-01

The purpose of our study is (1) to characterise patients with congenital heart disease undergoing heart transplantation by adult cardiac surgeons in a large academic medical centre and (2) to describe successful outcomes associated with our multidisciplinary approach to the evaluation and treatment of adults with congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT). Heart failure is the leading cause of death in patients with ACHD leading to increasing referrals for OHT. The Penn Congenital Transplant Database comprises a cohort of patients with ACHD who underwent OHT between March 2010 and April 2016. We performed a retrospective cohort study of the 20 consecutive patients. Original cardiac diagnoses include single ventricle palliated with Fontan (n=8), dextro-transposition of the great arteries after atrial switch (n=4), tetralogy of Fallot (n=4), pulmonary atresia (n=1), Ebstein anomaly (n=1), unrepaired ventricular septal defect (n=1) and Noonan syndrome with coarctation of the aorta (n=1). Eight patients required pretransplant inotropes and two required pretransplant mechanical support. Nine patients underwent heart-liver transplant and three underwent heart-lung transplant. Three patients required postoperative mechanical circulatory support. Patients were followed for an average of 38 months as of April 2016, with 100% survival at 30 days and 1 year and 94% overall survival (19/20 patients). ACHD-OHT patients require highly specialised, complex and multidisciplinary healthcare. The success of our programme is attributed to using team-based, patient-centred care including our multidisciplinary staff and specialists across programmes and departments. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Astigmatism after keratoplasty: influence of orthotopic transplantation].

PubMed

Feuerstacke, J; Hellwinkel, O; Naydis, I; Linke, S; Klemm, M

2014-09-01

Patients undergoing corneal transplantation often suffer from postoperative reduced vision due to high astigmatism. This retrospective study analyzed the influence of heterotopic or orthotopic transplantation on astigmatism and visual outcome. In this study 373 eyes of 334 patients were analyzed. Group 1 (OT) contained 186 eyes, which underwent orthotopic transplantation (side of recipient and donor corresponded), whereas group 2 (HT) included 187 heterotopic keratoplasties (donor cornea placed in the recipient's contralateral side). After 1, 3, 6, 12 and 24 months the median of keratometric astigmatism, objective astigmatism, topographic astigmatism and best corrected visual acuity (BCVA) were assessed and compared between groups. The long-term results showed no statistically significant differences regarding keratometric and objective astigmatism, whereas topographic astigmatism differed significantly (p = 0.04) after 3 months. We observed a lower astigmatism of 5.7 dpt (range 3.08-7.78 dpt) in group OT than in the group HT with 7.1 dpt (range 3.9-10.7 dpt). No differences were found at the other time points. The BCVA showed a significantly better effect after 1 month (p = 0.01) in the OT group of 0.2 (0.1-0.3) than in HT group of 0.1 (0.05/0.25). In the postoperative course no additional significant dissimilarities were documented. Heterotopic and orthotopic keratoplasty show no significant long-term differences in astigmatism and visual outcom.

Ultrastructural basis for the efficiency of an ileal orthotopic neobladder 27 years after surgery.

PubMed

Orlandini, G; Guizzardi, S; Ferretti, S; Simonazzi, M; Bucci, G; Gatti, R

2002-01-01

The morphological and functional basis of the excellent clinical outcome of ileal orthotopic neobladders are largely unknown. Only long-term follow-up studies will provide an adequate answer to this unsettled question. We have studied a patient who underwent this type of surgery over 27 years ago. Besides an important secretive adaptation we have found, at the ultrastructural level, that the monolayered epithelium does not show signs of true metaplasia and that changes had occurred in the intercellular junctions, namely that desmosomes are significantly increased. Although limited to a single case, these features, if confirmed by further observations, suggest a working hypothesis for the understanding of the definitive phenotypic adaptation of the ileal epithelium to the new aggressive environment. Copyright 2002 S. Karger AG, Basel

Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning.

PubMed

Faybik, Peter; Hetz, Hubert; Baker, Amir; Bittermann, Clemens; Berlakovich, Gabriela; Werba, Alois; Krenn, Claus-Georg; Steltzer, Heinz

2003-01-01

Ingestion of Amanita phalloides is the most common cause of lethal mushroom poisoning. The relative late onset of symptoms is a distinct diagnostic feature of Amanita intoxication and also the main reason of failure for extracorporeal removal of Amanita-specific toxins from the gut and circulation. Extracorporeal albumin dialysis (ECAD) has been used on six consecutive patients admitted after A. phalloides poisoning with acute liver failure (ALF). Six patients, with mean age of 46 years (range: 9-70 years), underwent one to three ECAD treatments. The mean time from mushroom ingestion until the first ECAD treatment was 76 h. Two patients regenerated spontaneously under ECAD treatment and orthotopic liver transplantation (OLT) could be avoided. Two patients were successfully bridged to OLT and one patient died because of cerebral herniation. One patient was treated with ECAD immediately after OLT because of the graft dysfunction and survived without re-transplantation. ECAD appeared to be a successful treatment perspective in supporting liver regeneration or in sufficient bridging to OLT and also in treatment of graft dysfunction after OLT in patients with A. phalloides poisoning.

[Cardiac transplantation and neoplasms: experiences at Escola Paulista de Medicina of the Federal University of São Paulo].

PubMed

Mello Junior, Walter Teixeira de; Branco, João Nelson R; Catani, Roberto; Aguiar, Luciano de Figueiredo; Paez, Rodrigo Pereira; Buffolo, Enio

2006-02-01

To study the occurrence and types of neoplasms developed by patients who underwent an orthotopic cardiac transplantation under the Program of Cardiac Transplantation of Escola Paulista de Medicina, Federal University of São Paulo. This is an observational study of 106 patients who underwent orthotopic cardiac transplantation from November 1986 to September 2002 and survived at least thirty days following the procedure. The triple immunosuppressive regimen given included cyclosporin A, azathioprine and a corticosteroid agent. Only two patients received OKT3 in addition to the regimen established. Mean follow-up was 61.4 months (ranging from two months to 192 months). Twenty-three patients (21.3%) developed neoplasms--56.5% of these were skin neoplasm, 30.1%, solid tumors, and 13.4% of post-transplant lymphoproliferative disease (PTLD). Mean interval between transplantation and diagnosis of neoplasm was: 54.9 months for skin neoplasm; 24.8 months for solid tumors and 70.3 months for PTLD. Malignant neoplasms are relatively common in the population studied. Skin cancer was the most common type compared to the other types of neoplasms. Solid tumors were more frequently diagnosed than the lymphoproliferative diseases in the population examined.

Liver transplantation for lethal genetic syndromes: a novel model of personalized genomic medicine.

PubMed

Petrowsky, Henrik; Brunicardi, F Charles; Leow, Voon Meng; Venick, Robert S; Agopian, Vatche; Kaldas, Fady M; Zarrinpar, Ali; Markovic, Daniela; McDiarmid, Sue V; Hong, Johnny C; Farmer, Douglas G; Hiatt, Jonathan R; Busuttil, Ronald W

2013-04-01

Our aim was to analyze our single-center experience with orthotopic liver transplantation for metabolic lethal genetic syndromes in children and adults. From 1984 to 2012, all pediatric (younger than 18 years) and adult (18 years and older) patients who underwent orthotopic liver transplantation for lethal genetic disorders were identified. Data on diagnostic pathways and specific outcomes were analyzed for both groups. Outcomes measures included recurrence rate as well as graft and patient survival. Metabolic lethal genetic syndrome was the primary indication for orthotopic liver transplantation in 152 of 4,564 patients (3.3%) at University of California, Los Angeles during the study period (74 pediatric patients and 78 adults). Genetic testing was performed in only 12% of the 152 patients and in 39% of patients after 2006. Two patients (1.3%) experienced a recurrence of the genetic disease. Overall 5- and 20-year survival rates were 89% and 77% for children and 73% and 50% for adults. Survival of pediatric patients was superior to adults (log-rank p < 0.009). Multivariate analysis identified age (hazard ratio = 2.18), preoperative life support (hazard ratio = 2.68), and earlier transplantation (hazard ratio = 3.41) as independent predictors of reduced survival. Orthotopic liver transplantation achieved excellent long-term survival in pediatric and adult patients with lethal genetic syndromes and represents a model of personalized genomic medicine by providing gene therapy through solid organ transplantation. Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Bombesin functionalized 64Cu-copper sulfide nanoparticles for targeted imaging of orthotopic prostate cancer.

PubMed

Cai, Huawei; Xie, Fang; Mulgaonkar, Aditi; Chen, Lihong; Sun, Xiankai; Hsieh, Jer-Tsong; Peng, Fangyu; Tian, Rong; Li, Lin; Wu, Changqiang; Ai, Hua

2018-05-22

To synthesize and evaluate the imaging potential of Bom-PEG-[ 64 Cu]CuS nanoparticles (NPs) in orothotopic prostate tumor. [ 64 Cu]CuS NPs were synthesized in aqueous solution by 64 CuCl 2 and Na 2 S reaction. Then PEG linker with or without bombesin peptide were conjugated to the surface of [ 64 Cu]CuS NPs to produce Bom-PEG-[ 64 Cu]CuS and PEG-[ 64 Cu]CuS NPs. These two kinds of NPs were used for testing specific uptake in prostate cancer cells in vitro and imaging of orthotopic prostate tumor in vivo. Bom-PEG-[ 64 Cu]CuS and PEG-[ 64 Cu]CuS NPs were successfully synthesized with core diameter of approximately 5 nm. Radioactive cellular uptake revealed that Bom-PEG-[ 64 Cu]CuS was able to specifically bind to prostate cancer cells, and the microPET-CT imaging indicated clear visualization of orthotopic prostate tumors. Radiolabeled Bom-PEG-[ 64 Cu]CuS NPs have potential as an ideal agent for orthotopic prostate tumor imaging by microPET-CT.

Postoperative effects of intraoperative hyperglycemia in liver transplant patients.

PubMed

Kömürcü, Özgür; Camkıran Fırat, Aynur; Kaplan, Şerife; Torgay, Adnan; Pirat, Arash; Haberal, Mehmet; Arslan, Gülnaz

2015-04-01

The aim of this study was to determine the effects of intraoperative hyperglycemia on postoperative outcomes in orthotopic liver transplant recipients. After ethics committee approval was obtained, we retrospectively analyzed the records of patients who underwent orthotopic liver transplant from January 2000 to December 2013. A total 389 orthotopic liver transplants were performed in our center, but patients aged < 15 years (179 patients) were not included in the analyses. Patients were divided into 2 groups based on their maximum intraoperative blood glucose level: group 1 (patients with intraoperative blood glucose level < 200 mg/dL) and group 2 (patients with intraoperative blood glucose level > 200 mg/dL). Postoperative complications between the 2 groups were compared. There were 58 patients (37.6%; group 1, blood glucose < 200 mg/dL) who had controlled blood glucose and 96 patients (62.3%; group 2, blood glucose > 200 mg/dL) who had uncontrolled blood glucose. The mean age and weight for groups 1 and 2 were similar. There were no differences between the 2 groups regarding the duration of anhepatic phase (P = .20), operation time (P = .41), frequency of immediate intraoperative extubation (P = .14), and postoperative duration of mechanical ventilation (P = .06). There were no significant differences in frequency of patients who had postoperative infectious complications, acute kidney injury, or need for hemodialysis. Mortality rates after liver transplant were similar between the 2 groups (P = .81). Intraoperative hyperglycemia during orthotopic liver transplant was not associated with an increased risk of postoperative infection, acute renal failure, or mortality.

Characterization of thyroid cancer cell lines in murine orthotopic and intracardiac metastasis models.

PubMed

Morrison, Jennifer A; Pike, Laura A; Lund, Greg; Zhou, Qiong; Kessler, Brittelle E; Bauerle, Kevin T; Sams, Sharon B; Haugen, Bryan R; Schweppe, Rebecca E

2015-06-01

Thyroid cancer incidence has been increasing over time, and it is estimated that ∼1950 advanced thyroid cancer patients will die of their disease in 2015. To combat this disease, an enhanced understanding of thyroid cancer development and progression as well as the development of efficacious, targeted therapies are needed. In vitro and in vivo studies utilizing thyroid cancer cell lines and animal models are critically important to these research efforts. In this report, we detail our studies with a panel of authenticated human anaplastic and papillary thyroid cancer (ATC and PTC) cell lines engineered to express firefly luciferase in two in vivo murine cancer models-an orthotopic thyroid cancer model as well as an intracardiac injection metastasis model. In these models, primary tumor growth in the orthotopic model and the establishment and growth of metastases in the intracardiac injection model are followed in vivo using an IVIS imaging system. In the orthotopic model, the ATC cell lines 8505C and T238 and the PTC cell lines K1/GLAG-66 and BCPAP had take rates >90 % with final tumor volumes ranging 84-214 mm(3) over 4-5 weeks. In the intracardiac model, metastasis establishment was successful in the ATC cell lines HTh74, HTh7, 8505C, THJ-16T, and Cal62 with take rates ≥70 %. Only one of the PTC cell lines tested (BCPAP) was successful in the intracardiac model with a take rate of 30 %. These data will be beneficial to inform the choice of cell line and model system for the design of future thyroid cancer studies.

Safe and successful endoscopic initial treatment and long-term eradication of gastric varices by endoscopic ultrasound-guided Histoacryl (N-butyl-2-cyanoacrylate) injection.

PubMed

Gubler, Christoph; Bauerfeind, Peter

2014-09-01

Optimal endoscopic treatment of gastric varices is still not standardized nowadays. Actively bleeding varices may prohibit a successful endoscopic injection therapy of Histoacryl® (N-butyl-2-cyanoacrylate). Since 2006, we have treated gastric varices by standardized endoscopic ultrasound (EUS) guided Histoacryl injection therapy without severe adverse events. We present a large single-center cohort over 7 years with a standardized EUS-guided sclerotherapy of all patients with gastric varices. Application was controlled by fluoroscopy to immediately detect any glue embolization. Only perforating veins located within the gastric wall were treated. In the follow up, we repeated this treatment until varices were eradicated. Utmost patients (36 of 40) were treated during or within 24 h of active bleeding. About 32.5% of patients were treated while visible bleeding. Histoacryl injection was always technically successful and only two patients suffered a minor complication. Acute bleeding was stopped in all patients. About 15% (6 of 40) of patients needed an alternative rescue treatment in the longer course. Three patients got a transjugular portosystemic shunt and another three underwent an orthotopic liver transplantation. Mean long-term survival of 60 months was excellent. Active bleeding of gastric varices can be treated successfully without the necessity of gastric rinsing with EUS-guided injection of Histoacryl.

Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT.

PubMed

Liu, Xiang; Liu, Jun; Guan, Yubao; Li, Huiling; Huang, Liyan; Tang, Hailing; He, Jianxing

2012-04-01

To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. A549 cells (5×10(6) mL(-1)) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically.

Establishment of an orthotopic lung cancer model in nude mice and its evaluation by spiral CT

PubMed Central

Liu, Xiang; Liu, Jun; Guan, Yubao; Li, Huiling; Huang, Liyan; Tang, Hailing

2012-01-01

Objective To establish a simple and highly efficient orthotopic animal model of lung cancer cell line A549 and evaluate the growth pattern of intrathoracic tumors by spiral CT. Methods A549 cells (5×106 mL-1) were suspended and inoculated into the right lung of BALB/c nude mice via intrathoracic injection. Nude mice were scanned three times each week by spiral CT after inoculation of lung cancer cell line A549. The survival time and body weight of nude mice as well as tumor invasion and metastasis were examined. Tissue was collected for subsequent histological assay after autopsia of mice. Results The tumor-forming rate of the orthotopic lung cancer model was 90%. The median survival time was 30.7 (range, 20-41) days. The incidence of tumor metastasis was 100%. The mean tumor diameter and the average CT value gradually increased in a time-dependent manner. Conclusions The method of establishing the orthotopic lung cancer model through transplanting A549 cells into the lung of nude mice is simple and highly successful. Spiral CT can be used to evaluate intrathoracic tumor growth in nude mice vividly and dynamically. PMID:22833819

Incidence, risk factors and ERCP outcome for biliary complications after cadaveric OLT.

PubMed

Martins, Fernanda Prata; De Paulo, Gustavo Andrade; Conceição, Raquel Dilgerian; Zurstrassen, Maria Paula; Thomé, Tadeu; Ferraz-Neto, Ben-Hur; Ferrari, Angelo Paulo

2011-01-01

Biliary complications (BC) occur in up to 39.5% of patients after orthotopic liver transplantation (OLT), being an important source of post-transplant morbidity. The aim is to evaluate the incidence of BC after OLT, associated risk factors and outcome after endoscopic treatment. A retrospective case series between June 2005 and December 2008, including 195 patients that underwent 216 OLT from deceased donors. Thirty-one patients (14.3%) presented at least 1 BC, anastomotic stricture being the most frequent (83.8%). Non-anastomotic stricture was present in 1 (3.2%) and anastomotic fistula in 1. One patient presented anastomotic disconnection at ERCP. BC occurred 94.6 (7-487) days after OLT. Twenty-seven patients underwent endoscopic treatment, on average 2.6 ERCPs were performed per patient. Global endoscopic treatment success rate was 77.3%; being 73.7% for stenosis and 100% (3/3) for anastomotic fistula with stenosis. Recurrence of biliary stricture was observed in 3 patients, all referred to endoscopic re-treatment. ERCP complications: 2 (2.8%) stent migrations, 1 (1.4%) early stent occlusion, 1 (1.4%) respiratory distress and 1(1.4%) severe acute pancreatitis and death. There was no correlation between studied risk factors and BC's occurrence. ERCP was effective for the treatment of BC after OLT. Studied risk factors had no correlation with BC.

Use of the Viatorr Expanded Polytetrafluoroethylene-Covered Stent-Graft for Transjugular Intrahepatic Portosystemic Shunt Creation in Children: Initial Clinical Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mermuys, Koen; Maleux, Geert, E-mail: geert.maleux@uzleuven.be; Heye, Sam

2008-07-15

Four children, three boys and one girl, with a median age of 9 years 8 months, underwent transjugular intrahepatic portosystemic shunt creation with an expanded polytetrafluoroethylene (e-PTFE)-covered nitinol stent. The stent-graft was successfully placed in all four patients without any complication. Clinical and biochemical improvement was noted in all four patients during follow-up. Radiological follow-up with use of duplex ultrasound showed a recurrent stenosis of the shunt 180 days after stent-graft implantation in one patient. This was treated with placement of an additional stent-graft, re-expanding completely the recurrent stenosis. In the other three patients, the stent-graft remained fully patent untilmore » the end of the study or until orthotopic liver transplantation. These preliminary results suggest that use of the Viatorr ePTFE-covered stent-graft in children is safe and feasible, with potentially the same high patency rate and improved clinical outcome as reported in adult patients.« less

Percutaneous Transluminal Angioplasty of Hepatic Artery Stenosis in Patients After Orthotopic Liver Transplantation: Mid-term Results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarmila, Lastovickova, E-mail: jala@ikem.cz; Jan, Peregrin

2011-12-15

Purpose: This study was designed to present our experience with percutaneous treatment of hepatic artery stenosis in orthotopic liver transplant patients and to evaluate the efficacy, technical outcomes, and mid-term clinical results of the procedure. Methods: Twenty-two percutaneous transluminal angioplasties (PTAs) were performed in 19 liver transplant recipients at our institution between 1998 and 2010. Stents were placed into the hepatic/celiac artery in 16 PTAs, but balloon dilatation alone was performed in 6 because of the anatomical condition of the vessel. PTA/stenting was indicated in 17 patients because of elevated liver enzymes; 2 patients were asymptomatic. The objective of treatingmore » stenosis was prevention of long-term complications, including thrombosis. Results: Technical success was achieved in all patients. There was only one complication: dissection of the treated artery without any subsequent adverse effects. In all patients, elevated liver enzyme levels improved after treatment. No restenosis was observed in any patient during a mean follow-up of 2.6 years (1 month to 5.5 years). Conclusions: Percutaneous angioplasty/stent placement is a safe method for the treatment of hepatic artery stenosis after orthotopic liver transplantation, with a high technical success rate and promising mid-term results.« less

Postoperative Pleural Effusions After Orthotopic Heart Transplant: Cause, Clinical Manifestations, and Course.

PubMed

Ulubay, Gaye; Küpeli, Elif; Er Dedekargınoğlu, Balam; Savaş Bozbaş, Şerife; Alekberov, Mahal; Salman Sever, Özlem; Sezgin, Atilla

2016-11-01

Postoperative pleural effusions are common in patients who undergo cardiac surgery and orthotopic heart transplant. Postoperative pleural effusions may also occur as postcardiac injury syndrome. Most of these effusions are nonspecific and develop as a harmless complication of the surgical procedure itself and generally have a benign course. Here, we investigated the cause and clinical and laboratory features of postoperative early and late pleural effusions in orthotopic heart transplant patients. We retrospectively reviewed the medical records of 50 patients who underwent orthotopic heart transplant between 2004 and 2015 at Baskent University. Patient demographics and clinical and laboratory data, including cause of heart failure, presence of pleural effusions at chest radiography in the first year after transplant, timing of onset, microbiologic and biochemical analyses of pleural effusions, and treatment strategies were noted. Mean age of patients was 39.22 ± 13.83 years (39 men, 11 women). Reason for heart failure was dilated cardiomyopathy in most patients (76%). Nineteen patients (38%) had postoperative pleural effusions, with 15 patients (78.9%) with pleural effusion during the first week after transplant. Of these, 4 patients had recurrent pleural effusion. A diagnostic thoracentesis was performed in 10 patients, with 4 showing transudative effusion and 6 showing exudative effusion secondary to infection (2 patients), postcardiac injury syndrome (1 patient), and hemothorax (3 patients). Aspergillus fumigatus was detected by quantitative culture from pleural effusion in 1 patient. Tube thoracoscopy drainage was performed in 10 patients (25%), and 2 patients received antibiotic therapy. Pleural effusions are frequent after cardiac transplant. Complications may occur in a small portion of patients, with most effusions being nonspecific and having a benign course with spontaneous resolution. Early diagnostic thoracentesis could improve postoperative outcomes in these patients.

Liver transplantation: history, outcomes and perspectives

PubMed Central

Meirelles, Roberto Ferreira; Salvalaggio, Paolo; de Rezende, Marcelo Bruno; Evangelista, Andréia Silva; Guardia, Bianca Della; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Pedroso, Pamella Tung; Rocco, Rodrigo Andrey; Meira, Sérgio Paiva

2015-01-01

In 1958 Francis Moore described the orthotopic liver transplantation technique in dogs. In 1963, Starzl et al. performed the first liver transplantation. In the first five liver transplantations no patient survived more than 23 days. In 1967, stimulated by Calne who used antilymphocytic serum, Starzl began a successful series of liver transplantation. Until 1977, 200 liver transplantations were performed in the world. In that period, technical problems were overcome. Roy Calne, in 1979, used the first time cyclosporine in two patients who had undergone liver transplantation. In 1989, Starzl et al. reported a series of 1,179 consecutives patients who underwent liver transplantation and reported a survival rate between one and five years of 73% and 64%, respectively. Finally, in 1990, Starzl et al. reported successful use of tacrolimus in patents undergoing liver transplantation and who had rejection despite receiving conventional immunosuppressive treatment. Liver Transplantation Program was initiated at Hospital Israelita Albert Einstein in 1990 and so far over 1,400 transplants have been done. In 2013, 102 deceased donors liver transplantations were performed. The main indications for transplantation were hepatocellular carcinoma (38%), hepatitis C virus (33.3%) and alcohol liver cirrhosis (19.6%). Of these, 36% of patients who underwent transplantation showed biological MELD score > 30. Patient and graft survival in the first year was, 82.4% and 74.8%, respectively. A major challenge in liver transplantation field is the insufficient number of donors compared with the growing demand of transplant candidates. Thus, we emphasize that appropriated donor/receptor selection, allocation and organ preservation topics should contribute to improve the number and outcomes in liver transplantation. PMID:25993082

Evolving experience with prevention and treatment of splenic artery syndrome after orthotopic liver transplantation.

PubMed

Mogl, Martina T; Nüssler, Natascha C; Presser, Sabine J; Podrabsky, Petr; Denecke, Timm; Grieser, Christian; Neuhaus, Peter; Guckelberger, Olaf

2010-08-01

Impaired hepatic arterial perfusion after orthotopic liver transplantation (OLT) may lead to ischemic biliary tract lesions and graft-loss. Hampered hepatic arterial blood flow is observed in patients with hypersplenism, often described as arterial steal syndrome (ASS). However, arterial and portal perfusions are directly linked via the hepatic arterial buffer response (HABR). Recently, the term 'splenic artery syndrome' (SAS) was coined to describe the effect of portal hyperperfusion leading to diminished hepatic arterial blood flow. We retrospectively analyzed 650 transplantations in 585 patients. According to preoperative imaging, 78 patients underwent prophylactic intraoperative ligation of the splenic artery. In case of postoperative SAS, coil-embolization of the splenic artery was performed. After exclusion of 14 2nd and 3rd retransplantations and 83 procedures with arterial interposition grafts, SAS was diagnosed in 28 of 553 transplantations (5.1%). Twenty-six patients were treated with coil-embolization, leading to improved liver function, but requiring postinterventional splenectomy in two patients. Additionally, two patients with SAS underwent splenectomy or retransplantation without preceding embolization. Prophylactic ligation could not prevent SAS entirely (n = 2), but resulted in a significantly lower rate of complications than postoperative coil-embolization. We recommend prophylactic ligation of the splenic artery for patients at risk of developing SAS. Post-transplant coil-embolization of the splenic artery corrected hemodynamic changes of SAS, but was associated with a significant morbidity.

Ferret lung transplant: an orthotopic model of obliterative bronchiolitis.

PubMed

Sui, H; Olivier, A K; Klesney-Tait, J A; Brooks, L; Tyler, S R; Sun, X; Skopec, A; Kline, J; Sanchez, P G; Meyerholz, D K; Zavazava, N; Iannettoni, M; Engelhardt, J F; Parekh, K R

2013-02-01

Obliterative bronchiolitis (OB) is the primary cause of late morbidity and mortality following lung transplantation. Current animal models do not reliably develop OB pathology. Given the similarities between ferret and human lung biology, we hypothesized an orthotopic ferret lung allograft would develop OB. Orthotopic left lower lobe transplants were successfully performed in 22 outbred domestic ferrets in the absence of immunosuppression (IS; n = 5) and presence of varying IS protocols (n = 17). CT scans were performed to evaluate the allografts. At intervals between 3-6 months the allografts were examined histologically for evidence of acute/chronic rejection. IS protects allografts from acute rejection and early graft loss. Reduction of IS dosage by 50% allowed development of controlled rejection. Allografts developed infiltrates on CT and classic histologic acute rejection and lymphocytic bronchiolitis. Cycling of IS, to induce repeated episodes of controlled rejection, promoted classic histologic hallmarks of OB including fibrosis-associated occlusion of the bronchiolar airways in all allografts of long-term survivors. In conclusion, we have developed an orthotopic lung transplant model in the ferret with documented long-term functional allograft survival. Allografts develop acute rejection and lymphocytic bronchiolitis, similar to humans. Long-term survivors develop histologic changes in the allografts that are hallmarks of OB. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

[A simple and efficient method for establishing a mouse model of orthotopic MB49 bladder cancer].

PubMed

Liang, Zhong-kun; Zhang, Lin; Hu, Zhi-ming; Chen, Zhong; Huang, Xin; Shi, Xiang-hua; Tan, Wan-long; Gao, Ji-min

2009-04-01

To establish a simple and efficient method for establishing a mouse model of orthotopic superficial bladder cancer. C57BL/6 mice were anesthetized with sodium pentobarbital and catheterized with modified IV catheter (24 G). The mice were intravesically pretreated with HCl and then with NaOH, and after washing the bladders with phosphate-buffered saline (PBS), 100 microl (1 x 10(7)) MB49 cells were infused and allowed to incubate in the bladder for 2 h followed intravesical mitomycin C (MMC) administration. The tumor formation rate, survival, gross hematuria, and bladder weight were determined as the outcome variables, and the pathology of the bladders was observed. Instillation of MB49 tumor cells resulted in a tumor formation rates of 100% in all the pretreated groups while 0% in the control group without pretreatment. MMC significantly reduced the bladder weight as compared to PBS. We have successfully established a stable, reproducible, and reliable orthotopic bladder cancer model in mice.

Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model.

PubMed

Metildi, Cristina A; Kaushal, Sharmeela; Luiken, George A; Talamini, Mark A; Hoffman, Robert M; Bouvet, Michael

2014-04-01

The aim of this study was to evaluate a new fluorescently labeled chimeric anti-CEA antibody for improved detection and resection of colon cancer. Frozen tumor and normal human tissue samples were stained with chimeric and mouse antibody-fluorophore conjugates for comparison. Mice with patient-derived orthotopic xenografts (PDOX) of colon cancer underwent fluorescence-guided surgery (FGS) or bright-light surgery (BLS) 24 hr after tail vein injection of fluorophore-conjugated chimeric anti-CEA antibody. Resection completeness was assessed using postoperative images. Mice were followed for 6 months for recurrence. The fluorophore conjugation efficiency (dye/mole ratio) improved from 3-4 to >5.5 with the chimeric CEA antibody compared to mouse anti-CEA antibody. CEA-expressing tumors labeled with chimeric CEA antibody provided a brighter fluorescence signal on frozen human tumor tissues (P = 0.046) and demonstrated consistently lower fluorescence signals in normal human tissues compared to mouse antibody. Chimeric CEA antibody accurately labeled PDOX colon cancer in nude mice, enabling improved detection of tumor margins for more effective FGS. The R0 resection rate increased from 86% to 96% with FGS compared to BLS. Improved conjugating efficiency and labeling with chimeric fluorophore-conjugated antibody resulted in better detection and resection of human colon cancer in an orthotopic mouse model. © 2013 Wiley Periodicals, Inc.

AS30D Model of Hepatocellular Carcinoma: Tumorigenicity and Preliminary Characterization by Imaging, Histopathology, and Immunohistochemistry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thompson, Scott M.; Callstrom, Matthew R.; Knudsen, Bruce

This study was designed to determine the tumorigenicity of the AS30D HCC cell line following orthotopic injection into rat liver and preliminarily characterize the tumor model by both magnetic resonance imaging (MRI) and ultrasound (US) as well as histopathology and immunohistochemistry.MaterialsAS30D cell line in vitro proliferation was assessed by using MTT assay. Female rats (N = 5) underwent injection of the AS30D cell line into one site in the liver. Rats subsequently underwent MR imaging at days 7 and 14 to assess tumor establishment and volume. One rat underwent US of the liver at day 7. Rats were euthanized atmore » day 7 or 14 and livers were subjected to gross, histopathologic (H and E), and immunohistochemical (CD31) analysis to assess for tumor growth and neovascularization. AS30D cell line demonstrated an in vitro doubling time of 33.2 {+-} 5.3 h. MR imaging demonstrated hyperintense T2-weighted and hypointense T1-weighted lesions with tumor induction in five of five and three of three sites at days 7 and 14, respectively. The mean (SD) tumor volume was 126.1 {+-} 36.2 mm{sup 3} at day 7 (N = 5). US of the liver demonstrated a well-circumscribed, hypoechoic mass and comparison of tumor dimensions agreed well with MRI. Analysis of H and E- and CD31-stained sections demonstrated moderate-high grade epithelial tumors with minimal tumor necrosis and evidence of diffuse intratumoral and peritumoral neovascularization by day 7. AS30D HCC cell line is tumorigenic following orthotopic injection into rat liver and can be used to generate an early vascularizing, slower-growing rat HCC tumor model.« less

Establishment of a reversible model of prehepatic portal hypertension in rats

PubMed Central

Zhao, Xin; Dou, Jian; Gao, Qing-Jun

2016-01-01

The aim of the present study was to improve upon the traditional model of pre-hepatic portal hypertension in rats, and simulate the anhepatic phase of orthotopic liver transplantation without veno-venous bypass. A reversible model of portal hypertension was induced by portal vein ligation, with a label ring ligated along the portal vein. A total of 135 male Wistar rats were divided into three groups: i) Normal control (NC) group; ii) portal hypertensive control (PHTC) group; and iii) reperfusion (R) group. In the R group, rats with portal hypertension underwent simultaneous clamping of the portal triad and retrohepatic vena cava for 1 h, followed by removal of the clamps to enable blood reperfusion. Portal venography and portal vein pressure were recorded during the surgery. Arterial oxygen pressure (PaO2), and alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) levels were determined, and pathological changes of the liver were investigated by immunohistochemical staining. The results demonstrated that, 3 weeks after portal vein ligation, the vein area and the free portal pressures in the PHTC group were significantly increased compared with those in the NC group. The serum ALT and AST levels in the R group at different time points were significantly elevated compared with those in the PHTC group, and reached their maximal levels at 24 h after reperfusion. Furthermore, the PaO2 at 24 h after reperfusion was significantly decreased. In conclusion, the reversible model of pre-hepatic portal hypertension in rats was successfully established using the introduction of a label ring. This model may be useful for basic research focusing on the anhepatic phase of orthotopic liver transplantation without veno-venous bypass. PMID:27446299

Establishment of a reversible model of prehepatic portal hypertension in rats.

PubMed

Zhao, Xin; Dou, Jian; Gao, Qing-Jun

2016-08-01

The aim of the present study was to improve upon the traditional model of pre-hepatic portal hypertension in rats, and simulate the anhepatic phase of orthotopic liver transplantation without veno-venous bypass. A reversible model of portal hypertension was induced by portal vein ligation, with a label ring ligated along the portal vein. A total of 135 male Wistar rats were divided into three groups: i) Normal control (NC) group; ii) portal hypertensive control (PHTC) group; and iii) reperfusion (R) group. In the R group, rats with portal hypertension underwent simultaneous clamping of the portal triad and retrohepatic vena cava for 1 h, followed by removal of the clamps to enable blood reperfusion. Portal venography and portal vein pressure were recorded during the surgery. Arterial oxygen pressure (PaO 2 ), and alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) levels were determined, and pathological changes of the liver were investigated by immunohistochemical staining. The results demonstrated that, 3 weeks after portal vein ligation, the vein area and the free portal pressures in the PHTC group were significantly increased compared with those in the NC group. The serum ALT and AST levels in the R group at different time points were significantly elevated compared with those in the PHTC group, and reached their maximal levels at 24 h after reperfusion. Furthermore, the PaO 2 at 24 h after reperfusion was significantly decreased. In conclusion, the reversible model of pre-hepatic portal hypertension in rats was successfully established using the introduction of a label ring. This model may be useful for basic research focusing on the anhepatic phase of orthotopic liver transplantation without veno-venous bypass.

Orthotopic tumorgrafts in nude mice: A new method to study human prostate cancer.

PubMed

Saar, Matthias; Körbel, Christina; Linxweiler, Johannes; Jung, Volker; Kamradt, Jörn; Hasenfus, Andrea; Stöckle, Michael; Unteregger, Gerhard; Menger, Michael D

2015-10-01

In vivo model systems in prostate cancer research that authentically reproduce tumor growth are still sparse. While orthotopic implantation is technically difficult, particularly in the mouse, most models favor subcutaneous tumor growth. This however provides little information about natural tumor growth behavior and tumor stroma interaction. Furthermore, established prostate cancer cell lines grown as in vivo xenografts are not able to reflect the variety of tumor specific growth patterns and growth behavior in men. Primary cell cultures are difficult to handle and an induction of orthotopic tumors has not been successful yet. Therefore, a tumorgraft model using tumor tissue from prostatectomy specimens was developed. Balb/c nude mice were used to graft fresh prostate tumor tissue by renal subcapsular and orthotopic implantation. Testosterone propionate was supplemented. Animals were tracked by means of 30 MHz ultrasound to monitor tumor engraftment and growth. Autopsy, histology, PSA measurements as well as immunostaining and PCR for human tissue were performed to confirm orthotopic tumor growth. Renal subcapsular engraftment was seen in 2 of 3 mice. Orthotopic engraftment was observed in 7 of 11 animals (63.6%) with an overall engraftment of 5 out of 9 patient specimens (55.6%). Ultrasound confirmed the tumor growth over time. Of interest, the tumorgrafts not only retained essential features of the parental tumors, but also stained positive for tumor specific markers such as AR, PSA, and AMACR. Tumor positive animals showed highly elevated serum PSA levels with confirmation of a human specific PCR sequence and a human endothelial cell lining in the tumor vessels. Standardized implantation of fresh tumor tissue in nude mice prostates generates tumorgrafts with histological properties of organ-confined prostate cancer. These tumorgrafts display a new approach for an optimized in vivo model of prostate cancer and will allow further investigations on specific pathways of tumor initiation and progression as well as therapeutic response. © 2015 Wiley Periodicals, Inc.

Orthotopic xenografts of RCC retain histological, immunophenotypic and genetic features of tumors in patients

PubMed Central

Grisanzio, Chiara; Seeley, Apryle; Chang, Michelle; Collins, Michael; Di Napoli, Arianna; Cheng, Su-Chun; Percy, Andrew; Beroukhim, Rameen; Signoretti, Sabina

2013-01-01

Renal cell carcinoma (RCC) is an aggressive malignancy with limited responsiveness to existing treatments. In vivo models of human cancer, including RCC, are critical for developing more effective therapies. Unfortunately, current RCC models do not accurately represent relevant properties of the human disease. The goal of this study was to develop clinically relevant animal models of RCC for preclinical investigations. We transplanted intact human tumor tissue fragments orthotopically in immunodeficient mice. The xenografts were validated by comparing the morphologic, phenotypic, and genetic characteristics of the kidney tumor tissues before and after implantation. Twenty kidney tumors were transplanted into mice. Successful tumor growth was detected in 19 cases (95%). The histopathologic and immunophenotypic features of the xenografts and those of the original tumors largely overlapped in all the cases. Evaluation of genetic alterations in a subset of 10 cases demonstrated that the grafts largely retained the genetic features of the pre-implantation RCC tissues. Indeed, primary tumors and corresponding grafts displayed identical VHL mutations. Moreover, an identical pattern of DNA copy amplification or loss was observed in 6 of 10 cases (60%). In summary, orthotopic engrafting of RCC tissue fragments can be successfully used to generate animal models that closely resemble RCC in patients. These models will be invaluable for in vivo preclinical drug testing, and for deeper understanding of kidney carcinogenesis. PMID:21710693

Successful Outflow Reconstruction to Salvage Traumatic Hepatic Vein-Caval Avulsion of a Normothermic Machine Ex-Situ Perfused Liver Graft

PubMed Central

Athanasopoulos, Panagiotis G.; Hadjittofi, Christopher; Dharmapala, Arinda Dinesh; Orti-Rodriguez, Rafael Jose; Ferro, Alessandra; Nasralla, David; Konstantinidou, Sofia K.; Malagó, Massimo

2016-01-01

Abstract Donor organ shortage continues to limit the availability of liver transplantation, a successful and established therapy of end-stage liver diseases. Strategies to mitigate graft shortage include the utilization of marginal livers and recently ex-situ normothermic machine perfusion devices. A 59-year-old woman with cirrhosis due to primary sclerosing cholangitis was offered an ex-situ machine perfused graft with unnoticed severe injury of the suprahepatic vasculature due to road traffic accident. Following a complex avulsion, repair and reconstruction of all donor hepatic veins as well as the suprahepatic inferior vena cava, the patient underwent a face-to-face piggy-back orthotopic liver transplantation and was discharged on the 11th postoperative day after an uncomplicated recovery. This report illustrates the operative technique to utilize an otherwise unusable organ, in the current environment of donor shortage and declining graft quality. Normothermic machine perfusion can definitely play a role in increasing the graft pool, without compromising the quality of livers who had vascular or other damage before being ex-situ perfused. Furthermore, it emphasizes the importance of promptly and thoroughly communicating organ injuries, as well as considering all reconstructive options within the level of expertise at the recipient center. PMID:27082550

Successful Outflow Reconstruction to Salvage Traumatic Hepatic Vein-Caval Avulsion of a Normothermic Machine Ex-Situ Perfused Liver Graft: Case Report and Management of Organ Pool Challenges.

PubMed

Athanasopoulos, Panagiotis G; Hadjittofi, Christopher; Dharmapala, Arinda Dinesh; Orti-Rodriguez, Rafael Jose; Ferro, Alessandra; Nasralla, David; Konstantinidou, Sofia K; Malagó, Massimo

2016-04-01

Donor organ shortage continues to limit the availability of liver transplantation, a successful and established therapy of end-stage liver diseases. Strategies to mitigate graft shortage include the utilization of marginal livers and recently ex-situ normothermic machine perfusion devices. A 59-year-old woman with cirrhosis due to primary sclerosing cholangitis was offered an ex-situ machine perfused graft with unnoticed severe injury of the suprahepatic vasculature due to road traffic accident. Following a complex avulsion, repair and reconstruction of all donor hepatic veins as well as the suprahepatic inferior vena cava, the patient underwent a face-to-face piggy-back orthotopic liver transplantation and was discharged on the 11th postoperative day after an uncomplicated recovery. This report illustrates the operative technique to utilize an otherwise unusable organ, in the current environment of donor shortage and declining graft quality. Normothermic machine perfusion can definitely play a role in increasing the graft pool, without compromising the quality of livers who had vascular or other damage before being ex-situ perfused. Furthermore, it emphasizes the importance of promptly and thoroughly communicating organ injuries, as well as considering all reconstructive options within the level of expertise at the recipient center.

Successful treatment of donor-derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens.

PubMed

Shah, Ashesh P; Cameron, Andrew; Singh, Pooja; Frank, Adam M; Fenkel, Jonathan M

2017-04-01

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)-negative donor to three HCV-negative recipients-two renal transplants and one liver. Both renal recipients underwent standard deceased-donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39-year-old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV-infected male partner. Recipient 1 was a 45-year-old man with a history of end-stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62-year-old woman with a history of end-stage renal disease caused by hypertension and insulin-dependent diabetes. Recipient 3 was a 42-year-old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post-transplant follow-up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipient's liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor-derived HCV in transplant recipients. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Orthotopic liver transplantation in an adult with cholesterol ester storage disease.

PubMed

Ambler, Graeme K; Hoare, Matthew; Brais, Rebecca; Shaw, Ashley; Butler, Andrew; Flynn, Paul; Deegan, Patrick; Griffiths, William J H

2013-01-01

Cholesterol ester storage disease (CESD) is a rare autosomal recessive lipid storage disorder associated with mutations of the gene encoding lysosomal acid lipase, manifestations of which include chronic liver disease and early atherosclerosis. Although normally presenting in childhood, severity is variable and the condition can occasionally remain undetected until middle age. Typical presentation is with asymptomatic hepatosplenomegaly and hyperlipidaemia, though the condition is probably underdiagnosed. Treatment is supportive and may include attention to cardiovascular risk factors. Phase I/II trials of enzyme replacement therapy are ongoing, but this approach remains experimental. We present the case of a 42-year-old woman diagnosed with CESD in childhood who ran an indolent course until re-presentation with cirrhotic hydrothorax. She underwent orthotopic liver transplantation but required re-transplantation for hepatic artery thrombosis. She remains well with excellent graft function 2 years later. Although atherosclerosis was apparent at assessment, and may have contributed to hepatic artery thrombosis, partial correction of the metabolic defect and restoration of liver function by transplantation together with ongoing medical therapy should permit reasonable survival over the longer term from both a liver and a vascular perspective. This is the first reported case of orthotopic liver transplantation for CESD in an adult, which was the only available option to improve survival. The case highlights the importance of monitoring patients with CESD through adulthood and suggests that liver replacement at a later stage may yet be indicated and remain of benefit.

Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer.

PubMed

Scatena, Caroline D; Hepner, Mischa A; Oei, Yoko A; Dusich, Joan M; Yu, Shang-Fan; Purchio, Tony; Contag, Pamela R; Jenkins, Darlene E

2004-05-15

Animal experiments examining hormone-sensitive metastatic prostate cancer using the human LNCaP cell line have been limited to endpoint analyses. To permit longitudinal studies, we generated a luciferase-expressing cell line and used bioluminescent imaging (BLI) to non-invasively monitor the in vivo growth of primary LNCaP tumors and metastasis. LNCaP.FGC cells were transfected to constitutively express firefly luciferase. LNCaP-luc-M6 cells were tested for bioluminescent signal intensity and hormone responsiveness in vitro. The cells were implanted in subcutaneous and orthotopic sites in SCID-bg mice and imaged over time. The LNCaP-luc-M6 cells formed subcutaneous and orthotopic tumors in SCID-bg mice, and nearly all tumor-bearing animals developed pulmonary metastases. Early detection and temporal growth of primary tumors and metastatic lesions was successfully monitored by BLI. The LNCaP-luc-M6 cell line is a bioluminescent, hormone-sensitive prostate cancer cell line applicable for BLI studies to non-invasively monitor subcutaneous and orthotopic prostate tumor growth and metastasis in vivo. Copyright 2004 Wiley-Liss, Inc.

Early Spontaneous Graft Intra- and Perihepatic Hematoma after Liver Transplantation.

PubMed

Lupaşcu, Cristian; Apopei, Oana; Vlad, Nutu; Vasiluta, Ciprian; Trofin, Ana-Maria; Zabara, Mihai; Vornicu, Alexandra; Lupaşcu-Ursulescu, Corina; Nitu, Mioara; Crumpei, Felicia; Braşoveanu, Vladislav; Popescu, Irinel

2017-01-01

Hematoma of the graft is a life threatening complication of liver transplantation (LT) and there has been no overt conclusion in the literature about optimal management except in scarcely reported cases. It may be either intrahepatic or subcapsular, then again it may develop spontaneously or following parenchimal injuries or transhepatic percutaneous invasive manoeuvers. In this report we describe a rare case of large spontaneous graft intra- and perihepatic hematoma. A 62 year-old man underwent a whole graft orthotopic liver transplantation (OLT) for decompensated chronic liver disease due to alcoholic cirrhosis. The surgical procedure was uneventful. During the early postoperative course, routine Doppler ultrasound examination and CT-scan revealed an extrahepatic paracaval hematoma, 7 days after transplantation, which was stable and conservatively managed until the 18-th postoperative day, when rapidly expanding intraparenchimal hematoma involving the right hemiliver, several other perihepatic hematomas, significant right pleural effusion and hemorrhagic ascites were described. The patient was successfully treated conservatively (nonsurgically) with slow recovery of the liver allograft and discharged one month later in good general status. Celsius.

A liver-metastatic model of human primary gastric lymphoma in nude mice orthotopically constructed by using histologically intact patient specimens.

PubMed

Yang, Bo; Tuo, Shuai; Tuo, Chao-Wei; Zhang, Ning; Liu, Qiu-Zhen

2010-06-01

In recent years, incidence and mortality of lymphoma are markedly increasing worldwide. However, the pathogenesis and mechanism of invasion and metastasis for lymphoma are not yet fully clarified. It is mainly due to the lack of ideal animal models, which can precisely simulate the invasion and metastasis of lymphoma in the human body. So, it is very necessary to establish a highly metastatic nude mouse model of human lymphoma. This study developed a liver-metastatic model of primary gastric lymphoma in nude mice by using orthotopic surgical implantation of histologically intact patient specimens into the corresponding organs of the recipient small animals. A histologically intact fragment of liver metastasis derived from a surgical specimen of a patient with primary gastric lymphoma was implanted into the submucosa of the stomach in nude mice. Tumorigenicity, invasion, metastasis, morphologic characteristics (via light microscopy, electron microscopy, and immunohistochemistry), karyotype analysis, and DNA content of the orthotopically transplanted tumors were studied. An orthotopic liver metastatic model of human primary gastric lymphoma in nude mice (termed HGBL-0304) was successfully established. The histopathology of the transplanted tumors showed primary gastric diffuse large B-cell lymphoma. CD19, CD20, CD22, and CD79alpha were positive, but CD3 and CD7 were negative. The serum level of lactate dehydrogenase (LDH) was elevated [(1010.56+/-200.85) U/L]. The number of chromosomes ranged from 75 to 89. The DNA index (DI) was 1.45+/-0.25 (that is, heteroploid). So far, the HGBL-0304 model has been passed on for 45 generations of nude mice. A total of 263 nude mice were used for the transplantation. Both the growth and resuscitation rates of liquid nitrogen cryopreservation of the transplanted tumors were 100%. The transplanted tumors autonomically invasively grew and damaged a whole layer in the stomach of nude mice. The metastasis rates of liver, spleen, lymph node, and peritoneal seeding were 100%, 94.3%, 62.6%, and 43.5%, respectively. The study successfully establishes an orthotopic liver metastatic model of human primary gastric lymphoma in nude mice. The HGBL-0304 model can completely simulate the natural clinical process of primary gastric lymphoma and provides an ideal animal model for the research on the biology of metastasis and antimetastatic experimental therapies of primary gastric lymphoma.

Hepatic gas gangrene following orthotopic liver transplantation: three cases treated with re-transplantation and a review of the literature.

PubMed

Doblecki-Lewis, S; Palaios, E; Bejarano, P A; Tzakis, A G; Selvaggi, G; Morris, M I

2008-07-01

Gas gangrene is a rare and devastating infectious process that can occur after liver transplantation, most often following hepatic artery thrombosis. We here report 3 cases of gas gangrene following orthotopic liver transplantation. Blood cultures were positive for Clostridium clostridiiforme in one case. In 2 other cases liver tissue from explanted specimens was positive for Enterobacter cloacae. Ultrasound demonstrated hepatic artery thrombosis and computed tomography imaging revealed diffuse liver necrosis with gas formation in each case. All 3 patients were successfully treated with a combination of antibiotics and emergent re-transplantation. We review previously published cases of gas gangrene after liver transplant and emphasize the importance of hepatic artery thrombosis in the development of this syndrome as well as the frequent involvement of non-clostridial organisms. Early diagnosis and aggressive combined medical and surgical treatment including re-transplantation are essential for successful treatment of these rare and catastrophic infections.

Auxiliary partial orthotopic living donor liver transplantation with a small-for-size graft for congenital absence of the portal vein.

PubMed

Matsuura, Toshiharu; Soejima, Yuji; Taguchi, Tomoaki

2010-12-01

Congenital absence of the portal vein (CAPV) with an extrahepatic portosystemic shunt is a rare malformation; the completely absent type, Abernethy malformation type I, is especially rare. Liver transplantation for CAPV type I has been recently recognized as the only curative operation, but few reports have been published so far; meanwhile, auxiliary partial orthotopic liver transplantation (APOLT) has been proposed to be a very effective option, especially for pediatric patients. Here we present an 18-year-old adult patient with CAPV, asplenia, and an iliac shunt vessel who was managed successfully with APOLT using a small-for-size graft. To the best of our knowledge, this is the first adult patient who has experienced success with APOLT for CAPV. This is a feasible procedure: it not only fulfills the metabolic demands of the liver for adult patients but also potentially cures CAPV. Copyright © 2010 American Association for the Study of Liver Diseases.

Welfare Assessment following Heterotopic or Orthotopic Inoculation of Bladder Cancer in C57BL/6 Mice.

PubMed

Miller, Amy; Burson, Hannah; Söling, Ariane; Roughan, Johnny

2016-01-01

Few studies have assessed whether mice used as cancer models experience pain. Despite this possibility, the usual practice is to withhold analgesics as these are generally viewed as confounding. However, pain also alters cancer progression, so preventing it might not only be beneficial to welfare but also to study validity. Establishing the extent to which different cancer models result in pain is an important first step towards their refinement. We used conditioned place preference (CPP) testing and body-weight and behaviour analyses to evaluate the assumption that heterotopically implanted tumours result in less pain and fewer welfare concerns than those implanted orthotopically. C57Bl/6 mice received MB49Luc luciferase expressing bladder cancer cells or saline implanted subcutaneously or into the bladder. These tumour-bearing or control groups underwent 2 daily 45 minute conditioning trials to saline or morphine (2mg/kg) and then a 15 minute drug-free preference test on day 3 of a 3 day cycle, continuing until the study ended. Tumours were imaged and behaviour data obtained following preference tests. Development of preference for the morphine-paired chamber (morphine-seeking) was determined over time. Heterotopic tumour development had no effect on morphine-seeking, and although the restraint used for heterotopic inoculation caused greater initial weight losses than anaesthesia, these mice steadily gained weight and behaved comparatively normally throughout the study. Orthotopic tumour inoculation caused no initial weight losses, but over the final 7 days these mice became less active and lost more body weight than cancer-free controls. This indicated orthotopic implantation probably caused a more negative impact on welfare or conceivably pain; but only according to the current test methods. Pain could not be confirmed because morphine-seeking in the tumour-bearing groups was similar to that seen in controls. Imaging was not found to be an effective method of monitoring tumour development surpassing manual tumour inspection.

Ultrasound-Accelerated, Catheter-Directed Thrombolysis for Inferior Vena Cava Thrombosis After an Orthotopic Liver Transplant

PubMed Central

Latchana, Nicholas; Dowell, Joshua D.; Taani, Jamal Al; Michaels, Anthony; Elkhammas, Elmadhi; Black, Sylvester M.

2015-01-01

Inferior vena cava thrombosis is a rare occurrence after an orthotopic liver transplant that is associated with a high rate of retransplant and mortality. There is no consensus regarding the optimal therapeutic strategy. Surgical management, including thrombectomy with revision of the cavocaval anastomosis, has been described. With the use of endovascular therapies, several minimally invasive approaches are available that are effective and avoid the high morbidity associated with reoperative surgery. We describe our successful experience using an approach after a liver transplant in which the inferior vena cava thrombosis in a patient presenting with acute renal failure, anorexia, weight loss, and fatigue using an ultrasound-accelerated, catheter-directed thrombolysis platform in conjunction with systemic anticoagulation. PMID:24918871

[Long-term, tumor-free survival after radiotherapy combining hepatectomy-Whipple en bloc and orthotopic liver transplantation for early-stage hilar cholangiocarcinoma].

PubMed

Wu, You-min; Johlin, Frederick C; Rayhill, Stephen C; Jensen, Chris S; Jin, Xie; Mitros, Frank A

2009-08-01

To report the experience in surveillance and early detection of cholangiocarcinoma (CC) and in using en bloc total hepatectomy-pancreaticoduodenectomy-orthotopic liver transplantation (OLT-Whipple) to achieve complete eradication of early-stage CC complicating primary sclerosing cholangitis (PSC). Asymptomatic PSC patients underwent surveillance using endoscopic ultrasound and endoscopic retrograde cholangiopancreatography (ERCP) with multilevel brushings for cytological evaluation. Patients diagnosed with CC were treated with combined extra-beam radiotherapy, lesion-focused brachytherapy, and OLT-Whipple. Between January 1988 and February 2001, 42 of 119 PSC patients were followed according to the surveillance protocol. CC was detected in 8 patients, 6 of whom underwent OLT-Whipple. Of those 6 patients, 4 had stage I CC, and 2 had stage II CC. All 6 OLT-Whipple patients received combined external-beam and brachytherapy radiotherapy. The median time from diagnosis to OLT-Whipple was 144 days. One patient died 55 months post-transplant of an unrelated cause, without tumor recurrence. The other 5 were well without recurrence at 79, 82, 108, 128, 129 and 145 months. For patients with PSC, ERCP surveillance cytology and intralumenal endoscopic ultrasound examination allow for early detection of CC. Broad and lesion-focused radiotherapy combined with OLT-Whipple to remove the biliary epithelium en bloc offers promising long-term, tumor-free survival. All patients tolerated this extensive surgery well with good quality of life following surgery and recovery. These findings support consideration of the complete excision of an intact biliary tree via OLT-Whipple in patients with early-stage hilar CC complicating PSC.

Orthotopic Implantation of Intact Tumor Tissue Leads to Metastasis of OCUM-2MD3 Human Gastric Cancer in Nude Mice Visualized in Real Time by Intravital Fluorescence Imaging.

PubMed

Murakami, Takashi; Zhang, Yong; Wang, Xiaoen; Hiroshima, Yukihiko; Kasashima, Hiroaki; Yashiro, Masakazu; Hirakawa, Kosei; Miwa, Atsushi; Kiyuna, Tasuku; Matsuyama, Ryusei; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2016-05-01

Orthotopic (literally "correct place") implantation of cancer in nude mice has long been known to be superior to subcutaneous transplantation because the orthotopic tumor can metastasize. We reported previously on surgical orthotopic implantation (SOI) of gastric cancer tissue in nude mice resulting in the formation of metastases in 100% of the mice with extensive primary growth to the regional lymph nodes, liver, and lung. In contrast, when cell suspensions were used to inject gastric cancer cells orthotopically, metastases occurred in only 6.7% of the mice with local tumor formation, emphasizing the importance of orthotopically implanting intact tissue to allow full expression of metastatic potential. However, the different behavior of tumors implanted orthotopically by the two methods has not been visualized in real time. OCUM-2MD3 human gastric cancer cells labeled with the fluorescent protein Azami-Green were implanted orthotopically as cells or tissue in nude mice. Orthotopic implantation of cells resulted in local spread on the stomach. In contrast, SOI of tumor tissue of OCUM-2MD3 resulted in vessel spread of the Azami-Green-expressing cancer cells. Metastasis was also observed in the left lobe of the liver after SOI. These results demonstrate the physiological importance of intact cancer tissue for orthotopic implantation in order for tumors to properly grow and express their metastatic potential. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Total donor ischemic time: relationship to early hemodynamics and intensive care morbidity in pediatric cardiac transplant recipients.

PubMed

Rodrigues, Warren; Carr, Michelle; Ridout, Deborah; Carter, Katherine; Hulme, Sara Louise; Simmonds, Jacob; Elliott, Martin; Hoskote, Aparna; Burch, Michael; Brown, Kate L

2011-11-01

Single-center studies have failed to link modest increases in total donor ischemic time to mortality after pediatric orthotopic heart transplant. We aimed to investigate whether prolonged total donor ischemic time is linked to pediatric intensive care morbidity after orthotopic heart transplant. Retrospective cohort review. Tertiary pediatric transplant center in the United Kingdom. Ninety-three pediatric orthotopic heart transplants between 2002 and 2006. Total donor ischemic time was investigated for association with early post-orthotopic heart transplant hemodynamics and intensive care unit morbidities. Of 43 males and 50 females with median age 7.2 (interquartile range 2.2, 13.0) yrs, 62 (68%) had dilated cardiomyopathy, 20 (22%) had congenital heart disease, and nine (10%) had restrictive cardiomyopathy. The mean total donor ischemic time was 225.9 (sd 65.6) mins. In the first 24 hrs after orthotopic heart transplant, age-adjusted mean arterial blood pressure increased (p < .001), mean pulmonary arterial pressure fell (p = .012), but central venous pressure (p = .58) and left atrial pressure (p = .20) were unchanged. After adjustment for age, primary diagnosis, pre-orthotopic heart transplant mechanical support, and marginal donor factors, longer total donor ischemic time was significantly associated with lower mean arterial blood pressure (p < .001) in the first 24 hrs after orthotopic heart transplant, longer post-orthotopic heart transplant mechanical ventilation (p = .03), longer post-orthotopic heart transplant stay in the intensive care unit (p = .004), and longer post-orthotopic heart transplant stay in hospital (p = .02). Total donor ischemic time was not related to levels of mean pulmonary arterial pressure (p = .62), left atrial pressure (p = .38), or central venous pressure (p = .76) early after orthotopic heart transplant. Prolonged total donor ischemic time has an adverse effect on the donor organ, contributing to lower mean arterial blood pressure, as well as more prolonged ventilation and intensive care unit and hospital stays post-orthotopic heart transplant, reflecting increased morbidity.

Clinical experience with the N-shaped ileal neobladder: assessment of complications, voiding patterns, and quality of life in our series of 58 patients.

PubMed

Joniau, S; Benijts, J; Van Kampen, M; De Waele, M; Ooms, J; Van Cleynenbreugel, B; Van Poppel, H

2005-05-01

The purpose of this retrospective study was to assess complications, voiding patterns, and quality of life in patients with an orthotopic bladder substitution, using an N-shaped ileal neobladder. Between May 1996 and December 2002, 58 patients (52 men and 6 women) underwent an orthotopic ileal neobladder reconstruction after radical cystectomy. The mean age was 47 for the female and 60 for the male patients. In all patients an N-shaped ileal pouch was constructed. This pouch has not yet been described in the literature before. All procedures were performed by the same surgeon (HVP) and the mean follow-up was 38 months. Complications were registered as early (occurring within 3 months) or late (occurring after 3 months), and as pouch-related and non-pouch-related. The patients took part in a pelvic floor re-education programme for as long as they were incontinent. All patients completed a retrospective Quality of Life questionnaire, based on the QLQ-C30 questionnaire, which was validated by the EORTC's Study Group on Quality of Life. In 38% of the patients, early complications occurred, whereas 48% had late complications. The most frequent early complications were diarrhea (24%) and pyelonephritis (9%). Diarrhea was again the most frequently mentioned non-pouch-related complication (19%). The most frequently observed pouch-related late complication was ileo-urethral stenosis. This occurred in five patients. All of these 5 patients were re-operated using a minimally invasive approach. Daytime continence was achieved in 95% of patients and nighttime continence in 66%. Hyper-continence with subsequent need for CISC was observed in 5 out of 6 women (83%) and 0 out of 52 men (0%). The retrospective QoL questionnaire learned that the impact of bladder removal and orthotopic bladder substitution has acceptable impact on patient's everyday life. Diarrhea was mentioned as being the most discomforting complication by most of the patients. We describe a modified orthotopic ileal neobladder: the ileal N-pouch. The functional results with this pouch are good. Complication rates and QoL are comparable with the larger series published by other authors, using different ileal neobladder reconstructions.

First pediatric transatlantic air ambulance transportation on a Berlin Heart EXCOR left ventricular assist device as a bridge to transplantation.

PubMed

Tissot, Cecile; Buchholz, Holger; Mitchell, Max B; da Cruz, Eduardo; Miyamoto, Shelley D; Pietra, Bill A; Charpentier, Arnaud; Ghez, Olivier

2010-03-01

Mechanical circulatory devices are indicated in patients with refractory cardiac failure as a bridge to recovery or to transplantation. Whenever required, transportation while on mechanical support is a challenge and still limited by technical restrictions or distance. We report the first pediatric case of transatlantic air transportation on a Berlin Heart EXCOR ventricular assist device (Berlin Heart, Berlin, Germany) of a 13-yr-old American female who presented in cardiogenic shock with severe systolic dysfunction while vacationing in France. Rapid hemodynamic deterioration occurred despite maximal medical treatment, and she was supported initially with extracorporeal membrane oxygenation converted to a Berlin Heart EXCOR left ventricular assist device. Long-distance air transportation of the patient was accomplished 3 wks after implantation from Marseille, France, to Denver, Colorado. No adverse hemodynamic effects were encountered during the 13.5-hr flight (8770 km). The patient did not recover sufficient cardiac function and underwent successful orthotopic heart transplantation 3 months after the initial event. Our experience suggests that long-distance air transportation of pediatric patients using the Berlin Heart EXCOR mobile unit as a bridge to recovery or transplantation is feasible and appears safe.

Role of Doppler Sonography in Early Detection of Splenic Steal Syndrome.

PubMed

Li, Chaolun; Quintini, Cristiano; Hashimoto, Koji; Fung, John; Obuchowski, Nancy A; Sands, Mark J; Wang, Weiping

2016-07-01

To retrospectively investigate the role of Doppler sonography in the early detection of splenic steal syndrome. Fifty cases of splenic steal syndrome after orthotopic liver transplantation were identified. A control group was matched to the splenic steal syndrome group. Information was collected about the clinical presentation, liver enzyme levels, Doppler sonographic results, and follow-up after patients underwent splenic artery embolization. A persistent hepatic arterial diastolic reversal waveform was observed in 25 patients with splenic steal syndrome versus 0 control patients. The mean hepatic arterial resistive index (RI) values ± SD were 0.95 ± 0.09 in patients with splenic steal syndrome and 0.80 ± 0.10 in control patients (P < .0001). One week after orthotopic liver transplantation, the area under the receiver operating characteristic curve for the RI was 0.884 (95% confidence interval, 0.793-0.975; P = .001) for splenic steal syndrome diagnosis. After splenic artery embolization, there was normalization of the reversal waveform, with an average RI of 0.77 ± 0.11 (P < .0001). Dynamic changes in the hepatic arterial waveform and RI are keys to detecting splenic steal syndrome with Doppler sonography.

Bariatric Surgery Is Gaining Ground as Treatment of Obesity After Heart Transplantation: Report of Two Cases.

PubMed

Tsamalaidze, Levan; Elli, Enrique F

2017-11-01

Experience with bariatric surgery in patients after orthotopic heart transplantation (OHT) is still limited. We performed a retrospective review of patients who underwent bariatric surgery after OHT from January 1, 2010 to December 31, 2016. Two post-OHT patients with BMI of 37.5 and 36.2 kg/m² underwent laparoscopic robotic-assisted Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy, respectively. Quality of life substantially improved for both patients. Bariatric surgery is safe and feasible in OHT patients, despite numerous risk factors. Careful selection of patients is required with proper preoperative management and overall care. Due to the complexity of treatment and perioperative care in this specific population, these operations should be done in high-volume centers with multidisciplinary teams composed of bariatric, cardiac transplant surgeons and critical care physicians. Bariatric surgery can be highly effective for treatment of obesity after OHT.

Long-Term Follow-Up After Successful Transjugular Intrahepatic Portosystemic Shunt Placement in a Pediatric Patient with Budd-Chiari Syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carnevale, Francisco Cesar, E-mail: fcarnevale@uol.com.br; Szejnfeld, Denis, E-mail: denis@cura.com.br; Moreira, Airton Mota

Orthotopic liver transplantation is the standard of care in patients with Budd-Chiari syndrome (BCS), and transjugular intrahepatic portosystemic shunt (TIPS) has become an important adjunct procedure while the patient is waiting for a liver. No long-term follow up of TIPS in BCS patients has been published in children. We report successful 10-year follow-up of a child with BCS and iatrogenic TIPS dysfunction caused by oral contraceptive use.

Side-to-side cavo-cavostomy: a useful aid in "complicated" piggy-back liver transplantation.

PubMed

Lerut, J; Gertsch, P

1993-01-01

Piggy-back liver transplantation is a useful technical variant of orthotopic liver transplantation. Its success can, however, be compromised by severe stenosis or obstruction of the recipient's inferior vena cava at the level of the anastomosis. A technique is described--side-to-side cavocavostomy--to resolve this difficult intraoperative situation.

A point-based prediction model for cardiovascular risk in orthotopic liver transplantation: The CAR-OLT score.

PubMed

VanWagner, Lisa B; Ning, Hongyan; Whitsett, Maureen; Levitsky, Josh; Uttal, Sarah; Wilkins, John T; Abecassis, Michael M; Ladner, Daniela P; Skaro, Anton I; Lloyd-Jones, Donald M

2017-12-01

Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk-assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point-based prediction model (risk score) for CVD complications after OLT, the Cardiovascular Risk in Orthotopic Liver Transplantation risk score, among a cohort of 1,024 consecutive patients aged 18-75 years who underwent first OLT in a tertiary-care teaching hospital (2002-2011). The main outcome measures were major 1-year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias-corrected 95% confidence intervals for the regression coefficients of the final model. Among 1,024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included preoperative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the point-based score (C statistic = 0.78, bias-corrected C statistic = 0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer-Lemeshow P = 0.33). The point-based risk score can identify patients at risk for CVD complications after OLT surgery (available at www.carolt.us); this score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. (Hepatology 2017;66:1968-1979). © 2017 by the American Association for the Study of Liver Diseases.

Risk of in-hospital complications after radical cystectomy for urinary bladder carcinoma: population-based follow-up study of 7608 patients

PubMed Central

Hemelrijck, Mieke; Thorstenson, Andreas; Smith, Philip; Adolfsson, Jan; Akre, Olof

2013-01-01

Objective To evaluate the risk of different in-hospital complications for patients undergoing a radical cystectomy (RC), as limited nationwide population data on short- and long-term complications after RC is available, despite it being the standard treatment for localised muscle-invasive urinary bladder cancer (UBC). Patients and Methods In all, 7608 persons underwent a RC after UBC diagnosis, as registered in the Swedish National Patient Register between 1964 and 2008. We estimated the frequency and incidences and calculated hazard ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards models. Results Urinary tract infection/septicaemia was the most common complication following radical cystectomy, with an incidence of 90.4 per 1,000 person years. There was a higher risk of urinary tract infection among patients who had a continent cutaneous reservoir (HR: 1.11 (0.94–1.30) or orthotopic neobladder 1.21 (1.05–1.39) than among those with ileal conduit. Similarly, continent cutaneous reservoir and orthotopic neobladder were associated with increased risks for wound and abdominal wall hernias, stones in the urinary tract, hydronephrosis and nephrostomy tube treatment, and kidney failure. In contrast, risk of bowel obstruction was lower among those with orthotopic neobladder than those with ileal conduit (HR: 0.64 (0.50–0.81)) and those with continent cutaneous reservoir (HR: 0.92 (0.73–1.16). Conclusions In-hospital complications after RC are numerous and continue to accumulate for many years after surgery, indicating the need for life-long follow-up of these patients. Comparison between different types of diversion should, however, be made with care because of potential confounding by indication. PMID:23906011

Orthotopic bladder substitution in men revisited: identification of continence predictors.

PubMed

Koraitim, M M; Atta, M A; Foda, M K

2006-11-01

We determined the impact of the functional characteristics of the neobladder and urethral sphincter on continence results, and determined the most significant predictors of continence. A total of 88 male patients 29 to 70 years old underwent orthotopic bladder substitution with tubularized ileocecal segment (40) and detubularized sigmoid (25) or ileum (23). Uroflowmetry, cystometry and urethral pressure profilometry were performed at 13 to 36 months (mean 19) postoperatively. The correlation between urinary continence and 28 urodynamic variables was assessed. Parameters that correlated significantly with continence were entered into a multivariate analysis using a logistic regression model to determine the most significant predictors of continence. Maximum urethral closure pressure was the only parameter that showed a statistically significant correlation with diurnal continence. Nocturnal continence had not only a statistically significant positive correlation with maximum urethral closure pressure, but also statistically significant negative correlations with maximum contraction amplitude, and baseline pressure at mid and maximum capacity. Three of these 4 parameters, including maximum urethral closure pressure, maximum contraction amplitude and baseline pressure at mid capacity, proved to be significant predictors of continence on multivariate analysis. While daytime continence is determined by maximum urethral closure pressure, during the night it is the net result of 2 forces that have about equal influence but in opposite directions, that is maximum urethral closure pressure vs maximum contraction amplitude plus baseline pressure at mid capacity. Two equations were derived from the logistic regression model to predict the probability of continence after orthotopic bladder substitution, including Z1 (diurnal) = 0.605 + 0.0085 maximum urethral closure pressure and Z2 (nocturnal) = 0.841 + 0.01 [maximum urethral closure pressure - (maximum contraction amplitude + baseline pressure at mid capacity)].

Successful Management of Neobladder Variceal Bleeding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atwal, Dinesh; Chatterjee, Kshitij, E-mail: kchatterjee@uams.edu; Osborne, Scott

Hematuria from a neobladder can occur due to a variety of pathologies including tumors, stones, and fistulas. Variceal bleeding in a neobladder is a very rare condition with only one case reported in literature. We present a case of a patient with cirrhosis and portal hypertension and an ileocolic orthotopic neobladder presenting with hematuria. Computed tomographic angiography showed dilated varices around the neobladder which were successfully embolized. To the best of our knowledge, this is the first report case of variceal bleeding in a neobladder successfully managed with the combination of TIPS (transjugular intrahepatic portosystemic shunt) procedure and embolization.

Laparoscopic kidney orthotopic transplant: preclinical study in the pig model.

PubMed

He, B; Musk, G C; Mou, L; Waneck, G L; Delriviere, L

2013-06-01

Laparoscopic surgery has rapidly expanded in clinical practice replacing conventional open surgery over the last three decades. Laparoscopic donor nephrectomy has been favored due to its multiple benefits. The aim of this study was to explore the safety and feasibility of kidney transplantation by a laparoscopic technique in a pig model. The study was approved by the university animal ethics committee. Eight female pigs (Sus Scrofra, weighing 45-50 kg) were divided into 2 groups: group I included 4 animals that underwent laparoscopic kidney orthotopic transplantation on the left side. The right kidney was remained functional in situ. The pigs recovered and were observed for 1 week. In the 4 hosts group II pigs underwent a laparoscopic kidney transplantation on the left side. With simultaneous clipping of the right ureter. After recovery, the pigs were observed for 4 weeks. A laparotomy for examination was performed prior to euthanasia. All 4 group I pigs survived for 1 week. The laparotomy showed normal graft perfusion with wall patent renal artery and vein as well as satisfactory urine output upon transection of ureter in 3 hosts. Renal artery stenosis occurred in one pig. In The Immediate kidney graft function was achieved in 3 group II pigs. The fourth died following extubation due to laryngospasm despite a functional graft. The average creatinine levels were 195.5 μmol/L on day 3; 224.5 μmol/L at week 1; 127 μmol/L at week 2; 182.7 umol/L at week 3; and 154.7 umol/L at week 4. Laparoscopic kidney transplantation was feasible and safe in a pig model with immediate graft function. This study will provide further evidence to support application of laparoscopic technique to human kidney transplant. Copyright © 2013 Elsevier Inc. All rights reserved.

Transplantations of frozen-thawed ovarian tissue demonstrate high reproductive performance and the need to revise restrictive criteria.

PubMed

Meirow, Dror; Ra'anani, Hila; Shapira, Moran; Brenghausen, Masha; Derech Chaim, Sanaz; Aviel-Ronen, Sarit; Amariglio, Ninette; Schiff, Eyal; Orvieto, Raoul; Dor, Jehoshua

2016-08-01

To report the single-center results of orthotopic retransplantations of cryopreserved ovarian tissue in cancer survivors and evaluate the validity of commonly accepted procedure limitations. Prospective cohort study. Tertiary university-affiliated assisted reproduction technology (ART) and oncology centers. Twenty cancer survivors who underwent ovarian transplantation of frozen-thawed ovarian tissue with the aim to conceive. Ovarian tissue cryopreservation (OTCP) and transplantation, endocrine monitoring, in vitro fertilization (IVF). Endocrine profile, IVF, pregnancies, live births. The patient ages at tissue harvesting ranged from 14 to 39 years. Fifteen women had hematologic malignancies, and two had leukemia (chronic myelogenous leukemia and acute myelogenous leukemia). Ten patients were exposed to nonsterilizing chemotherapy before OTCP. After transplantation, the endocrine recovery rate was 93%. Fourteen patients underwent IVF treatments with a fertilization rate of 58%. Sixteen pregnancies were achieved (10 after IVF, 6 spontaneous), resulting in 10 live births, two (twins) after harvesting from the mother at the age of 37. Two pregnancies are currently ongoing. After transplantation, 53% of patients conceived, and 32% delivered at least once. One patient conceived four times. Preharversting chemotherapy exposure was not associated with inferior outcomes. All patients, including two leukemia survivors, remained cancer free. Orthotopic transplantation of thawed ovarian tissue is a highly effective measure to restore fertility in sterilized cancer patients. Chemotherapy exposure before harvesting and age >35 is a realistic option in selected patients. Retransplantation in leukemic patients is possible after application of maximal safety measures. These results have led the national ethical and professional authorities to decide for the first time not to consider OTCP as an experimental modality for fertility preservation. NCT02659592. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Marked elevation of hepatic transaminases in recipients of an orthotopic liver transplant from a brain-dead donor receiving extracorporeal membrane oxygenation.

PubMed

Teng-Wei, Chen; Chung-Bao, Hsieh; Chan, De-Chuan; Yu, Jyh-Cherng; Kuo, Shih-Ming; Tsai, Chien-Sung; Fan, Hsiu-Lung

2014-12-29

Hemodynamic instability can lead to failure of donor organ procurement in brain-dead donors. Extracorporeal membrane oxygenation (ECMO) has been used in non-heart-beating donors to increase the donor pool, but the use of ECMO to salvage donor organs has been rarely used. We aimed to analyze postoperative liver function test results in patients receiving orthotopic liver transplants from ECMO-supported brain-dead donors. We retrospectively reviewed the records of 43 recipients of orthotopic liver transplantation from May 2009 to June 2012. Six recipients received liver grafts from ECMO-maintained donors designated as the ECMO group (n=6). The remaining patients were assigned to the non-ECMO group (n=37). Complication and mortality rates and liver function test results on postoperative days 1, 3, 5, 7, and 14 were compared between the 2 groups. Serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase levels were significantly elevated on postoperative Day 1 in the ECMO group. There were no significant differences in the complication and overall survival rates between the 2 groups (P=0.411). Although serum transaminases markedly elevated on postoperative Day 1, ECMO successfully preserved potential liver grafts in hemodynamically unstable brain-dead donors.

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

PubMed

El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

2015-01-01

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. © 2015. Published by The Company of Biologists Ltd.

A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

PubMed Central

El Meskini, Rajaa; Iacovelli, Anthony J.; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L.; Baran, Maureen; Householder, Deborah B.; Van Dyke, Terry; Weaver Ohler, Zoë

2015-01-01

Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. PMID:25431423

Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.

PubMed

Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; Deweese, Theodore L; Herman, Joseph M

2012-04-01

We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.

Development of a Novel Preclinical Pancreatic Cancer Research Model: Bioluminescence Image-Guided Focal Irradiation and Tumor Monitoring of Orthotopic Xenografts1

PubMed Central

Tuli, Richard; Surmak, Andrew; Reyes, Juvenal; Hacker-Prietz, Amy; Armour, Michael; Leubner, Ashley; Blackford, Amanda; Tryggestad, Erik; Jaffee, Elizabeth M; Wong, John; DeWeese, Theodore L; Herman, Joseph M

2012-01-01

PURPOSE: We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. MATERIALS AND METHODS: Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. RESULTS: Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. CONCLUSIONS: We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response. PMID:22496923

EGFR gene overexpression retained in an invasive xenograft model by solid orthotopic transplantation of human glioblastoma multiforme into nude mice.

PubMed

Yi, Diao; Hua, Tian Xin; Lin, Huang Yan

2011-03-01

Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM.

Total Pelvic Supralevator Exenteration with Ileo-Colic Orthotopic Neobladder for Locoregional Recurrence after Cervical Cancer - A Case Report.

PubMed

Bacalbaşa, Nicolae; Bălescu, Irina; Braşoveanu, Vladislav

2016-01-01

Pelvic exenteration is one of the most aggressive surgical interventions in gynaecologic surgical oncology, but, in the same time, is the only potentially curative treatment of locoregional recurrence after cervical cancer. Due to improvements in surgical technique and postoperative management, the overall survival increased signifficantly in the last decades. Trying to improve the quality of life, multiple models of reconstruction of urinary and digestive tract have been developed. In this report we present the case of a 51 years old female who underwent a total supralevator exenteration with ileo colic neobladder reconstruction with good oncologic and functional outcomes. Celsius.

[Highly metastatic nude mouse model of human primary gastric lymphoma constructed by surgical orthotopic transplantation and in vivo continuous screening method].

PubMed

Yang, Bo; Tuo, Shuai; Tuo, Chao-wei; Zhang, Ning; Liu, Qiu-zhen

2010-02-09

To develop a series of high metastatic models of human gastric malignant lymphoma in nude mice by orthotopic transplantation. Two histologically intact primary and hepatic metastatic fragments derived from surgical specimen of a patient with primary gastric lymphoma were implanted into the submucosa of stomach in nude mice. Highly metastatic and specific organ metastatic models were screened by selective orthotopic passage in nude mice. Transplantability, invasion, metastasis, morphological characteristics (light microscopy, electron microscopy and immunohistochemistry), karyotypic analysis and DNA content of orthotopically transplanted tumors were studied. Primary and hepatic metastatic fragments of primary gastric lymphoma were successfully transplanted in nude mice. Two nude mouse models of human primary gastric lymphoma, termed HGBL-0304 (hepatic metastasis model) and HGBL-0305 (high metastasis model), were developed, exhibiting different metastasis biology. Histopathology of transplanted tumors showed primary gastric diffuse large B cell lymphoma. Two models have been maintained for 45 generations by orthotopic passage in nude mice. A total of 419 nude mice were used for transplantation. The growth rate and resuscitation rate of liquid nitrogen cryopreservation of transplanted tumors were both 100%. Significant difference in metastasis biology was exhibited in four aspects of metastasis time, organ metastatic rate, the extent of hepatic metastasis and survival of cancer-bearing mice. The metastatic rates of liver, spleen, lymph nodes and peritoneal seeding in HGBL-0304 and HGBL-0305 models were 100% and 69.5%, 94.3% and 55.6%, 62.6% and 45.7%, and 43.5% and 30.5%. The onset time for metastases of liver, spleen, lymph nodes and peritoneal seeding was 2 w and 5 w, 3 w and 6 w, 2 w and 3 w, 3 w and 6 w respectively. The extent of hepatic metastasis in HGBL-0304 and HGBL-0305 models displayed diffuse involvement of the whole liver and mainly right lobe invasion of liver respectively. The mean survival time of HGBL-0304 and HGBL-0305 models was 54.3d and 106.9 d respectively. Surgical orthotopic implantation combined with in vivo selective passage screening is an effective method for establishing highly metastatic and specific organ metastatic models of human malignant lymphoma in nude mice. The study is the first time to establish hepatic metastasis and high metastasis nude mouse models of human primary gastric lymphoma with the same original patient and different potentials of invasion and metastasis.

Predictors of the use of orthotopic bladder reconstruction after radical cystectomy for bladder cancer: data from a pilot study of 1756 cases 2004-2011.

PubMed

Hounsome, Luke S; Abel, Gary A; Verne, Julia; Neal, David E; Lyratzopoulos, Georgios

2013-06-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: How often orthotopic reconstruction should be used after radical cystectomy is uncertain. Male sex, younger age, affluence, white ethnicity and treatment in specialist hospitals may be associated with more frequent use. More evidence about the level and likely variation in the use of orthotopic surgery is needed to establish whether there are inequalities and unmet need. In England during the study period orthotopic bladder reconstruction was likely to be used in about one in 15 patients treated by radical cystectomy. This is lower than previously reported in US series or European studies. Men and younger patients were more likely to be treated by orthotopic reconstruction, as were more affluent patients and those with less advanced disease. Whether clinical reasons or patient choice can explain some of this variation is unclear. There was no evidence for variation between different English cancer networks. A specific procedure code to allow routine analysis of population-based nationwide data would be invaluable for ongoing monitoring of potential inequalities and unmet need. To examine variation in the use of orthotopic bladder reconstruction. Variability in the use of orthotopic reconstruction may indicate potential for quality improvement. We analysed data from the British Association of Urological Surgeons Cancer Registry Complex Operations data set and Hospital Episode Statistics, covering the period 2004-2011. Three-level (patient, consultant and cancer network) mixed effect logistic regression models were used to examine sociodemographic and organizational variation in use of orthotopic reconstruction. The primary outcome was the odds ratio for use of orthotopic reconstruction for different patient groups. The final analysis sample included 1756 patients with bladder cancer who were treated by cystectomy by 121 consultants in 17 cancer networks. Of these, 120 (6.8%) were treated by orthotopic bladder reconstruction by 49 consultants in 14 cancer networks. In multivariable analysis, use of orthotopic surgery was higher in younger patients (odds ratio [OR] = 0.37 per increasing 10-year age group from 30-39 to ≥70, P ≤ 0.001) and men (OR = 2.31, P = 0.005). There was also some evidence of less frequent use among more deprived patients (OR per decreasing deprivation quintile 1.17, P = 0.037) and those with advanced disease (OR per increase in stage category 0.8, P = 0.037). After accounting for patient- and consultant-level variation, there was very limited variation in the use of orthotopic reconstruction between different cancer networks. Within the study context, use of orthotopic surgery was relatively rare and variable between patients with different characteristics but not between different cancer networks. The extent by which this variation reflects variation in quality of care or patient choice is uncertain. Examining the dissemination of orthotopic surgery use using nationwide data is advisable. © 2013 BJU International.

Vincristine and irinotecan in children with relapsed hepatoblastoma: a single-institution experience.

PubMed

Zhang, Yu-tong; Feng, Li-hua; Zhong, Xiao-dan; Wang, Li-zhe; Chang, Jian

2015-02-01

This study was to determine the efficacy of vincristine and irinotecan in children with relapsed hepatoblastoma (HB). A total of 10 patients with relapsed HB were enrolled. Three patients were excluded. Patients received irinotecan 50 mg/m(2)/day, day 1-5 and vincristine 1.5 mg/m(2)/day, day 1, repeated every 3 weeks. The maximum cycles were eight. Reevaluation of tumor was performed every two cycles. The primary outcome was the rate of complete resection. Secondary outcomes were event-free survival (EFS) and overall survival (OS). Of the seven patients assessable for response, one patient with normal AFP level showed a progressive disease and withdrew. He finally died 6 months later. Four had PR, all of them underwent a second surgery and achieved complete resection. Two patients had SD, one patient relapsed 6 months after orthotopic liver transplantation and died, the other one undergoing surgery had micro margin positive, he relapsed again but alive. The rate of complete resection was 71.4% (including orthotopic liver transplantation). The 2-year EFS and OS for the whole group were 57.1% (95% CI, 12.7% to 34.2%) and 71.4% (95% CI, 16.39% to 37.4%), respectively. The combination of irinotecan and vincristine has a significant antitumor activity and acceptable toxicity in children with relapsed HB.

Quality of life after radical cystectomy for bladder cancer in men with an ileal conduit or continent urinary diversion: A comparative study

PubMed Central

Asgari, M. A.; Safarinejad, M. R.; Shakhssalim, N.; Soleimani, M.; Shahabi, A.; Amini, E.

2013-01-01

Aim: To investigate quality of life (QoL) domains with three forms of urinary diversions, including ileal conduit, MAINZ pouch, and orthotopic ileal neobladder after radical cystectomy in men with muscle-invasive bladder cancer. Materials and Methods: In a prospective study, 149 men underwent radical cystectomy and urinary diversion (70 ileal conduit, 16 MAINZ pouch, and 63 orthotopic ileal neobladder). Different domains of QoL, including general and physical conditions, psychological status, social status, sexual life, diversion-related symptoms, and satisfaction with the treatment were assessed using an author constructed questionnaire. Assessment was performed at three months postoperatively. Results: In questions addressing psychological status, social status, and sexual life, patients with continent diversion had a more favorable outcome (P = 0.002, P = 0.01, and P = 0.002, respectively). The rate of erectile dysfunction did not differ significantly between the three groups (P = 0.21). The rate and global satisfaction was higher with the MAINZ pouch (68.7%) and ileal neobladder (76.2%) as compared with the ileal conduit group (52.8%) (P = 0.002). Conclusion: Continent urinary diversion after radical cystectomy provides better results in terms of QoL as compared with ileal conduit diversion. PMID:24049384

Endoscopic treatment of bile duct complications after orthotopic liver transplantation.

PubMed

Polese, L; Cillo, U; Brolese, A; Boccagni, P; Neri, D; Bassi, D; Erroi, F; Zanus, G; D'Amico, D F; Norberto, L

2007-01-01

To assess the indications and results of endoscopic retrograde cholangio-pancreatography (ERCP) in patients who have undergone ortotopic liver transplantation (OLT). We reviewed data from 42 consecutive patients who underwent ERCP for biliary complications after OLT over an 8-year period, in particular recording indications and success of the treatment after a mean of 17 months follow-up. Cholangiograms performed in 33/42 patients (79%) displayed anastomotic strictures in 17 patients (52%), bile duct stones in 8 (24%), both bile duct stones and an anastomotic stricture in 2 (6%), papillary stenosis in 1 (3%), and anastomotic biliary leakage in 1 (3%). In contrast, the contrastogram was normal in four patients (12%). Stone extraction was completed in 9/10 patients (90%) with a mean of 1.2 sessions, while stricture dilation was achieved in 12/19 patients (63%) after a mean of 1.7 sessions, by stent positioning (n = 7), balloon dilation (n = 4), or Soehendra dilator (n = 1). Both biliary leakage and papillary stenosis were cured by ERCP. Only one procedure-related complication -- severe pancreatitis (2.4%) -- was observed and no mortality. ERCP is a safe and effective mode of management of bile duct complications after OLT. It should be attempted before a surgical approach. Better results are obtained for treatment of biliary stones than of anastomotic strictures.

Cerebrovascular Complications After Heart Transplantation

PubMed Central

Alejaldre, Aída; Delgado-Mederos, Raquel; Santos, Miguel Ángel; Martí-Fàbregas, Joan

2010-01-01

Neurological complications in orthotopic heart transplantation represent a major cause of morbidity and mortality despite successful transplantation. The most frequent perioperative neurological complications are delirium or encephalopathy. In this period cerebrovascular complication ranges between 5-11%. After the perioperative period, the 5-year stroke risk after cardiac transplantation is 4.1%. In a retrospective study conducted with 314 patients who underwent cardiac transplantation, it was found that 20% of cerebrovascular complications occurred within the first two weeks after transplantation, while 80% occurred in the late postoperative phase. Of these, ischemic stroke is the most common subtype. In the perioperative periode, hemodynamic instability, cardiac arrest, extracorporeal circulation over 2 hours, prior history of stroke, and carotid stenosis greater than 50% have been reported to be risk factors for the occurrence of cerebrovascular complications. Perioperative cerebrovascular complications are associated with higher mortality and poor functional outcome at one year follow-up. After the perioperative period, the only factor that has been significantly associated with an increased risk of cerebrovascular complications is a history of prior stroke, either ischemic or hemorrhagic. Other associated factors include unknown atrial fibrillation, septic emboli from endocarditis, cardiac catheterization and perioperative hemodynamic shock. According to the TOAST etiologic classification, the most prevalent etiologic subtype of ischemic stroke is undetermined cause. PMID:21804780

Liver transplantation in Greek children: 15 years experience

PubMed Central

Xinias, Ioannis; Mavroudi, Antigoni; Vrani, Olga; Imvrios, Georgios; Takoudas, Dimitrios; Spiroglou, Kleomenis

2010-01-01

Liver transplantation (LT) is the only available live-saving procedure for children with irreversible liver failure. This paper reports our experience from the follow-up of 16 Greek children with end-stage liver failure who underwent a LT. Over a period of 15 years, 16 pediatric liver recipients received follow up after being subjected to OLT (orthotopic liver transplantation) due to end-stage liver failure. Nine children initially presented with extrahepatic biliary atresia, 2 with acute liver failure after toxic mushroom ingestion, 2 with intrahepatic cholestasis, 2 with metabolic diseases and one with hepatoblastoma. Ten children received a liver transplant in the Organ Transplantation Unit of Aristotle University of Thessaloniki and the rest in other transplant centers. Three transplants came from a living-related donor and 13 from a deceased donor. Six children underwent immunosuppressive treatment with cyclosporine, mycophenolate mofetil and corticosteroids, and 7 with tacrolimus, mycophenolate mofetil and corticosteroids. Three out of 16 children died within the first month after the transplantation due to post-transplant complications. Three children presented with acute rejection and one with chronic organ rejection which was successfully managed. Five children presented with cytomegalovirus infection, 5 with Epstein-Barr virus, 2 with HSV1,2, 2 with ParvoB19 virus, 2 with varicella-zoster virus and one with C. Albicans infection. One child presented with upper gastrointestinal hemorrhage and one with small biliary paucity. A satisfying outcome was achieved in most cases, with good graft function, except for the patient with small biliary paucity who required re-transplantation. The long-term clinical course of liver transplanted children is good under the condition that they are attended in specialized centers. PMID:21589827

Prediction of early postoperative infections in pediatric liver transplantation by logistic regression

NASA Astrophysics Data System (ADS)

Uzunova, Yordanka; Prodanova, Krasimira; Spassov, Lubomir

2016-12-01

Orthotopic liver transplantation (OLT) is the only curative treatment for end-stage liver disease. Early diagnosis and treatment of infections after OLT are usually associated with improved outcomes. This study's objective is to identify reliable factors that can predict postoperative infectious morbidity. 27 children were included in the analysis. They underwent liver transplantation in our department. The correlation between two parameters (the level of blood glucose at 5th postoperative day and the duration of the anhepatic phase) and postoperative infections was analyzed, using univariate analysis. In this analysis, an independent predictive factor was derived which adequately identifies patients at risk of infectious complications after a liver transplantation.

Comparison of Causes of Death After Heart Transplantation in Patients With Left Ventricular Ejection Fractions ≤35% Versus >35.

PubMed

Birati, Edo Y; Mathelier, Hansie; Molina, Maria; Hanff, Thomas C; Mazurek, Jeremy A; Atluri, Pavan; Acker, Michael A; Rame, J Eduardo; Margulies, Kenneth B; Goldberg, Lee R; Jessup, Mariell

2016-04-15

Sudden cardiac death (SCD) is a common cause of death in the general population, occurring in 300,000 to 350,000 people in the United States alone. Currently, there are no data supporting implantable cardioverter-defibrillator therapy in patients who underwent orthotopic heart transplant (OHT) with low left ventricular ejection fraction (LVEF). In this retrospective study, we included all patients who underwent primary OHT at our institution from 2007 to 2013. We compared the cause of death in patients who underwent OHT and evaluated the correlation of the cause of death and the patients' LVEF. Our objectives were to determine whether patients who underwent OHT with LVEF <35% are at increased risk for SCD compared with those who underwent OHT with normal LVEF. To summarize our results, a total of 345 patients were included in our study (mean age 50 ± 14 years, 68% men). The mean follow-up was 1,260 ± 698 days. Forty patients (11.5%) died >6 months after OHT. Surviving patients had higher LVEF compared with deceased patients (64 ± 7% and 50 ± 24%, respectively, p ≤0.001). In all, 10 (25%) of the deceased patients died suddenly, 9 (23%) from sepsis, and 8 (20%) from malignancy. Of the 11 deceased patients with LVEF ≤35%, 2 patients (18%) died suddenly compared with 9 SCDs among the 29 deceased patients (31%) with LVEF >35% (p = 0.54). In conclusion, patients who underwent OHT who died were more likely to have LVEF <35%, and a quarter of the deceased patients who underwent OHT died suddenly. A reduced LVEF was not associated with an increased risk of SCD. Copyright © 2016 Elsevier Inc. All rights reserved.

Prevalence, Cause, and Treatment of Respiratory Insufficiency After Orthotopic Heart Transplant.

PubMed

Savaş Bozbaş, Şerife; Ulubay, Gaye; Öner Eyüboğlu, Füsun; Sezgin, Atilla; Haberal, Mehmet

2015-11-01

Heart transplant is the best treatment for end-stage heart failure. Respiratory insufficiency after heart transplant is a potentially serious complication. Pulmonary complications, pulmonary hypertension, allograft failure or rejection, and structural heart defects in the donor heart are among the causes of hypoxemia after transplant. In this study, we evaluated the prevalence of hypoxemia and respiratory insufficiency in patients with orthotopic heart transplant during the early postoperative period. We retrospectively evaluated the medical records of 45 patients who had received orthotopic heart transplant at our center. Clinical and demographic variables and laboratory data were noted. Oxygen saturation values from patients in the first week and the first month after transplant were analyzed. We also documented the cause of respiratory insufficiency and the type of treatment. Mean age was 35.3 ± 15.3 years (range, 12-61 y), with males comprising 32 of 45 patients (71.1%). Two patients had mild chronic obstructive pulmonary disease and 1 had asthma. Twenty-five patients (55.6%) had a history of smoking. Respiratory insufficiency was noted in 9 patients (20%) during the first postoperative week. Regarding cause, 5 of these patients (11.1%) had pleural effusion, 2 (4.4%) had atelectasis, 1 (2.2%) had pneumonia, and 1 (2.2%) had acute renal failure. Therapies administered to patients with respiratory insufficiency were as follows: 5 patients had oxygen therapy with nasal canula/mask, 3 patients had continuous positive airway pressure, and 1 patient had mechanical ventilation. One month after transplant, 2 patients (4.4%) had respiratory insufficiency 1 (2.2%) due to pleural effusion and 1 (2.2%) due to atelectasis. Respiratory insufficiency is a common complication in the first week after orthotopic heart transplant. Identification of the underlying cause is an important indicator for therapy. With appropriate care, respiratory insufficiency can be treated successfully.

Usefulness for Predicting Cardiac Events After Orthotopic Liver Transplantation of Myocardial Perfusion Imaging and Dobutamine Stress Echocardiography Preoperatively.

PubMed

Snipelisky, David; Ray, Jordan; Vallabhajosyula, Saraschandra; Matcha, Gautam; Squier, Samuel; Lewis, Jacob; Holliday, Rex; Aggarwal, Niti; Askew, J Wells; Shapiro, Brian; Anavekar, Nandan

2017-04-01

Patients undergoing orthotopic liver transplantation have high rates of cardiac morbidity and mortality. Although guidelines recommend noninvasive stress testing as part of the preoperative evaluation, little data have evaluated clinical outcomes following orthotopic liver transplantation. A retrospective study at 2 high-volume liver transplantation centers was performed. All patients undergoing noninvasive stress testing (myocardial perfusion imaging [MPI] or dobutamine stress echocardiography [DSE]) over a 5-year period were included. Descriptive analyses, including clinical outcomes and perioperative and postoperative ischemic events, were performed. Comparisons were made between subsets of patients within each stress modality based on abnormal versus normal results. A total of 506 patients were included, of which 343 underwent DSE and 163 MPI. Few patients had abnormal results, with 19 (5.5%) in the DSE group and 13 (8%) in the MPI group. Perioperative and postoperative cardiac complications were low (n = 20, 5.8% and n = 3, 0.9% in DSE group and n = 15, 9.2% and n = 3, 1.8% in MPI group). Comparisons between abnormal versus normal findings showed a trend toward periprocedural cardiac complications in the abnormal DSE group (n = 3, 15.8% vs n = 17, 5.25%; p = 0.09) with no difference in 6-month postprocedural complications (n = 0 vs n = 3, 0.9%; p = 1.0). In the MPI group, a trend toward periprocedural ischemic complications (n = 3, 23.1% vs n = 12, 8%; p = 0.1) was noted with no difference in 6-month postprocedural complications (n = 0 vs n = 3, 2%; p = 1.0). In conclusion, our study found a significantly lower than reported cardiac event rate. In addition, it demonstrated that ischemic cardiac events are uncommon in patients with normal stress testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Cluster analysis identifies three urodynamic patterns in patients with orthotopic neobladder reconstruction.

PubMed

Kim, Kwang Hyun; Yoon, Hyun Suk; Song, Wan; Choo, Hee Jung; Yoon, Hana; Chung, Woo Sik; Sim, Bong Suk; Lee, Dong Hyeon

2017-01-01

To classify patients with orthotopic neobladder based on urodynamic parameters using cluster analysis and to characterize the voiding function of each group. From January 2012 to November 2015, 142 patients with bladder cancer underwent radical cystectomy and Studer neobladder reconstruction at our institute. Of the 142 patients, 103 with complete urodynamic data and information on urinary functional outcomes were included in this study. K-means clustering was performed with urodynamic parameters which included maximal cystometric capacity, residual volume, maximal flow rate, compliance, and detrusor pressure at maximum flow rate. Three groups emerged by cluster analysis. Urodynamic parameters and urinary function outcomes were compared between three groups. Group 1 (n = 44) had ideal urodynamic parameters with a mean maximal bladder capacity of 513.3 ml and mean residual urine volume of 33.1 ml. Group 2 (n = 42) was characterized by small bladder capacity with low compliance. Patients in group 2 had higher rates of daytime incontinence and nighttime incontinence than patients in group 1. Group 3 (n = 17) was characterized by large residual urine volume with high compliance. When we examined gender differences in urodynamics and functional outcomes, residual urine volume and the rate of daytime incontinence were only marginally significant. However, females were significantly more likely to belong to group 2 or 3 (P = 0.003). In multivariate analysis to identify factors associated with group 1 which has the most ideal urodynamic pattern, age (OR 0.95, P = 0.017) and male gender (OR 7.57, P = 0.003) were identified as significant factors. While patients with ileal neobladder present with various voiding symptoms, three urodynamic patterns were identified by cluster analysis. Approximately half of patients had ideal urodynamic parameters. The other two groups were characterized by large residual urine and small capacity bladder with low compliance. Young age and male gender appear to have a favorable impact on urodynamic and voiding outcomes in patients undergoing orthotopic neobladder reconstruction.

A High Capacity Polymeric Micelle of Paclitaxel: Implication of High Dose Drug Therapy to Safety and In Vivo Anti-Cancer Activity

PubMed Central

He, Zhijian; Wan, Xiaomeng; Schulz, Anita; Bludau, Herdis; Dobrovolskaia, Marina A.; Stern, Stephan T.; Montgomery, Stephanie A.; Yuan, Hong; Li, Zibo; Alakhova, Daria; Sokolsky, Marina; Darr, David B.; Perou, Charles M.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.

2016-01-01

The poor solubility of paclitaxel (PTX), the commercially most successful anticancer drug, has long been hampering the development of suitable formulations. Here, we present translational evaluation of a nanoformulation of PTX, which is characterized by a facile preparation, extraordinary high drug loading of 50 % wt. and PTX solubility of up to 45 g/L, excellent shelf stability and controllable, sub-100 nm size. We observe favorable in vitro and in vivo safety profiles and a higher maximum tolerated dose compared to clinically approved formulations. Pharmacokinetic analysis reveals that the higher dose administered leads to a higher exposure of the tumor to PTX. As a result, we observed improved therapeutic outcome in orthotopic tumor models including particularly faithful and aggressive “T11” mouse claudin-low breast cancer orthotopic, syngeneic transplants. The promising preclinical data on the presented PTX nanoformulation showcase the need to investigate new excipients and is a robust basis to translate into clinical trials. PMID:27315213

In vitro culture and characterization of human lung cancer circulating tumor cells isolated by size exclusion from an orthotopic nude-mouse model expressing fluorescent protein.

PubMed

Kolostova, Katarina; Zhang, Yong; Hoffman, Robert M; Bobek, Vladimir

2014-09-01

In the present study, we demonstrate an animal model and recently introduced size-based exclusion method for circulating tumor cells (CTCs) isolation. The methodology enables subsequent in vitro CTC-culture and characterization. Human lung cancer cell line H460, expressing red fluorescent protein (H460-RFP), was orthotopically implanted in nude mice. CTCs were isolated by a size-based filtration method and successfully cultured in vitro on the separating membrane (MetaCell®), analyzed by means of time-lapse imaging. The cultured CTCs were heterogeneous in size and morphology even though they originated from a single tumor. The outer CTC-membranes were blebbing in general. Abnormal mitosis resulting in three daughter cells was frequently observed. The expression of RFP ensured that the CTCs originated from lung tumor. These readily isolatable, identifiable and cultivable CTCs can be used to characterize individual patient cancers and for screening of more effective treatment.

Nanoparticle-assisted photothermal ablation of brain tumor in an orthotopic canine model

NASA Astrophysics Data System (ADS)

Schwartz, Jon A.; Shetty, Anil M.; Price, Roger E.; Stafford, R. Jason; Wang, James C.; Uthamanthil, Rajesh K.; Pham, Kevin; McNichols, Roger J.; Coleman, Chris L.; Payne, J. Donald

2009-02-01

We report on a pilot study demonstrating a proof of concept for the passive delivery of nanoshells to an orthotopic tumor where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photo-thermal ablation of canine Transmissible Venereal Tumor (cTVT) in a canine brain model. cTVT fragments grown in SCID mice were successfully inoculated in the parietal lobe of immuno-suppressed, mixed-breed hound dogs. A single dose of near-infrared absorbing, 150 nm nanoshells was infused intravenously and allowed time to passively accumulate in the intracranial tumors which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the intracranial cTVT suggesting that its neo-vasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, near-infrared radiation using a 3.5 W average, 3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8+/-4.1ºC. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sub-lethal temperatures of 48.6+/-1.1ºC. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Post-mortem histopathology of treated brain sections demonstrated the effectiveness and selectivity of the nanoshell-assisted thermal ablation.

Periosteum tissue engineering in an orthotopic in vivo platform.

PubMed

Baldwin, J G; Wagner, F; Martine, L C; Holzapfel, B M; Theodoropoulos, C; Bas, O; Savi, F M; Werner, C; De-Juan-Pardo, E M; Hutmacher, D W

2017-03-01

The periosteum plays a critical role in bone homeostasis and regeneration. It contains a vascular component that provides vital blood supply to the cortical bone and an osteogenic niche that acts as a source of bone-forming cells. Periosteal grafts have shown promise in the regeneration of critical size defects, however their limited availability restricts their widespread clinical application. Only a small number of tissue-engineered periosteum constructs (TEPCs) have been reported in the literature. A current challenge in the development of appropriate TEPCs is a lack of pre-clinical models in which they can reliably be evaluated. In this study, we present a novel periosteum tissue engineering concept utilizing a multiphasic scaffold design in combination with different human cell types for periosteal regeneration in an orthotopic in vivo platform. Human endothelial and bone marrow mesenchymal stem cells (BM-MSCs) were used to mirror both the vascular and osteogenic niche respectively. Immunohistochemistry showed that the BM-MSCs maintained their undifferentiated phenotype. The human endothelial cells developed into mature vessels and connected to host vasculature. The addition of an in vitro engineered endothelial network increased vascularization in comparison to cell-free constructs. Altogether, the results showed that the human TEPC (hTEPC) successfully recapitulated the osteogenic and vascular niche of native periosteum, and that the presented orthotopic xenograft model provides a suitable in vivo environment for evaluating scaffold-based tissue engineering concepts exploiting human cells. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Can tricuspid annuloplasty of the donor heart reduce valve insufficiency following cardiac transplantation with bicaval anastomosis?

PubMed

Fiorelli, Alfredo I; Oliveira, José L; Santos, Ronaldo H B; Coelho, Guilherme B; Oliveira, Adriana S; Lourenço-Filho, Domingos D; Lapenna, Gisele; Dias, Ricardo R; Bacal, Fernando; Bocchi, Edimar A; Stolf, Noedir A G

2010-06-01

The aim of this study was to evaluate the degree of tricuspid valve insufficiency after orthotopic cardiac transplantation with bicaval anastomosis and prophylactic donor heart annuloplasty. At present, our cardiac transplantation experience includes 478 cases. After January 2002, we included 30 consecutive patients in this study who had undergone orthotopic cardiac transplantation and survived >6 months. The patients were divided into 2 groups: group I, 15 patients who underwent transplantation with prophylactic tricuspid annuloplasty on the donor heart with the De Vega technique; and group II, 15 patients who underwent transplantation without this procedure. Their preoperative clinical characteristics were the same. During the late postoperative follow-up, the degree of tricuspid insufficiency was evaluated by transthoracic Doppler echocardiography and assessed according to the Simpson scale: 0, absent; 1, mild; 2, moderate; and 3, severe. Hemodynamic parameters were evaluated invasively by means of a Swan-Ganz catheter during routine endomyocardial biopsies. The mean follow-up time was 26.9 +/- 5.4 months (range, 12-36 months). In group I, 1 patient (6.6%) died from infection in the 18th month after the operation; the death was not related to the annuloplasty. In group II, 1 death (6.6%) occurred after 10 months because of rejection (P > .05). After the 24-month follow-up, the mean degree of tricuspid insufficiency was 0.4 +/- 0.5 in group I and 1.7 +/- 0.9 in group II (P < .05). Similarly, the 2 groups were significantly different with respect to the right atrium pressure, which was higher in group II. Prophylactic tricuspid annuloplasty on the donor heart was able to reduce significantly the degree of valvular insufficiency, even in cardiac transplantation with bicaval anastomosis; however, it did not modify significantly the hemodynamic performance of the allograft during the investigation period. It is very important to extend the observation period and casuistics to verify other benefits that this technique may offer.

Exploratory use of cardiovascular magnetic resonance imaging in liver transplantation: a one-stop shop for preoperative cardiohepatic evaluation.

PubMed

Reddy, Sahadev T; Thai, Ngoc L; Fakhri, Asghar A; Oliva, Jose; Tom, Kusum B; Dishart, Michael K; Doyle, Mark; Yamrozik, June A; Williams, Ronald B; Grant, Saundra B; Poydence, Jacqueline; Shah, Moneal; Singh, Anil; Nathan, Swami; Biederman, Robert W W

2013-11-15

Preoperative cardiovascular risk stratification in orthotopic liver transplantation candidates has proven challenging due to limitations of current noninvasive modalities. Additionally, the preoperative workup is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We evaluated the feasibility of a "one-stop shop" in a magnetic resonance suite, performing assessment of cardiac structure, function, and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy. In this pilot study, patients underwent steady-state free precession sequences and stress cardiac magnetic resonance (CMR), thoracoabdominal magnetic resonance angiography, and abdominal magnetic resonance imaging (MRI) on a standard MRI scanner. Pharmacologic stress was performed using regadenoson, adenosine, or dobutamine. Viability was assessed using late gadolinium enhancement. Over 2 years, 51 of 77 liver transplant candidates (mean age, 56 years; 35% female; mean Model for End-stage Liver Disease score, 10.8; range, 6-40) underwent MRI. All referred patients completed standard dynamic CMR, 98% completed stress CMR, 82% completed late gadolinium enhancement for viability, 94% completed liver MRI, and 88% completed magnetic resonance angiography. The mean duration of the entire study was 72 min, and 45 patients were able to complete the entire examination. Among all 51 patients, 4 required follow-up coronary angiography (3 for evidence of ischemia on perfusion CMR and 1 for postoperative ischemia), and none had flow-limiting coronary disease. Nine proceeded to orthotopic liver transplantation (mean 74 days to transplantation after MRI). There were six ascertained mortalities in the nontransplant group and one death in the transplanted group. Explant pathology confirmed 100% detection/exclusion of hepatocellular carcinoma. No complications during CMR examination were encountered. In this proof-of-concept study, it appears feasible to perform a comprehensive, efficient, and safe preoperative liver transplant imaging in a CMR suite-a one-stop shop, even in seriously ill patients.

Role of Stereotactic Body Radiation Therapy Before Orthotopic Liver Transplantation: Retrospective Evaluation of Pathologic Response and Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mannina, Edward Michael, E-mail: emmannina@gmail.com; Cardenes, Higinia Rosa; Lasley, Foster D.

Purpose: To analyze the results of stereotactic body radiation therapy (SBRT) in patients with early-stage, localized hepatocellular carcinoma who underwent definitive orthotopic liver transplantation (OLT). Methods and Materials: The subjects of this retrospective report are 38 patients diagnosed with hepatocellular carcinoma who underwent SBRT per institutional phase 1 to 2 eligibility criteria, before definitive OLT. Pre-OLT radiographs were compared with pathologic gold standard. Analysis of treatment failures and deaths was undertaken. Results: With median follow-up of 4.8 years from OLT, 9 of 38 patients (24%) recurred, whereas 10 of 38 patients (26%) died. Kaplan-Meier estimates of 3-year overall survival and disease-free survivalmore » are 77% and 74%, respectively. Sum longest dimension of tumors was significantly associated with disease-free survival (hazard ratio 1.93, P=.026). Pathologic response rate (complete plus partial response) was 68%. Radiographic scoring criteria performed poorly; modified Response Evaluation Criteria in Solid Tumors produced highest concordance (κ = 0.224). Explants revealed viable tumor in 74% of evaluable patients. Treatment failures had statistically larger sum longest dimension of tumors (4.0 cm vs 2.8 cm, P=.014) and non–statistically significant higher rates of lymphovascular space invasion (44% vs 17%), cT2 disease (44% vs 21%), ≥pT2 disease (67% vs 34%), multifocal tumors at time of SBRT (44% vs 21%), and less robust mean α-fetoprotein response (−25 IU/mL vs −162 IU/mL). Conclusions: Stereotactic body radiation therapy before to OLT is a well-tolerated treatment providing 68% pathologic response, though 74% of explants ultimately contained viable tumor. Radiographic response criteria poorly approximate pathology. Our data suggest further stratification of patients according to initial disease burden and treatment response.« less

Convection-Enhanced Delivery (CED) in an Animal Model of Malignant Peripheral Nerve Sheath Tumors and Plexiform Neurofibromas

DTIC Science & Technology

2013-02-01

successfully establish the xenograft within the sciatic nerve. Convection-Enhanced Delivery ( CED ), Malignant Peripheral Nerve Sheath ( MPNST ), Plexiform...intraneural PNs and MPNST via CED . Design: Orthotopic xenograft models of sciatic intraneural NF1 MPNST and PNs in scid mice as described by Perrin et...using convection-enhanced delivery ( CED ). Relative Growth of MPNST cells in vivo treated with rapamycin, imatinib or erlotinib: Elotinib

Evaluation of Multimodal Imaging Biomarkers of Prostate Cancer

DTIC Science & Technology

2015-09-01

and PET images. Figure 2 highlights the dynamic uptake of TSPO as compared to muscle. Across 60 minutes the %ID/cc continues to increase which is...p53 double null mutant mouse model. Towards that end, we have successfully acquired anatomic MRI and PET data in orthotopic tumors within the Pten...castration resistant prostate cancer, MRI, PET , FDHT, image optimization 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES

Twenty-Year Outcome After Right Ventricular Outflow Tract Repair Using Heterotopic Pulmonary Conduits in Infants and Children.

PubMed

Hoxha, Stiljan; Torre, Salvatore; Rungatscher, Alessio; Sandrini, Camilla; Rossetti, Lucia; Barozzi, Luca; Faggian, Giuseppe; Luciani, Giovanni Battista

2016-01-01

Durability of pulmonary conduits (PCs) used for reconstruction of the right ventricular outflow tract (RVOT) may be affected by a variety of factors. Among these, the technique used for PC implantation, whether in orthotopic or heterotopic position, strictly dependent upon the underlying anatomy, has been suggested to influence long-term outcome after RVOT repair. To determine the outcome of heterotopic implantation in infants and children treated at our institution, late results of heterotopic PC in non-Ross patients were analyzed and compared with data of orthotopic PC in age-matched pediatric Ross patients operated during the same time period. Between November 1991 and January 2015, 58 infants and children, 32 male and 26 female, with a median age of 9.4 years (range 1 day-18 years) underwent implantation of heterotopic PC (31 homografts [HG] and 27 xenografts [XG]) for reconstruction of RVOT. Median age in the XG group was significantly lower than in the HG group (0.9 vs. 13.4 years, P = 0.01), while male/female ratio was similar. Fifty (86%) patients had undergone one or more prior cardiac operations, while 32 (55%) required associated procedures during PC implantation. Comparison with data in 305 children and with a median age of 9.4 years, receiving orthotopic PC between 1990 and 2012 (Italian Pediatric Ross Registry), was undertaken. Descriptive, univariate, and Kaplan-Meier analysis defined outcome. There were three (5.2%) early and five (9.0%) late deaths, during a median follow-up of 7.6 years (range 2 months-23 years). Patients having XG had trend toward higher hospital mortality (2/27 vs. 1/31, P = 0.2), but similar late mortality (2/24 vs. 3/30, P = 0.3). Overall survival was 88 and 62%, while freedom from PC replacement was 49 and 21%, at 10 and 20 years, respectively. The latter proved significantly worse than freedom from orthotopic PC replacement, which was 94 ± 2 and 70 ± 9% at 10 and 20 years (P = 0.02). When stratified for type of heterotopic PC, late survival proved comparable (81 and 81% for XG vs. 92 and 60% for HG, at 10 and 20 years, respectively, P = 0.7). However, freedom from PC replacement was significantly higher in patients with heterotopic HG (21 and 5% for XG vs. 63 and 48% for HG, at 10 and 20 years, respectively, P = 0.001). RVOT repair using either XG or HG in heterotopic position is a safe procedure associated with low hospital mortality and satisfactory late survival. Freedom from reoperation is significantly lower than that observed in age-matched children having orthotopic HG. Freedom from reoperation in heterotopic XG is poorer than in HG, although different baseline demography may have influenced this finding. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Response of the oxygen uptake efficiency slope to orthotopic heart transplantation: lack of correlation with changes in central hemodynamic parameters and resting lung function.

PubMed

Van Laethem, Christophe; Goethals, Marc; Verstreken, Sofie; Walravens, Maarten; Wellens, Francis; De Proft, Margot; Bartunek, Jozef; Vanderheyden, Marc

2007-09-01

Recently, a new linear measure of ventilatory response to exercise, the oxygen uptake efficiency slope (OUES), was proposed in the evaluation of heart failure patients. No data are available on the response of the OUES after orthotopic heart transplantation (HTx). Thirty patients who underwent HTx between 1999 and 2003 were included in the study. Data from maximal cardiopulmonary exercise test, resting pulmonary function and hemodynamic assessment were collected before the transplant at time of screening and 1 year after HTx. During the first year after HTx, OUES and normalized OUES for body weight (OUES/kg) increased significantly from 15.6 +/- 4.9 to 19.7 +/- 4.8 (p < 0.05). Changes in OUES/kg were significantly correlated with changes in peak VO2, VAT and peak VE, and inversely to changes in peak VD/VT, but not to changes in VE/VCO2 slope (all p < 0.05). Changes in OUES or OUES/kg did not correlate with any changes in measures of resting lung volumes or capacities and measures of central hemodynamic function after HTx. OUES improved significantly after HTx, but, similar to other exercise parameters, remained considerably impaired. The changes in OUES were highly correlated with the improvements in other exercise variables, but did not correlate with marked improvements in central hemodynamics or resting lung function.

Predictors of renal function recovery among patients undergoing renal replacement therapy following orthotopic liver transplantation.

PubMed

Andreoli, Maria Claudia Cruz; Souza, Nádia Karina Guimarães de; Ammirati, Adriano Luiz; Matsui, Thais Nemoto; Carneiro, Fabiana Dias; Ramos, Ana Claudia Mallet de Souza; Iizuca, Ilson Jorge; Coelho, Maria Paula Vilela; Afonso, Rogério Carballo; Ferraz-Neto, Ben-Hur; Almeida, Marcio Dias de; Durão, Marcelino; Batista, Marcelo Costa; Monte, Julio Cesar; Pereira, Virgílio Gonçalves; Santos, Oscar Pavão Dos; Santos, Bento Cardoso Dos

2017-01-01

Renal dysfunction frequently occurs during the periods preceding and following orthotopic liver transplantation (OLT), and in many cases, renal replacement therapy (RRT) is required. Information regarding the duration of RRT and the rate of kidney function recovery after OLT is crucial for transplant program management. We evaluated a sample of 155 stable patients undergoing post-intensive care hemodialysis (HD) from a patient population of 908 adults who underwent OLT. We investigated the average time to renal function recovery (duration of RRT required) and determined the risk factors for remaining on dialysis > 90 days after OLT. Log-rank tests were used for univariate analysis, and Cox proportional hazards models were used to identify factors associated with the risk of remaining on HD. The results of our analysis showed that of the 155 patients, 28% had pre-OLT diabetes mellitus, 21% had pre-OLT hypertension, and 40% had viral hepatitis. Among the patients, the median MELD (Model for End-Stage Liver Disease) score was 27 (interquartile range [IQR] 22-35). When they were listed for liver transplantation, 32% of the patients had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD, and 50% had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD at the time of OLT. Of the transplanted patients, 25% underwent pre-OLT intermittent HD, and 14% and 41% underwent continuous renal replacement therapy (CRRT) pre-OLT and post-OLT, respectively. At 90 days post-OLT, 118 (76%) patients had been taken off dialysis, and 16 (10%) patients had died while undergoing HD. The median recovery time of these post-OLT patients was 33 (IQR 27-39) days. In the multivariate analysis, fulminant hepatic failure as the cause of liver disease (p<0.001), the absence of pre-OLT hypertension (p = 0.016), a lower intraoperative fresh-frozen plasma (FFP) transfusion volume (p = 0.019) and not undergoing pre-OLT intermittent HD (p = 0.032) were associated with performing RRT for less than 90 days. Therefore, a high proportion of OLT patients showed improved renal function after OLT, and those who were diagnosed with fulminant hepatic failure, had no pre-OLT hypertension, received a lower transfused volume of intraoperative FFP and did not undergo pre-OLT intermittent HD had a higher probability of recovery.

Predictors of renal function recovery among patients undergoing renal replacement therapy following orthotopic liver transplantation

PubMed Central

de Souza, Nádia Karina Guimarães; Ammirati, Adriano Luiz; Matsui, Thais Nemoto; Carneiro, Fabiana Dias; Ramos, Ana Claudia Mallet de Souza; Iizuca, Ilson Jorge; Afonso, Rogério Carballo; Ferraz-Neto, Ben-Hur; de Almeida, Marcio Dias; Durão, Marcelino; Batista, Marcelo Costa; Monte, Julio Cesar; Pereira, Virgílio Gonçalves; dos Santos, Oscar Pavão

2017-01-01

Renal dysfunction frequently occurs during the periods preceding and following orthotopic liver transplantation (OLT), and in many cases, renal replacement therapy (RRT) is required. Information regarding the duration of RRT and the rate of kidney function recovery after OLT is crucial for transplant program management. We evaluated a sample of 155 stable patients undergoing post-intensive care hemodialysis (HD) from a patient population of 908 adults who underwent OLT. We investigated the average time to renal function recovery (duration of RRT required) and determined the risk factors for remaining on dialysis > 90 days after OLT. Log-rank tests were used for univariate analysis, and Cox proportional hazards models were used to identify factors associated with the risk of remaining on HD. The results of our analysis showed that of the 155 patients, 28% had pre-OLT diabetes mellitus, 21% had pre-OLT hypertension, and 40% had viral hepatitis. Among the patients, the median MELD (Model for End-Stage Liver Disease) score was 27 (interquartile range [IQR] 22-35). When they were listed for liver transplantation, 32% of the patients had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD, and 50% had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD at the time of OLT. Of the transplanted patients, 25% underwent pre-OLT intermittent HD, and 14% and 41% underwent continuous renal replacement therapy (CRRT) pre-OLT and post-OLT, respectively. At 90 days post-OLT, 118 (76%) patients had been taken off dialysis, and 16 (10%) patients had died while undergoing HD. The median recovery time of these post-OLT patients was 33 (IQR 27–39) days. In the multivariate analysis, fulminant hepatic failure as the cause of liver disease (p<0.001), the absence of pre-OLT hypertension (p = 0.016), a lower intraoperative fresh-frozen plasma (FFP) transfusion volume (p = 0.019) and not undergoing pre-OLT intermittent HD (p = 0.032) were associated with performing RRT for less than 90 days. Therefore, a high proportion of OLT patients showed improved renal function after OLT, and those who were diagnosed with fulminant hepatic failure, had no pre-OLT hypertension, received a lower transfused volume of intraoperative FFP and did not undergo pre-OLT intermittent HD had a higher probability of recovery. PMID:28574999

Real-time Non-invasive Spectral Imaging of Orthotopic Red Fluorescent Protein-expressing Lung Tumor Growth in Nude Mice.

PubMed

Zhang, Yong; Zhang, Nan; Zhao, Ming; Hoffman, Robert M

2015-07-01

Orthotopic implantation of cancer allows metastasis to occur. The most patient-like metastatic orthotopic models are developed with surgical orthotopic implantation using intact tissue in order to preserve the natural tissue structure of the tumor which contains both cancer cells and stroma. In the present study, we performed a simple thoracotomy by making an intercostal incision between the fourth and fifth ribs on the left side of the chest of nude mice. Lung tumor fragments expressing red fluorescent protein were then implanted on the left lung. It was possible to monitor tumor formation in the lung non-invasively by spectral imaging using the Maestro system with a liquid tunable filter. The model described here has high tumorigenicity in the lung (100%) and a low mortality rate (5%). This imageable nude mouse model using surgical orthotopic implantation of lung cancer will be useful for all types of longitudinal studies. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Venous outflow obstruction and portopulmonary hypertension after orthotopic liver transplantation

PubMed Central

Aguirre-Avalos, Guadalupe; Covarrubias-Velasco, Marco Antonio; Rojas-Sánchez, Antonio Gerardo

2013-01-01

Patient: Female, 54 Final Diagnosis: Suprahepatic inferior vena cava anastomosis stricture Symptoms: Ascites • fatigue • lower limb edema • hepatomegaly Medication: — Clinical Procedure: — Specialty: Transplantology • Critical Care Medicine Objective: Unusual clinical course Background: Suprahepatic inferior vena cava anastomosis stricture is an unusual vascular complication after orthotopic liver transplantation with the “piggyback” technique. Clinical manifestations are dependent upon the severity of the stenosis. Portopulmonary hypertension after orthotopic liver transplantation is a complication that carries high mortality due to cardiopulmonary dysfunction. The pathogenesis of pulmonary vascular disorders after orthotopic liver transplantation remains uncertain. Case Report: We report a case of acute right heart pressure overload after surgical correction of the suprahepatic inferior vena cava anastomotic stricture in a 54-year-old woman who had preexisting pulmonary arterial hypertension associated with portal hypertension after orthotopic liver transplantation. Twenty months posttransplantation, she developed fatigue and progressive ascites. On admission, the patient had hepatomegaly, ascites, and lower limb edema. Symptoms in the patient developed gradually over time. Conclusions: Recurrent portal hypertension by vascular complications is a cause of pulmonary arterial hypertension after orthotopic liver transplantation. Clinical manifestations of suprahepatic inferior vena cava anastomotic stenosis are dependent upon their severity. Sildenafil is an effective drug for treatment of pulmonary arterial hyper-tension after portal hypertension by vascular complications. PMID:24046802

Effectivity of pazopanib treatment in orthotopic models of human testicular germ cell tumors

PubMed Central

2013-01-01

Background Cisplatin (CDDP) resistance in testicular germ cell tumors (GCTs) is still a clinical challenge, and one associated with poor prognosis. The purpose of this work was to test pazopanib, an anti-tumoral and anti-angiogenic multikinase inhibitor, and its combination with lapatinib (an anti-ErbB inhibitor) in mouse orthotopic models of human testicular GCTs. Methods We used two different models of human testicular GCTs orthotopically grown in nude mice; a CDDP-sensitive choriocarcinoma (TGT38) and a new orthotopic model generated from a metastatic GCT refractory to first-line CDDP chemotherapy (TGT44). Nude mice implanted with these orthotopic tumors were treated with the inhibitors and the effect on tumoral growth and angiogenesis was evaluated. Results TGT44 refractory tumor had an immunohistochemical profile similar to the original metastasis, with characteristics of yolk sac tumor. TGT44 did not respond when treated with cisplatin. In contrast, pazopanib had an anti-angiogenic effect and anti-tumor efficacy in this model. Pazopanib in combination with lapatinib in TGT38, an orthotopic model of choriocarcinoma had an additive effect blocking tumor growth. Conclusions We present pazopanib as a possible agent for the alternative treatment of CDDP-sensitive and CDDP-refractory GCT patients, alone or in combination with anti-ErbB therapies. PMID:23937707

[Urethroplasty in hypoplastic-dysplastic corpus spongiosum and short urethra].

PubMed

Vitarelli, Antonio; Divenuto, Lucia; Altomare, Mauro; Masiello, Giuseppe; Pagliarulo, Arcangelo

2013-01-01

Congenital penile curvature and chordee are a rare malformative condition most frequently associated with hypospadias, but varying degrees of penile curvature are observed with an orthotopic meatus. Disease becomes evident after puberty, when curvature becomes more apparent with erection. We present a case of a young man (16 years old), with ventral congenital penile curvature without hypospadias and with hypoplastic-dysplastic corpus spongiosum and short urethra, who could not have normal sexual intercourses. The patient underwent first-stage urethroplasty with urethral opening and graft of buccal mucosa and creation of a temporary hypospadic meatus. No post-operative complications were observed. There were no residual penile curvatures. Results are promising and satisfactory after the first surgical stage and provide a solid ground for the final reconstruction.

Success and complications of an intra-ductal fully covered self-expanding metal stent (ID-FCSEMS) to treat anastomotic biliary strictures (AS) after orthotopic liver transplantation (OLT).

PubMed

Aepli, Patrick; St John, Andrew; Gupta, Saurabh; Hourigan, Luke F; Vaughan, Rhys; Efthymiou, Marios; Kaffes, Arthur

2017-04-01

Anastomotic biliary strictures (AS) after orthotopic liver transplantation (OLT) belong to the most common biliary complications and cause the biggest morbidity burden after OLT. Metal stents for benign biliary strictures are gaining acceptance with many published series. Traditional metal stent designs seem to have poor durability in AS after OLT. Novel intra-ductal stents are showing promise in these strictures. As a result, we designed a special stent with an antimigration waist and a short stent length with a long removal string that rests in the duodenum for easy removal. This is a retrospective multi-centre Australian study of AS after OLT treated with a novel intra-ductal fully covered self-expanding metal stent. From August 2008 to October 2014, records from three liver transplant centres were reviewed. Totally 36 ID-FCSEMS were inserted in 31 cases to treat an AS after OLT. The mean age of the patients was 56 years, and 61 % were male. The mean time of AS presentation after OLT was 20.3 months. Eight out of our 31 patients were previously treated using multiple plastic stenting over time without any success. Treatment with the ID-FCSEMS was performed with an average treatment time of 3.8 months. Stricture resolution was achieved in 100 %. All attempted stents removals were successful without any difficulty. Complications were reported in 6.5 %. It was pleasing that only one case of stent migration (2.8 %) was seen. Follow-up showed seven cases of AS recurrence (24.1 %), and all were treated successfully with repeat ERCP and stenting (some metal, some plastic). This novel ID-FCSEMS has a high clinical success and low complication rate, and in particular, there was only one case of stent migration. As a result, this stent type is preferred to traditional metal stents for treating AS after OLT.

Left Lobe Auxiliary Liver Transplantation for End-stage Hepatitis B Liver Cirrhosis.

PubMed

Wang, S-F; Chen, X-P; Chen, Z-S; Wei, L; Dong, S-L; Guo, H; Jiang, J-P; Teng, W-H; Huang, Z-Y; Zhang, W-G

2017-06-01

Auxiliary liver transplantation (ALT) for hepatitis B virus (HBV)-related liver cirrhosis previously showed poor results, because the native liver was a significant source of HBV recurrence and the graft could be rapidly destroyed by HBV infection in an immunosuppressive condition. Four patients with HBV-related liver cirrhosis were unable to undergo orthotopic liver transplantation because the only available grafts of left lobe were too small. Under entecavir-based anti-HBV treatment, they underwent ALT in which the recipient left liver was removed and the small left lobe graft was implanted in the corresponding space. The mean graft weight/recipient weight was 0.49% (range, 0.38%-0.55%). One year after transplantation, the graft sizes were increased to 273% and the remnant livers were decreased to 44%. Serum HBV DNA was persistently undetectable. Periodic graft biopsy showed no signs of tissue injury and negative immunostaining for hepatitis B surface antigen and hepatitis B core antigen. After a mean follow-up period of 21 months, all patients live well with normal graft function. Our study suggests that ALT for HBV-related liver cirrhosis is feasible under entecavir-based anti-HBV treatment. Successful application of small left livers in end-stage liver cirrhosis may significantly increase the pool of left liver grafts for adult patients. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Targeting Cancer Protein Profiles with Split-Enzyme Reporter Fragments to Achieve Chemical Resolution for Molecular Imaging

DTIC Science & Technology

2013-08-01

We next tested the utility of the construct to accumulate in tumors expressing EGFR using an orthotopic mouse model for brain tumors. Glioma cells...filament tumor marker, identified implanted cells within the orthotopic mouse model which were of human origin, i.e. Gli36Δ5 cells, and demonstrated that...forward into in vivo animal tumor model studies. • In vivo imaging of EGFR targeted-complex in orthotopic mouse model of brain tumor. • Ex vivo validation

Stricture of the afferent isoperistaltic tubular segment: a late and rare cause of bilateral dilation of the upper urinary tract after ileal bladder substitution.

PubMed

Kiss, Bernhard; Schöndorf, Daniel; Studer, Urs E; Roth, Beat

2013-08-01

To evaluate the etiology and treatment of bilateral hydronephrosis not responding to bladder substitute drainage after ileal bladder substitution using an afferent isoperistaltic tubular segment. A retrospective analysis was performed of a consecutive series of 739 patients who had undergone bladder substitution from April 1985 to August 2012. Of the 739 ileal bladder substitute patients, 10 (1.4%) developed bilateral hydronephrosis unresponsive to complete bladder substitute drainage. The etiology was stenosis of the afferent isoperistaltic tubular segment. The median interval to presentation was 131 months (range 45-192). The incidence of afferent tubular segment stenosis was significantly higher in the 61 ileal bladder substitute patients with recurrent urinary tract infection (9 [15%]) than in the 678 without recurrent urinary tract infection (1 [0.15%]; P <.001). Urine cultures revealed mixed infections (34%), Escherichia coli (18%), Staphylococcus aureus (13%), enterococci (11%), Candida (8%), Klebsiella (8%), and others (8%). Seven patients underwent 10 endourologic interventions, only 1 of which was successful (10%). After failed endourologic treatment, 7 open surgical revisions with resection of the stricture were performed, with all 7 (100%) successful. Bilateral dilation of the upper urinary tract after ileal orthotopic bladder substitution unresponsive to complete bladder substitute drainage is likely to be caused by stenosis of the afferent isoperistaltic tubular segment. The stenosis occurs almost exclusively in patients with long-lasting, recurrent urinary tract infection and can develop many years after the ileal bladder substitution. Minimally invasive endourologic treatment is usually unsuccessful; however, open surgical revision offers excellent results. Copyright © 2013 Elsevier Inc. All rights reserved.

Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients.

PubMed

Popiel, K Y; Wong, P; Lee, M J; Langelier, M; Sheppard, D C; Vinh, D C

2015-06-01

Saccharomyces cerevisiae, an ascosporogenous yeast commonly used in the production of food, is an emerging infection in immunocompromised patients. We report the case of a 60-year-old man whose orthotopic liver transplant was complicated by S. cerevisiae fungemia and peritoneal abscess, successfully treated with caspofungin and drainage. We also review the literature of invasive saccharomycoses in recipients of hematologic and solid organ transplants. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Condyle-Specific Matching Does Not Improve Midterm Clinical Outcomes of Osteochondral Allograft Transplantation in the Knee.

PubMed

Wang, Dean; Jones, Kristofer J; Eliasberg, Claire D; Pais, Mollyann D; Rodeo, Scott A; Williams, Riley J

2017-10-04

Condyle-specific matching for osteochondral allograft transplantation (OCA) pairs donor and recipient condyles in an attempt to minimize articular incongruity. While the majority of cartilage defects are located on the medial femoral condyle, lateral femoral condyles are more commonly available as a graft source. The purpose of this study was to compare the clinical outcomes of patients treated with non-orthotopic (lateral-to-medial condyle or medial-to-lateral condyle) OCA with those treated with traditional orthotopic (medial-to-medial condyle or lateral-to-lateral condyle) OCA. We hypothesized that clinical outcomes would be similar between groups at midterm follow-up. A retrospective review of prospectively collected data on patients treated with OCA from 2000 to 2014 was conducted. Seventy-seven patients with a full-thickness cartilage defect of a femoral condyle were treated with either orthotopic (n = 50) or non-orthotopic (n = 27) OCA. A minimum follow-up of 2 years was required for analysis. Patients in each group were matched according to sex, age, and total chondral defect size. Reoperations and patient responses to validated outcome measures were reviewed. Failure was defined as any revision cartilage procedure or conversion to knee arthroplasty. The mean duration of follow-up was 4.0 years (range, 2 to 16 years). The orthotopic and non-orthotopic OCA groups were comparable in terms of demographics, the mean number of prior ipsilateral knee operations, and the percentage of concomitant procedures at baseline. Reoperation (p = 0.427) and failure (p = 0.917) rates did not differ significantly between groups. Both groups demonstrated significant increases in the Short Form-36 (SF-36) physical functioning and pain, International Knee Documentation Committee (IKDC), and Knee Outcome Survey-Activities of Daily Living (KOS-ADL) scores compared with baseline (p < 0.004). Outcome scores (baseline and postoperative) and change scores did not differ significantly between groups. Clinical outcomes do not differ between patients treated with orthotopic OCA and those treated with non-orthotopic OCA, suggesting that condyle-specific matching may not be necessary. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Incidence of late atrial fibrillation in bilateral lung versus heart transplants.

PubMed

Magruder, J Trent; Plum, William; Crawford, Todd C; Grimm, Joshua C; Borja, Marvin C; Berger, Ronald D; Tandri, Harikrishna; Calkins, Hugh; Cameron, Duke E; Mandal, Kaushik

2016-10-01

We compared the incidence of late-onset atrial fibrillation in orthotopic heart transplant recipients and bilateral orthotopic lung transplant recipients. We reviewed the records of all heart and lung transplant operations carried out in our institution between 1995 and 2015. We performed 1:1 propensity-matching based on patient age, sex, body mass index, and hypertension. Our primary outcome, late-onset atrial fibrillation, was defined as atrial fibrillation occurring after discharge following hospitalization for transplantation. Over the study period, 397 orthotopic heart transplants and 240 bilateral orthotopic lung transplants were performed. Propensity matching resulted in 173 pairs who were matched with respect to age, sex, body mass index, and preoperative hypertension. The median follow-up was 5.3 years for heart transplant patients and 3.1 years for lung transplant patients. Late-onset atrial fibrillation occurred in 11 heart transplant patients (5 of whom had biopsy-proven evidence of rejection) and 19 lung transplant patients (2 of whom had biopsy-proven evidence of rejection). On Kaplan-Meier analysis, the probability of late-onset atrial fibrillation at 5 years was 4.3% for heart transplant patients vs. 13.9% for lung transplant patients (log-rank p = 0.01). We documented an increased probability of late-onset atrial fibrillation among bilateral orthotopic lung transplant patients compared to orthotopic heart transplant patients. This was a hypothesis-generating study that suggests a potential role for cardiac autonomic innervation in the genesis of atrial fibrillation. © The Author(s) 2016.

The Effect of Bridging Locoregional Therapy and Sociodemographics on Survival in Hepatocellular Carcinoma Patients Undergoing Orthotopic Liver Transplantation: A United Network for Organ Sharing Population Study.

PubMed

Magnetta, Michael J; Xing, Minzhi; Zhang, Di; Kim, Hyun S

2016-12-01

To investigate socioeconomic and demographic factors associated with transplantation outcomes in patients with hepatocellular carcinoma (HCC) treated with bridging locoregional therapy (LRT) before orthotopic liver transplantation (OLT). The United Network for Organ Sharing (UNOS) database was used to identify all patients in the United States with HCC who were listed for OLT between 2002 and 2013. Mean overall survival (OS) after OLT was stratified based on age, sex, ethnicity, transplant year, region, and insurance status. Kaplan-Meier estimation was used for survival analysis with log-rank test and Cox proportional hazards model to assess independent prognostic factors for OS. Of the 17,291 listed patients with HCC, 14,511 underwent OLT. Mean age was 57.4 years (76.8% male). Favorable sociodemographic factors were associated with increased rates of bridging LRT before OLT and longer wait time on the transplant list and were shown to be independent prognostic factors for prolonged OS after OLT using multivariate analysis. Favorable demographic factors included patient age < 60 years, donor age < 45 years, year of diagnosis between 2008 and 2013, UNOS regions 4 and 5, Asian ethnicity, high functional status, postgraduate education, private payer insurance, and employment at the time of OLT. Patients with favorable sociodemographics had higher rates of LRT before OLT performed for HCC cure. These patients had longer transplant wait times and longer OS after OLT. Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.

Evaluation of neovascularization patterns in an orthotopic rat glioma model with dynamic contrast-enhanced MRI.

PubMed

Xuesong, Du; Wei, Xue; Heng, Liu; Xiao, Chen; Shunan, Wang; Yu, Guo; Weiguo, Zhang

2017-09-01

Background Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been proved useful in evaluating glioma angiogenesis, but the utility in evaluating neovascularization patterns has not been reported. Purpose To evaluate in vivo real-time glioma neovascularization patterns by measuring glioma perfusion quantitatively using DCE-MRI. Material and Methods Thirty Sprague-Dawley rats were used to establish C6 orthotopic glioma model and underwent MRI and pathology detections. As MRI and pathology were performed at six time points (i.e. 4, 8, 12, 16, 20, and 24 days) post transplantation, neovascularization patterns were evaluated via DCE-MRI. Results Four neovascularization patterns were observed in glioma tissues. Sprout angiogenesis and intussusceptive microvascular growth located inside tumor, while vascular co-option and vascular mimicry were found in the tumor margin and necrotic area, respectively. Sprout angiogenesis and intussusceptive microvascular growth increased with K trans , K ep , and V p inside tumor tissue. In addition, K ep and V p were positively correlated with sprout angiogenesis and intussusceptive microvascular growth. Vascular co-option was decreased at 12 and 16 days post transplantation and correlated negatively with K trans and K ep detected in the glioma margin, respectively. Changes of vascular mimicry showed no significant statistical difference at the six time points. Conclusion Our results indicate that DCE-MRI can evaluate neovascularization patterns in a glioma model. Furthermore, DCE-MRI could be an imaging biomarker for guidance of antiangiogenic treatments in humans in the future.

Papillary bile duct dysplasia in primary sclerosing cholangitis.

PubMed

Ludwig, J; Wahlstrom, H E; Batts, K P; Wiesner, R H

1992-06-01

A 62-year-old man with a 20-year history of chronic ulcerative colitis and a 9-year history of primary sclerosing cholangitis (PSC) underwent orthotopic liver transplantation because of symptoms related to PSC and cholangiographic features compatible with a biliary neoplasm. Study of the excised liver revealed papillary mucosal lesions in the common hepatic duct and the right and left hepatic ducts as well as cholangiectases and other features typically associated with PSC. The papillary lesions consisted of abundant fibrovascular stroma covered by biliary epithelium with low-grade and high-grade dysplasia. Some periductal glands were also dysplastic. These features distinguished papillary dysplasia from classic biliary papillomatosis. Only one focus of microinvasion was found; there were no metastases. Among 60 cases of PSC in whom the entire liver could be studied after orthotopic liver transplantation, this was the only instance of unequivocal dysplasia. However, in one specimen, papillary hyperplasia was found. Detailed macroscopic and microscopic rereview of 23 livers from our patients with the longest history of PSC (range, 5-24 years) failed to reveal any additional cases with dysplasia. It is concluded that (a) papillary mucosal lesions in PSC may represent papillary dysplasia without invasion; (b) these lesions may evolve from papillary hyperplasia; (c) the process may be largely, if not entirely, in situ; and (d) the prevalence of dysplasia and carcinoma of bile ducts may be less than the 7%-9% reported in the literature for malignancies associated with PSC.

Hepatic artery pseudoaneurysm with hemobilia following angioplasty after liver transplantation.

PubMed

Narumi, S; Osorio, R W; Freise, C E; Stock, P G; Roberts, J P; Ascher, N L

1998-12-01

A 58-yr-old female with primary biliary cirrhosis underwent an uncomplicated orthotopic liver transplantation. Elevated liver function tests 2 months post-transplantation were evaluated with Doppler ultrasound and a hepatic artery stricture was documented. The hepatic artery stenosis was treated with angioplasty. She developed hemobilia 1 d after the procedure, which was confirmed by angiography. Emergent exploratory laparotomy revealed a pseudoaneurysm at the hepatic artery anastomosis. The pseudoaneurysm was resected and the proper hepatic artery of the graft was anastomosed to the splenic artery of the host using preserved homograft. Her post-operative course was uneventful and liver function tests returned to normal quickly after the surgery. This report will discuss the unusual nature of this complication, and review the problem of hemobilia and pseudoaneurysms in liver transplant recipients.

Orthotopic Patient-Derived Glioblastoma Xenografts in Mice.

PubMed

Xu, Zhongye; Kader, Michael; Sen, Rajeev; Placantonakis, Dimitris G

2018-01-01

Patient-derived xenografts (PDX) provide in vivo glioblastoma (GBM) models that recapitulate actual tumors. Orthotopic tumor xenografts within the mouse brain are obtained by injection of GBM stem-like cells derived from fresh surgical specimens. These xenografts reproduce GBM's histologic complexity and hallmark biological behaviors, such as brain invasion, angiogenesis, and resistance to therapy. This method has become essential for analyzing mechanisms of tumorigenesis and testing the therapeutic effect of candidate agents in the preclinical setting. Here, we describe a protocol for establishing orthotopic tumor xenografts in the mouse brain with human GBM cells.

Randomized Trial of Studer Pouch versus T-Pouch Orthotopic Ileal Neobladder in Patients with Bladder Cancer.

PubMed

Skinner, Eila C; Fairey, Adrian S; Groshen, Susan; Daneshmand, Siamak; Cai, Jie; Miranda, Gus; Skinner, Donald G

2015-08-01

The need to prevent reflux in the construction of an orthotopic ileal neobladder is controversial. We designed the USC-STAR trial to determine whether the T-pouch neobladder that included an antireflux mechanism was superior to the Studer pouch in patients with bladder cancer undergoing radical cystectomy. This single center, randomized, controlled trial recruited patients with clinically nonmetastatic bladder cancer scheduled to undergo radical cystectomy with neobladder. Eligible patients were randomly assigned to undergo T-pouch or Studer ileal orthotopic neobladder. Treatment assignment was not masked. The primary end point was change in renal function from baseline to 3 years. The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was used to calculate the estimated glomerular filtration rate. Between February 2002 and November 2009, 237 patients were randomly assigned to T-pouch ileal orthotopic neobladder and 247 to Studer ileal orthotopic neobladder. Baseline characteristics did not differ between the groups. Between baseline and 3 years the estimated glomerular filtration rate decreased by 6.4 ml/minute/1.73 m(2) in the Studer group and 6.6 ml/minute/1.73 m(2) in the T-pouch group (p=0.35). Multivariable analysis showed that type of ileal orthotopic neobladder was not independently associated with 3-year renal function (p=0.63). However, baseline estimated glomerular filtration rate, age and urinary tract obstruction were independently associated with 3-year decline in renal function. Cumulative risk of urinary tract infection and overall late complications were not different between the groups, but the T-pouch was associated with an increased risk of secondary diversion related surgeries. T-pouch ileal orthotopic neobladder with an antireflux mechanism did not prevent a moderate reduction in renal function observed at 3 years compared to the Studer pouch, but did result in an increase in diversion related secondary surgical procedures. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Transcatheter aortic valve implantation using anatomically oriented, marrow stromal cell-based, stented, tissue-engineered heart valves: technical considerations and implications for translational cell-based heart valve concepts.

PubMed

Emmert, Maximilian Y; Weber, Benedikt; Behr, Luc; Sammut, Sebastien; Frauenfelder, Thomas; Wolint, Petra; Scherman, Jacques; Bettex, Dominique; Grünenfelder, Jürg; Falk, Volkmar; Hoerstrup, Simon P

2014-01-01

While transcatheter aortic valve implantation (TAVI) has rapidly evolved for the treatment of aortic valve disease, the currently used bioprostheses are prone to continuous calcific degeneration. Thus, autologous, cell-based, living, tissue-engineered heart valves (TEHVs) with regeneration potential have been suggested to overcome these limitations. We investigate the technical feasibility of combining the concept of TEHV with transapical implantation technology using a state-of-the-art transcatheter delivery system facilitating the exact anatomical position in the systemic circulation. Trileaflet TEHVs fabricated from biodegradable synthetic scaffolds were sewn onto self-expanding Nitinol stents seeded with autologous marrow stromal cells, crimped and transapically delivered into the orthotopic aortic valve position of adult sheep (n = 4) using the JenaValve transapical TAVI System (JenaValve, Munich, Germany). Delivery, positioning and functionality were assessed by angiography and echocardiography before the TEHV underwent post-mortem gross examination. For three-dimensional reconstruction of the stent position of the anatomically oriented system, a computed tomography analysis was performed post-mortem. Anatomically oriented, transapical delivery of marrow stromal cell-based TEHV into the orthotopic aortic valve position was successful in all animals (n = 4), with a duration from cell harvest to TEHV implantation of 101 ± 6 min. Fluoroscopy and echocardiography displayed sufficient positioning, thereby entirely excluding the native leaflets. There were no signs of coronary obstruction. All TEHV tolerated the loading pressure of the systemic circulation and no acute ruptures occurred. Animals displayed intact and mobile leaflets with an adequate functionality. The mean transvalvular gradient was 7.8 ± 0.9 mmHg, and the mean effective orifice area was 1.73 ± 0.02 cm(2). Paravalvular leakage was present in two animals, and central aortic regurgitation due to a single-leaflet prolapse was detected in two, which was primarily related to the leaflet design. No stent dislocation, migration or affection of the mitral valve was observed. For the first time, we demonstrate the technical feasibility of a transapical TEHV delivery into the aortic valve position using a commercially available and clinically applied transapical implantation system that allows for exact anatomical positioning. Our data indicate that the combination of TEHV and a state-of-the-art transapical delivery system is feasible, representing an important step towards translational, transcatheter-based TEHV concepts.

MicroPET/CT Imaging of an Orthotopic Model of Human Glioblastoma Multiforme and Evaluation of Pulsed Low-Dose Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Sean S.; Chunta, John L.; Robertson, John M.

2011-07-01

Purpose: Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. Methods: Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CTmore » (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. Results: Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 x 10{sup 6} cells produced a 50- to 70-mm{sup 3} tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). Conclusion: This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage.« less

MicroPET/CT imaging of an orthotopic model of human glioblastoma multiforme and evaluation of pulsed low-dose irradiation.

PubMed

Park, Sean S; Chunta, John L; Robertson, John M; Martinez, Alvaro A; Oliver Wong, Ching-Yee; Amin, Mitual; Wilson, George D; Marples, Brian

2011-07-01

Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CT (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 × 10(6) cells produced a 50- to 70-mm(3) tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage. Copyright © 2011 Elsevier Inc. All rights reserved.

A study of MRI-guided diffuse fluorescence molecular tomography for monitoring PDT effects in pancreas cancer

NASA Astrophysics Data System (ADS)

Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; O'Hara, Julia A.; Hasan, Tayyaba; Pogue, Brian W.

2009-06-01

Over the last several decades little progress has been made in the therapy and treatment monitoring of pancreas adenocarcinoma, a devastating and aggressive form of cancer that has a 5-year patient survival rate of 3%. Currently, investigations for the use of interstitial Verteporfin photodynamic therapy (PDT) are being undertaken in both orthotopic xenograft mouse models and in human clinical trials. In the mouse models, magnetic resonance (MR) imaging has been used as a measure of surrogate response to Verteporfin PDT; however, MR imaging alone lacks the molecular information required to assess the metabolic function and growth rates of the tumor immediately after treatment. We propose the implementation of MR-guided fluorescence tomography in conjunction with a fluorescently labeled (IR-Dye 800 CW, LI-COR) epidermal growth factor (EGF) as a molecular measure of surrogate response. To demonstrate the effectiveness of MR-guided diffuse fluorescence tomography for molecular imaging, we have used the AsPC-1 (+EGFR) human pancreatic adenocarcinoma in an orthotopic mouse model. EGF IRDye 800CW was injected 48 hours prior to imaging. MR image sequences were collected simultaneously with the fluorescence data using a MR-coupled diffuse optical tomography system. Image reconstruction was performed multiple times with varying abdominal organ segmentation in order to obtain a optimal tomographic image. It is shown that diffuse fluorescence tomography of the orthotopic pancreas model is feasible, with consideration of confounding fluorescence signals from the multiple organs and tissues surrounding the pancreas. MR-guided diffuse fluorescence tomography will be used to monitor EGF response after photodynamic therapy. Additionally, it provide the opportunity to individualize subsequent therapies based on response to PDT as well as to evaluate the success of combination therapies, such as PDT with chemotherapy, antibody therapy or even radiation.

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

PubMed Central

Mastorakos, Panagiotis; Zhang, Clark; Song, Eric; Kim, Young Eun; Park, Hee Won; Berry, Sneha; Choi, Won Kyu; Hanes, Justin; Suk, Jung Soo

2018-01-01

The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain. PMID:28694032

Ovarian tissue cryopreservation in girls undergoing haematopoietic stem cell transplant: experience of a single centre.

PubMed

Biasin, E; Salvagno, F; Berger, M; Nesi, F; Quarello, P; Vassallo, E; Evangelista, F; Marchino, G L; Revelli, A; Benedetto, C; Fagioli, F

2015-09-01

Fertility after childhood haemopoietic stem cell transplant (HSCT) is a major concern. Conditioning regimens before HSCT present a high risk (>80%) of ovarian failure. Since 2000, we have proposed cryopreservation of ovarian tissue to female patients undergoing HSCT at our centre, to preserve future fertility. After clinical and haematological evaluation, the patients underwent ovarian tissue collection by laparoscopy. The tissue was analysed by histologic examination to detect any tumour contamination and then frozen following the slow freezing procedure and cryopreserved in liquid nitrogen. From August 2000 to September 2013, 47 patients planned to receive HSCT, underwent ovarian tissue cryopreservation. The median age at diagnosis was 11.1 years and at the time of procedure it was 13 years, respectively. Twenty-four patients were not pubertal at the time of storage, whereas 23 patients had already experienced menarche. The median time between laparoscopy and HSCT was 25 days. Twenty-six out of 28 evaluable patients (93%) developed hypergonadotropic hypogonadism at a median time of 23.3 months after HSCT. One patient required autologous orthotopic transplantation that resulted in one live birth. Results show a very high rate of iatrogenic hypergonadotropic hypogonadism, highlighting the need for fertility preservation in these patients.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model

PubMed Central

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco’s Modified Eagle’s Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection. PMID:26855572

Modified Uterine Allotransplantation and Immunosuppression Procedure in the Sheep Model

PubMed Central

Yang, Hong; Zhao, Guang-Yue; Zhang, Geng; Lu, Zhi-Hong; Huang, Yan-Hong; Ma, Xiang-Dong; Liu, Hai-Xia; Liang, Sheng-Ru; Yang, Fang; Chen, Bi-Liang

2013-01-01

Objective To develop an orthotopic, allogeneic, uterine transplantation technique and an effective immunosuppressive protocol in the sheep model. Methods In this pilot study, 10 sexually mature ewes were subjected to laparotomy and total abdominal hysterectomy with oophorectomy to procure uterus allografts. The cold ischemic time was 60 min. End-to-end vascular anastomosis was performed using continuous, non-interlocking sutures. Complete tissue reperfusion was achieved in all animals within 30 s after the vascular re-anastomosis, without any evidence of arterial or venous thrombosis. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil and methylprednisolone tablets. Graft viability was assessed by transrectal ultrasonography and second-look laparotomy at 2 and 4 weeks, respectively. Results Viable uterine tissue and vascular patency were observed on transrectal ultrasonography and second-look laparotomy. Histological analysis of the graft tissue (performed in one ewe) revealed normal tissue architecture with a very subtle inflammatory reaction but no edema or stasis. Conclusion We have developed a modified procedure that allowed us to successfully perform orthotopic, allogeneic, uterine transplantation in sheep, whose uterine and vascular anatomy (apart from the bicornuate uterus) is similar to the human anatomy, making the ovine model excellent for human uterine transplant research. PMID:24278415

An integrated nanotechnology-enabled transbronchial image-guided intervention strategy for peripheral lung cancer

PubMed Central

Jin, Cheng S.; Wada, Hironobu; Anayama, Takashi; McVeigh, Patrick Z; Hu, Hsin Pei; Hirohashi, Kentaro; Nakajima, Takahiro; Kato, Tatsuya; Keshavjee, Shaf; Hwang, David; Wilson, Brian C.; Zheng, Gang; Yasufuku, Kazuhiro

2016-01-01

Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current non-surgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically-administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460 and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon non-surgical treatment of early-stage peripheral lung cancer. PMID:27543602

Orthotopic tumorgrafts in nude mice as a model to evaluate calcitriol effects in breast cancer.

PubMed

Fonseca-Filho, V C N; Katayama, M L H; Lyra, E C; Maria, D A; Basso, R A; Nonogaki, S; Guerra, J M; Maistro, S; Góes, J C G S; Folgueira, M A A K

2017-11-01

Calcitriol antiproliferative effects were observed in xenografts of breast cancer cell lines, however they were not yet investigated in tumorgrafts, consisting of freshly collected breast cancer samples xenografted into animals. To establish a tumorgraft model, from freshly collected breast cancer samples, which were directly implanted in nude mice, to study calcitriol effects. Breast cancer samples collected from 12 patients were orthotopically implanted into nude mice. Animals were treated with weekly intratumoral injections of calcitriol 3 μg/Kg, which was previously shown to induce peak serum calcitriol levels in the predicted therapeutic range. Success engraftment rate was 25%. Tumorgrafts were established from aggressive (HER2 positive or histological grade 3) highly proliferative samples and original tumor characteristics were preserved. Calcitriol highly induced its target gene, CYP24A1, indicating that the genomic vitamin D pathway is active in tumorgrafts. However, no differences in the expression of proliferation and apoptosis markers (BrdU incorporation, Ki67, CDKN1A, CDKN1B, BCL2 expression) were observed in these highly proliferative tumor samples. Tumorgrafts seem a promising model to explore other calcitriol doses and regimens, considering the heterogeneity of the disease and microenvironment interactions.

Pregnancy after orthotopic continent urinary diversion.

PubMed

Kennedy, W A; Hensle, T W; Reiley, E A; Fox, H E; Haus, T

1993-10-01

Continent urinary diversion has become a common form of bladder management for the female exstrophy patient in whom primary reconstruction has failed. Reported are the results of successful pregnancies in four young adult females, who had previously undergone a flap vaginoplasty as part of earlier management and more recently a continent right colonic urinary reservoir with a perineal stoma (Indiana pouch). Pregnancy in each of these patients was characterized by several urinary tract infections, cervical prolapse and mild to severe maternal hydronephrosis. All of the patients had some degree of difficulty with clean intermittent catheterization. One patient required an indwelling catheter with prolonged bed rest. Maternal hydronephrosis resolved after delivery in all instances. All four patients delivered their infants by way of cesarean section, either emergently for maternal or fetal distress or electively. Cervical prolapse did not resolve in three patients and will require surgical repair. After delivery, all patients returned to their previous pattern of clean intermittent catheterization without loss of continence. All the infants delivered were healthy with appropriate weights and high Apgar scores (more than 8). Orthotopic (perineal stoma) continent urinary diversion is not a contraindication to pregnancy. However, our experience mandates delivery by cesarean section with close monitoring for maternal or fetal distress during gestation.

Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model.

PubMed

Choi, Goeun; Piao, Huiyan; Alothman, Zeid A; Vinu, Ajayan; Yun, Chae-Ok; Choy, Jin-Ho

2016-01-01

Methotrexate (MTX), an anticancer agent, was successfully intercalated into the anionic clay, layered double hydroxides to form a new nanohybrid drug. The coprecipitation and subsequent hydrothermal method were used to prepare chemically, structurally, and morphologically well-defined two-dimensional drug-clay nanohybrid. The resulting two-dimensional drug-clay nanohybrid showed excellent colloidal stability not only in deionized water but also in an electrolyte solution of Dulbecco's Modified Eagle's Medium with 10% fetal bovine serum, in which the average particle size in colloid and the polydispersity index were determined to be around 100 and 0.250 nm, respectively. The targeting property of the nanohybrid drug was confirmed by evaluating the tumor-to-blood and tumor-to-liver ratios of the MTX with anionic clay carrier, and these ratios were compared to those of free MTX in the C33A orthotopic cervical cancer model. The biodistribution studies indicated that the mice treated with the former showed 3.5-fold higher tumor-to-liver ratio and fivefold higher tumor-to-blood ratio of MTX than those treated with the latter at 30 minutes postinjection.

Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice.

PubMed

Harris, Jamie; Herrero-Garcia, Erika; Russo, Angela; Kajdacsy-Balla, Andre; O'Bryan, John P; Chiu, Bill

2017-11-01

Neuroblastoma accounts for 15% of all pediatric cancer deaths. Intersectin 1 (ITSN1), a scaffold protein involved in phosphoinositide 3-kinase (PI3K) signaling, regulates neuroblastoma cells independent of MYCN status. We hypothesize that by silencing ITSN1 in neuroblastoma cells, tumor growth will be decreased in an orthotopic mouse tumor model. SK-N-AS neuroblastoma cells transfected with empty vector (pSR), vectors expressing scrambled shRNA (pSCR), or shRNAs targeting ITSN1 (sh#1 and sh#2) were used to create orthotopic neuroblastoma tumors in mice. Volume was monitored weekly with ultrasound. End-point was tumor volume >1000 mm. Tumor cell lysates were analyzed with anti-ITSN1 antibody by Western blot. Orthotopic tumors were created in all cell lines. Twenty-five days post injection, pSR tumor size was 917.6±247.7 mm, pSCR was 1180±159.9 mm, sh#1 was 526.3±212.8 mm, and sh#2 was 589.2±74.91 mm. sh#1-tumors and sh#2-tumors were smaller than pSCR (P=0.02), no difference between sh#1 and sh#2. Survival was superior in sh#2-tumors (P=0.02), trended towards improved survival in sh#1-tumors (P=0.09), compared with pSCR-tumors, no difference in pSR tumors. Western blot showed decreased ITSN1 expression in sh#1 and sh#2 compared with pSR and pSCR. Silencing ITSN1 in neuroblastoma cells led to decreased tumor growth in an orthotopic mouse model. Orthotopic animal models can provide insight into the role of ITSN1 pathways in neuroblastoma tumorigenesis.

Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.

PubMed

Abe, Shinji; Kaneko, Mika Kato; Tsuchihashi, Yuki; Izumi, Toshihiro; Ogasawara, Satoshi; Okada, Naoto; Sato, Chiemi; Tobiume, Makoto; Otsuka, Kenji; Miyamoto, Licht; Tsuchiya, Koichiro; Kawazoe, Kazuyoshi; Kato, Yukinari; Nishioka, Yasuhiko

2016-09-01

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

PubMed

Kuo, Elbert; Bharat, Ankit; Shih, Jennifer; Street, Tyler; Norris, Jenyi; Liu, Wei; Parks, William; Walter, Michael; Patterson, G Alexander; Mohanakumar, T

2006-10-01

Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection. Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts. Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio. Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.

Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

PubMed Central

Krygier, Darin S; Steinbrecher, Urs P; Petric, Martin; Erb, Siegfried R; Chung, Stephen W; Scudamore, Charles H; Buczkowski, Andrzej K; Yoshida, Eric M

2009-01-01

Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation. PMID:19705505

How do we manage post-OLT redundant bile duct?

PubMed

Torres, Victor; Martinez, Nicholas; Lee, Gabriel; Almeda, Jose; Gross, Glenn; Patel, Sandeep; Rosenkranz, Laura

2013-04-28

To address endoscopic outcomes of post-Orthotopic liver transplantation (OLT) patients diagnosed with a "redundant bile duct" (RBD). Medical records of patients who underwent OLT at the Liver Transplant Center, University Texas Health Science Center at San Antonio Texas were retrospectively analyzed. Patients with suspected biliary tract complications (BTC) underwent endoscopic retrograde cholangiopancreatography (ERCP). All ERCP were performed by experienced biliary endoscopist. RBD was defined as a looped, sigmoid-shaped bile duct on cholangiogram with associated cholestatic liver biomarkers. Patients with biliary T-tube placement, biliary anastomotic strictures, bile leaks, bile-duct stones-sludge and suspected sphincter of oddi dysfunction were excluded. Therapy included single or multiple biliary stents with or without sphincterotomy. The incidence of RBD, the number of ERCP corrective sessions, and the type of endoscopic interventions were recorded. Successful response to endoscopic therapy was defined as resolution of RBD with normalization of associated cholestasis. Laboratory data and pertinent radiographic imaging noted included the pre-ERCP period and a follow up period of 6-12 mo after the last ERCP intervention. One thousand two hundred and eighty-two patient records who received OLT from 1992 through 2011 were reviewed. Two hundred and twenty-four patients underwent ERCP for suspected BTC. RBD was reported in each of the initial cholangiograms. Twenty-one out of 1282 (1.6%) were identified as having RBD. There were 12 men and 9 women, average age of 59.6 years. Primary indication for ERCP was cholestatic pattern of liver associated biomarkers. Nineteen out of 21 patients underwent endoscopic therapy and 2/21 required immediate surgical intervention. In the endoscopically managed group: 65 ERCP procedures were performed with an average of 3.4 per patient and 1.1 stent per session. Fifteen out of 19 (78.9%) patients were successfully managed with biliary stenting. All stents were plastic. Selection of stent size and length were based upon endoscopist preference. Stent size ranged from 7 to 11.5 Fr (average stent size 10 Fr); Stent length ranged from 6 to 15 cm (average length 9 cm). Concurrent biliary sphincterotomy was performed in 10/19 patients. Single ERCP session was sufficient in 6/15 (40.0%) patients, whereas 4/15 (26.7%) patients needed two ERCP sessions and 5/15 (33.3%) patients required more than two (average of 5.4 ERCP procedures). Single biliary stent was sufficient in 5 patients; the remaining patients required an average of 4.9 stents. Four out of 19 (21.1%) patients failed endotherapy (lack of resolution of RBD and recurrent cholestasis in the absence of biliary stent) and required either choledocojejunostomy (2/4) or percutaneous biliary drainage (2/4). Endoscopic complications included: 2/65 (3%) post-ERCP pancreatitis and 2/10 (20%) non-complicated post-sphincterotomy bleeding. No endoscopic related mortality was found. The medical records of the 15 successful endoscopically managed patients were reviewed for a period of one year after removal of all biliary stents. Eleven patients had continued resolution of cholestatic biomarkers (73%). One patient had recurrent hepatitis C, 2 patients suffered septic shock which was not associated with ERCP and 1 patient was transferred care to an outside provider and records were not available for our review. Although surgical biliary reconstruction techniques have improved, RBD represents a post-OLT complication. This entity is rare however, endoscopic management of RBD represents a reasonable initial approach.

Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ.

PubMed

Joo, Kyeung Min; Kim, Jinkuk; Jin, Juyoun; Kim, Misuk; Seol, Ho Jun; Muradov, Johongir; Yang, Heekyoung; Choi, Yoon-La; Park, Woong-Yang; Kong, Doo-Sik; Lee, Jung-Il; Ko, Young-Hyeh; Woo, Hyun Goo; Lee, Jeongwu; Kim, Sunghoon; Nam, Do-Hyun

2013-01-31

Frequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable "patient tumor's phenocopy" that represents molecular and functional heterogeneity of GBMs. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibiting platelet-derived growth factor beta reduces Ewing's sarcoma growth and metastasis in a novel orthotopic human xenograft model.

PubMed

Wang, Yong Xin; Mandal, Deendayal; Wang, Suizhau; Hughes, Dennis; Pollock, Raphael E; Lev, Dina; Kleinerman, Eugenie; Hayes-Jordan, Andrea

2009-01-01

Despite aggressive therapy, Ewing's sarcoma (ES) patients have a poor five-year overall survival of only 20-40%. Pulmonary metastasis is the most common form of demise in these patients. The pathogenesis of pulmonary metastasis is poorly understood and few orthotopic models exist that allow study of spontaneous pulmonary metastasis in ES. We have developed a novel orthotopic xenograft model in which spontaneous pulmonary metastases develop. While the underlying biology of ES is incompletely understood, in addition to the EWS-FLI-1 mutation, it is known that platelet-derived growth factor receptor beta (PDGFR-beta) is highly expressed in ES. Hypothesizing that PDGFR-beta expression is indicative of a specific role for this receptor protein in ES progression, the effect of PDGFR-beta inhibition on ES growth and metastasis was assessed in this novel orthotopic ES model. Silencing PDGFR-beta reduced spontaneous growth and metastasis in ES. Preclinical therapeutically relevant findings such as these may ultimately lead to new treatment initiatives in ES.

Symptomatic osteonecrosis of the femoral head after adult orthotopic liver transplantation.

PubMed

Li, Hua; Zhang, Jian; He, Ji-Wen; Wang, Kun; Wang, Gen-Shu; Jiang, Nan; Fu, Bin-Sheng; Wang, Guo-Ying; Yang, Yang; Chen, Gui-Hua

2012-07-01

With the increase of survival in liver transplantation recipients, more patients are at a high risk of developing osteonecrosis, especially in the femoral head, due to immunosuppressive treatment. The purpose of this study was to report the incidence, possible risk factors, and outcome of symptomatic osteonecrosis of the femoral head (ONFH) in adult patients with current immunosuppressive agents and individual protocol after liver transplantation in China. A retrospective analysis was performed on 226 adult patients who underwent orthotopic liver transplantation (OLT) at a single liver transplantation institution between January 2004 and December 2008. The posttransplant survival time (or pre-retransplantation survival time) of all the patients were more than 24 months. The possible pre- and post-transplantation risk factors of symptomatic ONFH were investigated and the curative effects of the treatment were also reported. The incidence of ONFH was 1.33% in patients after OLT. ONFH occurred at a mean of (14 ± 6) months (range, 10 - 21 months) after transplantation. Male patients more often presented with osteonecrosis as a complication than female patients. The patients with lower pre-transplantation total bilirubin and direct bilirubin levels (P < 0.05). There was no difference in the cumulative dose of corticosteroids or tacrolimus between the patients with or without symptomatic ONFH. Patients were treated either pharmacologically or surgically. All patients showed a nice curative effect without major complications during the 18 - 63 months post-treatment follow up. The symptomatic ONFH does not occur commonly after adult OLT in the current individual immunosuppressive protocol in China.

Transgenic nude mouse with green fluorescent protein expression-based human glioblastoma multiforme animal model with EGFR expression and invasiveness.

PubMed

Tan, Guo-Wei; Lan, Fo-Lin; Gao, Jian-Guo; Jiang, Cai-Mou; Zhang, Yi; Huang, Xiao-Hong; Ma, Yue-Hong; Shao, He-Dui; He, Xue-Yang; Chen, Jin-Long; Long, Jian-Wu; Xiao, Hui-Sheng; Guo, Zhi-Tong; Diao, Yi

2012-08-01

Previously, we developed an orthotopic xenograft model of human glioblastoma multiforme (GBM) with high EGFR expression and invasiveness in Balb/c nu/nu nude mice. Now we also developed the same orthotopic xenograft model in transgenic nude mice with green fluorescent protein (GFP) expression. The present orthotopic xenografts labeled by phycoerythrin fluorescing red showed high EGFR expression profile, and invasive behavior under a bright green-red dual-color fluorescence background. A striking advantage in the present human GBM model is that the change of tumor growth can be observed visually instead of sacrificing animals in our further antitumor therapy studies.

Hybrid liposomes showing enhanced accumulation in tumors as theranostic agents in the orthotopic graft model mouse of colorectal cancer.

PubMed

Okumura, Masaki; Ichihara, Hideaki; Matsumoto, Yoko

2018-11-01

Hybrid liposomes (HLs) can be prepared by simply sonicating a mixture of vesicular and micellar molecules in a buffer solution. This study aimed to elucidate the therapeutic effects and ability of HLs to detect (diagnosis) cancer in an orthotopic graft mouse model of colorectal cancer with HCT116 cells for the use of HLs as theranostic agents. In the absence of a chemotherapeutic drug, HLs exhibited therapeutic effects by inhibiting the growth of HCT116 colorectal cancer cells in vitro, possibly through an increase in apoptosis. Intravenously administered HLs also caused a remarkable reduction in the relative cecum weight in an orthotopic graft mouse model of colorectal cancer. A decrease in tumor size in the cecal sections was confirmed by histological analysis using HE staining. TUNEL staining indicated an induction of apoptosis in HCT116 cells in the orthotopic graft mouse model of colorectal cancer. For the detection (diagnosis) of colorectal cancer by HLs, the accumulation of HLs encapsulating a fluorescent probe (ICG) was observed in HCT116 cells in the in vivo colorectal cancer model following intravenous administration. These data indicate that HLs can accumulate in tumor cells in the cecum of the orthotopic graft mouse model of colorectal cancer for a prolonged period of time, and inhibit the growth of HCT116 cells.

Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.

PubMed

Van der Ven, H; Liebenthron, J; Beckmann, M; Toth, B; Korell, M; Krüssel, J; Frambach, T; Kupka, M; Hohl, M K; Winkler-Crepaz, K; Seitz, S; Dogan, A; Griesinger, G; Häberlin, F; Henes, M; Schwab, R; Sütterlin, M; von Wolff, M; Dittrich, R

2016-09-01

What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. None. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

[Orthotopic cartilage transplantation. Morphologic, angiography and histochemical studies of the vitality of free septum transplants].

PubMed

Gubisch, W; Donath, K

1999-11-01

Orthotopic cartilage transplantation is a technique frequently used in modern septal surgery. The prerequisite for a stable long-term result is viability of the transplanted cartilage. Therefore, we studied the healing process histologically, angiographically, and histochemically. We found a characteristic picture. Due to chondronal structure of the cartilage, the healing process varied in time and location. Reintegration took place by chondroneogenesis, commencing at the inner perichondrium. Reintegration depended directly on the distance of the cartilage cells to the surrounding vessels. Histochemically, we found an intact respiratory chain in the mitochondria and thus, we were able to demonstrate the preservation of viability in orthotopic transplanted cartilage.

Simplified technique for auxiliary orthotopic liver transplantation using a whole graft

PubMed Central

ROCHA-SANTOS, Vinicius; NACIF, Lucas Souto; PINHEIRO, Rafael Soares; DUCATTI, Liliana; ANDRAUS, Wellington; D'ALBURQUERQUE, Luiz Carneiro

2015-01-01

Background Acute liver failure is associated with a high mortality rate and the main purposes of treatment are to prevent cerebral edema and infections, which often are responsible for patient death. The orthotopic liver transplantation is the gold standard treatment and improves the 1-year survival. Aim To describe an alternative technique to auxiliary liver transplant on acute liver failure. Method Was performed whole auxiliary liver transplantation as an alternative technique for a partial auxiliary liver transplantation using a whole liver graft from a child removing the native right liver performed a right hepatectomy. The patient met the O´Grady´s criteria and the rational to indicate an auxiliary orthotopic liver transplantation was the acute classification without hemodynamic instability or renal failure in a patient with deterioration in consciousness. Results The procedure improved liver function and decreased intracranial hypertension in the postoperative period. Conclusion This technique can overcome some postoperative complications that are associated with partial grafts. As far as is known, this is the first case of auxiliary orthotopic liver transplantation in Brazil. PMID:26176253

Heart transplantation for Chagas cardiomyopathy.

PubMed

Ramalho, Ana Rita; Prieto, David; Antunes, Pedro; Franco, Fátima; Antunes, Manuel J

2017-11-01

Chagas disease is an endemic disease in Latin America that is increasingly found in non-endemic areas all over the world due to the flow of migrants from Central and South America. We present the case of a Brazilian immigrant in Portugal who underwent orthotopic heart transplantation for end-stage Chagas cardiomyopathy. Immunosuppressive therapy included prednisone, mycophenolate mofetil and tacrolimus. Twelve months after the procedure she is asymptomatic, with good graft function, and with no evidence of complications such as graft rejection, opportunistic infections, neoplasms or reactivation of Trypanosoma cruzi infection. By reporting the first case in Portugal of heart transplantation for Chagas cardiomyopathy, we aim to increase awareness of Chagas disease as an emerging global problem and of Chagas cardiomyopathy as a serious complication for which heart transplantation is a valuable therapeutic option. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Impact of intraoperative factor concentrates on blood product transfusions during orthotopic liver transplantation.

PubMed

Colavecchia, A Carmine; Cohen, David A; Harris, Jesse E; Thomas, Jeena M; Lindberg, Scott; Leveque, Christopher; Salazar, Eric

2017-12-01

Major bleeding in orthotopic liver transplantation is associated with significant morbidity and mortality. Limited literature exists regarding comparative effectiveness of prothrombin complex concentrate and fibrinogen concentrate during orthotopic liver transplantation on blood product utilization. This retrospective, single-institution study evaluated the impact of prothrombin complex concentrate and fibrinogen concentrate on blood product utilization during orthotopic liver transplantation from December 2013 to April 2016. This study included patients age 18 years or older and excluded patients who received simultaneous heart or lung transplantation or did not meet documentation criteria. A propensity score matching technique was used to match patients who were exposed to prothrombin complex concentrate with unexposed patients, at a 2 to 1 ratio, to control for selection bias. During this study, 212 patients received orthotopic liver transplantation with 39 prothrombin complex concentrate exposures. The matched study population included 39 patients who were exposed to prothrombin complex concentrate and 78 unexposed patients. Overall, 84.6% of patients who were exposed to prothrombin complex concentrate also received concomitant fibrinogen concentrate, whereas only 2% of patients in the control group received fibrinogen concentrate. After propensity score matching, no other factors that were included in the model differed significantly or had a standardized mean difference of 0.11 or greater. There was no statistical difference in the utilization of red blood cells or fresh frozen plasma for the exposed group versus the unexposed group after matching (mean ± standard deviation: red blood cell units, 12.4 ± 8.0 units vs. 9.7 ± 5.6 units [p = 0.058]; fresh-frozen plasma units, 10.0 ± 6.3 vs. 12.7 ± 9.7 units [p = 0.119], respectively). The intraoperative use of prothrombin complex concentrate and fibrinogen concentrate during orthotopic liver transplantation did not reduce intraoperative blood product requirements at a single institution. © 2017 AABB.

EGF targeted fluorescence molecular tomography as a predictor of PDT outcomes in pancreas cancer models

NASA Astrophysics Data System (ADS)

Samkoe, Kimberley S.; Davis, Scott C.; Srinivasan, Subhadra; Isabelle, Martin E.; O'Hara, Julia; Hasan, Tayyaba; Pogue, Brian W.

2010-02-01

Verteporfin photodynamic therapy (PDT) is a promising adjuvant therapy for pancreas cancer and investigations for its use are currently underway in both orthotopic xenograft mouse models and in human clinical trials. The mouse models have been studied extensively using magnetic resonance (MR) imaging as a measure of surrogate response to verteporfin PDT and it was found that tumor lines with different levels of aggression respond with varying levels to PDT. MR imaging was successful in determining the necrotic volume caused by PDT but there was difficultly in distinguishing inflamed tissues and regions of surviving tumor. In order to understand the molecular changes within the tumor immediately post-PDT we propose the implementation of MR-guided fluorescence molecular tomography (FMT) in conjunction with an exogenously administered fluorescently labeled epidermal growth factor (EGF-IRDye800CW, LI-COR Biosciences). We have previously shown that MR-guided FMT is feasible in the mouse abdomen when multiple regions of fluorescence are considered from contributing internal organs. In this case the highly aggressive AsPC-1 (+EGFR) orthotopic tumor was implanted in SCID mice, interstitial verteporfin PDT (1mg/kg, 20J/cm) was performed when the tumor reached ~60mm3 and both tumor volume and EGF binding were followed with MR-guided FMT.

Using PEGylated iron oxide nanoparticles with ultrahigh relaxivity for MR imaging of an orthotopic model of human hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Wang, Ruizhi; Hu, Yong; Yang, Yuchan; Xu, Wei; Yao, Mingrong; Gao, Dongmei; Zhao, Yan; Zhan, Songhua; Shi, Xiangyang; Wang, Xiaolin

2017-02-01

Hepatocellular carcinoma (HCC) is the most common type of liver malignant tumor, which is often diagnosed in advanced stages, resulting in low survival rate. The sensitive diagnosis of early HCC presents a great interest. Herein, a novel superparamagnetic contrast agent composed of iron oxide nanoparticles is reported. Firstly, polyethyleneimine-coated iron oxide (Fe3O4@PEI) nanoparticles (NPs) were synthesized via a mild reduction route, followed by their modification of polyethylene glycol monomethyl ether ( mPEG-COOH) via 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride coupling chemistry. After acetylation of the remaining PEI amines, the PEGylated Fe3O4 (Fe3O4@PEI.Ac- mPEG-COOH) NPs were successively characterized via different techniques. The Fe3O4@PEI.Ac- mPEG-COOH probes with an Fe3O4 NP size of 9 nm are water dispersible and cytocompatible within the given concentration range. The percentages of PEI and m-PEG-COOH on the particles surface are calculated to be 15.5 and 7.2%, respectively. Prior to the administration of Fe3O4@PEI.Ac- mPEG-COOH NPs of ultrahigh r 2 relaxivity (461.29 mM-1 s-1) via tail intravenous injection for MR imaging of HCC, the orthotopic model of HCC was established in the nude mice by surgical transplantation with HCCLM3 cells. The analysis of MR signal intensity (SI) in the orthotopic tumor model demonstrated that the developed Fe3O4@PEI.Ac- mPEG-COOH NPs were able to infiltrate into the tumor area through the enhanced permeability and retention (EPR) effect reaching the bottom at 2 h postinjection. The developed Fe3O4@PEI.Ac- mPEG-COOH NPs may be further applied for theranostics of different diseases through combing various therapeutic agents.

MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

PubMed

Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James; Jiang, Steve B; Mason, Ralph P; Stojadinovic, Strahinja

2018-01-01

Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol is wide-ranging and not limited to the orthotopic prostate tumor study presented in the study.

Impact of MLH1 expression on tumor evolution after curative surgical tumor resection in a murine orthotopic xenograft model for human MSI colon cancer.

PubMed

Meunier, Katy; Ferron, Marianne; Calmel, Claire; Fléjou, Jean-François; Pocard, Marc; Praz, Françoise

2017-09-01

Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumor evolution after curative surgical resection using a xenograft tumor model. Transplantable tumors established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumors were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumor evolution in mice who underwent curative surgical resection and in mice whose tumor was left in situ. Our data indicate that the behavior of MLH1-deficient CRC is not only governed by mutations arising in genes harboring microsatellite repeated sequences but also from their defect in MLH1 as such. © 2017 Wiley Periodicals, Inc.

Survival benefits of interferon-based therapy in patients with recurrent hepatitis C after orthotopic liver transplantation

PubMed Central

Zanaga, L.P.; Vigani, A.G.; Angerami, R.N.; Giorgetti, A.; Escanhoela, C.A.F.; Ataíde, E.C.; Boin, I.F.S.F.; Stucchi, R.S.B.

2017-01-01

Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct-acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death. PMID:28076451

Optimization of Glioblastoma Mouse Orthotopic Xenograft Models for Translational Research.

PubMed

Irtenkauf, Susan M; Sobiechowski, Susan; Hasselbach, Laura A; Nelson, Kevin K; Transou, Andrea D; Carlton, Enoch T; Mikkelsen, Tom; deCarvalho, Ana C

2017-08-01

Glioblastoma is an aggressive primary brain tumor predominantly localized to the cerebral cortex. We developed a panel of patient-derived mouse orthotopic xenografts (PDOX) for preclinical drug studies by implanting cancer stem cells (CSC) cultured from fresh surgical specimens intracranially into 8-wk-old female athymic nude mice. Here we optimize the glioblastoma PDOX model by assessing the effect of implantation location on tumor growth, survival, and histologic characteristics. To trace the distribution of intracranial injections, toluidine blue dye was injected at 4 locations with defined mediolateral, anterioposterior, and dorsoventral coordinates within the cerebral cortex. Glioblastoma CSC from 4 patients and a glioblastoma nonstem-cell line were then implanted by using the same coordinates for evaluation of tumor location, growth rate, and morphologic and histologic features. Dye injections into one of the defined locations resulted in dye dissemination throughout the ventricles, whereas tumor cell implantation at the same location resulted in a much higher percentage of small multifocal ventricular tumors than did the other 3 locations tested. Ventricular tumors were associated with a lower tumor growth rate, as measured by in vivo bioluminescence imaging, and decreased survival in 4 of 5 cell lines. In addition, tissue oxygenation, vasculature, and the expression of astrocytic markers were altered in ventricular tumors compared with nonventricular tumors. Based on this information, we identified an optimal implantation location that avoided the ventricles and favored cortical tumor growth. To assess the effects of stress from oral drug administration, mice that underwent daily gavage were compared with stress-positive and -negative control groups. Oral gavage procedures did not significantly affect the survival of the implanted mice or physiologic measurements of stress. Our findings document the importance of optimization of the implantation site for preclinical mouse models of glioblastoma.

Optimization of Glioblastoma Mouse Orthotopic Xenograft Models for Translational Research

PubMed Central

Irtenkauf, Susan M; Sobiechowski, Susan; Hasselbach, Laura A; Nelson, Kevin K; Transou, Andrea D; Carlton, Enoch T; Mikkelsen, Tom; deCarvalho, Ana C

2017-01-01

Glioblastoma is an aggressive primary brain tumor predominantly localized to the cerebral cortex. We developed a panel of patient-derived mouse orthotopic xenografts (PDOX) for preclinical drug studies by implanting cancer stem cells (CSC) cultured from fresh surgical specimens intracranially into 8-wk-old female athymic nude mice. Here we optimize the glioblastoma PDOX model by assessing the effect of implantation location on tumor growth, survival, and histologic characteristics. To trace the distribution of intracranial injections, toluidine blue dye was injected at 4 locations with defined mediolateral, anterioposterior, and dorsoventral coordinates within the cerebral cortex. Glioblastoma CSC from 4 patients and a glioblastoma nonstem-cell line were then implanted by using the same coordinates for evaluation of tumor location, growth rate, and morphologic and histologic features. Dye injections into one of the defined locations resulted in dye dissemination throughout the ventricles, whereas tumor cell implantation at the same location resulted in a much higher percentage of small multifocal ventricular tumors than did the other 3 locations tested. Ventricular tumors were associated with a lower tumor growth rate, as measured by in vivo bioluminescence imaging, and decreased survival in 4 of 5 cell lines. In addition, tissue oxygenation, vasculature, and the expression of astrocytic markers were altered in ventricular tumors compared with nonventricular tumors. Based on this information, we identified an optimal implantation location that avoided the ventricles and favored cortical tumor growth. To assess the effects of stress from oral drug administration, mice that underwent daily gavage were compared with stress-positive and ‑negative control groups. Oral gavage procedures did not significantly affect the survival of the implanted mice or physiologic measurements of stress. Our findings document the importance of optimization of the implantation site for preclinical mouse models of glioblastoma. PMID:28830577

Establishment of a patient-derived orthotopic osteosarcoma mouse model.

PubMed

Blattmann, Claudia; Thiemann, Markus; Stenzinger, Albrecht; Roth, Eva K; Dittmar, Anne; Witt, Hendrik; Lehner, Burkhard; Renker, Eva; Jugold, Manfred; Eichwald, Viktoria; Weichert, Wilko; Huber, Peter E; Kulozik, Andreas E

2015-04-30

Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue. Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin. A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established. We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.

CETUXIMAB AND IRINOTECAN INTERACT SYNERGISTICALLY TO INHIBIT THE GROWTH OF ORTHOTOPIC ANAPLASTIC THYROID CARCINOMA XENOGRAFTS IN NUDE MICE

PubMed Central

Kim, Seungwon; Prichard, Christopher N.; Younes, Maher N.; Yazici, Yasemin D.; Jasser, Samar A.; Bekele, B. Nebiyou; Myers, Jeffrey N.

2006-01-01

Objective Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against EGFR, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. Design The in vitro anti-proliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. Results Cetuximab alone did not show any anti-proliferative or pro-apoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. Conclusions Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study. PMID:16428506

Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human Disease.

PubMed

Go, Kristina L; Delitto, Daniel; Judge, Sarah M; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Judge, Andrew R; Trevino, Jose G

2017-07-01

Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model. The purpose of this study was to evaluate the degree to which an orthotopic PDX model of PC recapitulates these aspects of the human disease. Human PDX-derived PC tumors were implanted directly into the pancreas of NOD.Cg-Prkdc Il2rg/SzJ mice. Tumor growth, metastasis, and muscle wasting were then evaluated. Orthotopically implanted PDX-derived tumors consistently incorporated into the murine pancreatic parenchyma, metastasized to both the liver and lungs and induced muscle wasting directly proportional to the size of the tumor, consistent of the cancer cachexia syndrome. Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer.

PubMed

Daman, Zahra; Faghihi, Homa; Montazeri, Hamed

2018-05-02

Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice. SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E-cadherin, β-catenin, and transforming growth factor beta receptor (TGFβR) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGFβR2 over-expression was induced in stroma cells after treatment with SAL NPs. These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested.

Transplantation of "high-risk" donor hearts: Implications for infection.

PubMed

Gaffey, Ann C; Doll, Stacey L; Thomasson, Arwin M; Venkataraman, Chantel; Chen, Carol W; Goldberg, Lee R; Blumberg, Emily A; Acker, Michael A; Stone, Francis; Atluri, Pavan

2016-07-01

Heart transplantation is the gold-standard treatment for end-stage heart failure. Short- and long-term outcomes have been excellent, but the shortage of organs persists. The number of potential recipients who die while awaiting orthotopic heart transplantation increases yearly. In 2004, the label "high-risk donor" (HRD) was applied, by the United Network for Organ Sharing (UNOS), to any organ donor who met the Centers for Disease Control (CDC) criteria for behavior that put them at high risk of infection. Despite organ shortages, grafts from HRD CDCs are often declined, because of concerns regarding infection. We undertook this study to analyze our extensive experience with orthotopic heart transplantation of grafts from HRD CDCs, and to determine the short- and long-term outcomes associated with recipients of hearts from HRD CDCs, particularly transmission of infection. We performed 367 heart transplantations at our center from September 2008 to September 2014, a timeframe during which the HRD CDC labeling had been implemented. Of the total number of orthotopic heart transplantations performed, 55 patients (15%) received organs from HRD CDCs that had known negative serology for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. We reviewed demographic, perioperative, and short- and long-term outcomes. The recipients of grafts from HRD CDCs were followed closely, with 3- and 12-month surveillance laboratory testing of viral load for HIV, for hepatitis B, and for hepatitis C core- and surface-antigen serology. All 55 patients (72.7% were men) underwent a successful transplantation procedure. One patient was excluded from follow-up analysis because he was re-transplanted within 4 days owing to the posttransplant finding of metastatic lung adenocarcinoma within the donor. Primary etiology of heart failure was ischemic in 18 of the patients. The most common blood type was O positive, in 20 patients (37.1%), followed by A positive, in 19 patients (35.2%). A total of 19 (35.2%) patients were supported with a mechanical assist device before the transplantation. The average allograft ischemic time was 173 ± 96 minutes. The median length of hospital stay was 19.5 days. A low incidence was observed of the postoperative complications of stroke (1.9%), dialysis (3.9%), and complete heart block (3.9%). Kaplan-Meier analysis demonstrated excellent survival, both short-term (1 year; 94%) and long-term (3 years; 80%). Allograft function was excellent at time of discharge with a left ejection fraction of 67.8% ± 7.3%. Only one patient (1.9%) was noted to have hepatitis C seroconversion at 105 days after receiving the transplant. After antiviral treatment, the patient has had undetectable viral loads to date. All other patients had undetectable plasma viral loads of HIV, hepatitis C, and hepatitis B, determined using rigorous testing. We present the only single-center series on recipients of heart transplants from HRD CDCs. This potential source of suitable donor organs is shown to lead to excellent survival, without an increased incidence of perioperative or postoperative complications. Furthermore, the risk of transmission of infection from donors in this subgroup seems to be minimal. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Improved facial nerve identification during parotidectomy with fluorescently labeled peptide.

PubMed

Hussain, Timon; Nguyen, Linda T; Whitney, Michael; Hasselmann, Jonathan; Nguyen, Quyen T

2016-12-01

Additional intraoperative guidance could reduce the risk of iatrogenic injury during parotid gland cancer surgery. We evaluated the intraoperative use of fluorescently labeled nerve binding peptide NP41 to aid facial nerve identification and preservation during parotidectomy in an orthotopic model of murine parotid gland cancer. We also quantified the accuracy of intraoperative nerve detection for surface and buried nerves in the head and neck with NP41 versus white light (WL) alone. Twenty-eight mice underwent parotid gland cancer surgeries with additional fluorescence (FL) guidance versus WL reflectance (WLR) alone. Eight mice were used for additional nerve-imaging experiments. Twenty-eight parotid tumor-bearing mice underwent parotidectomy. Eight mice underwent imaging of both sides of the face after skin removal. Postoperative assessment of facial nerve function measured by automated whisker tracking were compared between FL guidance (n = 13) versus WL alone (n=15). In eight mice, nerve to surrounding tissue contrast was measured under FL versus WLR for all nerve branches detectable in the field of view. Postoperative facial nerve function after parotid gland cancer surgery tended to be better with additional FL guidance. Fluorescent labeling significantly improved nerve to surrounding tissue contrast for both large and smaller buried nerve branches compared to WLR visualization and improved detection sensitivity and specificity. NP41 FL imaging significantly aids the intraoperative identification of nerve braches otherwise nearly invisible to the naked eye. Its application in a murine model of parotid gland cancer surgery tended to improve functional preservation of the facial nerve. NA Laryngoscope, 126:2711-2717, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Improved Facial Nerve Identification During Parotidectomy With Fluorescently Labeled Peptide

PubMed Central

Hussain, Timon; Nguyen, Linda T.; Whitney, Michael; Hasselmann, Jonathan; Nguyen, Quyen T.

2016-01-01

Objectives/Hypothesis Additional intraoperative guidance could reduce the risk of iatrogenic injury during parotid gland cancer surgery. We evaluated the intraoperative use of fluorescently labeled nerve binding peptide NP41 to aid facial nerve identification and preservation during parotidectomy in an orthotopic model of murine parotid gland cancer. We also quantified the accuracy of intraoperative nerve detection for surface and buried nerves in the head and neck with NP41 versus white light (WL) alone. Study Design Twenty-eight mice underwent parotid gland cancer surgeries with additional fluorescence (FL) guidance versus WL reflectance (WLR) alone. Eight mice were used for additional nerve-imaging experiments. Methods Twenty-eight parotid tumor-bearing mice underwent parotidectomy. Eight mice underwent imaging of both sides of the face after skin removal. Postoperative assessment of facial nerve function measured by automated whisker tracking were compared between FL guidance (n = 13) versus WL alone (n = 15). In eight mice, nerve to surrounding tissue contrast was measured under FL versus WLR for all nerve branches detectable in the field of view. Results Postoperative facial nerve function after parotid gland cancer surgery tended to be better with additional FL guidance. Fluorescent labeling significantly improved nerve to surrounding tissue contrast for both large and smaller buried nerve branches compared to WLR visualization and improved detection sensitivity and specificity. Conclusions NP41 FL imaging significantly aids the intraoperative identification of nerve braches otherwise nearly invisible to the naked eye. Its application in a murine model of parotid gland cancer surgery tended to improve functional preservation of the facial nerve. PMID:27171862

An alternative technique for orthotopic cardiac transplantation, with preservation of the normal anatomy of the right atrium.

PubMed

Sievers, H H; Weyand, M; Kraatz, E G; Bernhard, A

1991-04-01

The standard technique for orthotopic cardiac transplantation implies large atrial anastomoses which do not preserve the anatomical integrity of the donor atria. This may become a potential source of electrophysiological and mechanical atrial dysfunction, especially in the right atrium with the sinus node and the sensitive low-pressure atrioventricular valve. As an improvement we suggest an alternative technique which we have recently developed for orthotopic cardiac transplantation; it combines the simple, convenient left atrial connection of the standard technique with individual anastomoses of the superior and inferior venae cavae, preserving the right atrium of the donated heart intact. This technique and our first results in two cases are described. Postoperatively, no arrhythmias and no signs of tricuspid insufficiency were observed.

Evolution of robot-assisted orthotopic ileal neobladder formation: a step-by-step update to the University of Southern California (USC) technique.

PubMed

Chopra, Sameer; de Castro Abreu, Andre Luis; Berger, Andre K; Sehgal, Shuchi; Gill, Inderbir; Aron, Monish; Desai, Mihir M

2017-01-01

To describe our, step-by-step, technique for robotic intracorporeal neobladder formation. The main surgical steps to forming the intracorporeal orthotopic ileal neobladder are: isolation of 65 cm of small bowel; small bowel anastomosis; bowel detubularisation; suture of the posterior wall of the neobladder; neobladder-urethral anastomosis and cross folding of the pouch; and uretero-enteral anastomosis. Improvements have been made to these steps to enhance time efficiency without compromising neobladder configuration. Our technical improvements have resulted in an improvement in operative time from 450 to 360 min. We describe an updated step-by-step technique of robot-assisted intracorporeal orthotopic ileal neobladder formation. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

Selective Imaging of VEGFR-1 and VEGFR-2 Using 89Zr-Labeled Single-Chain VEGF Mutants.

PubMed

Meyer, Jan-Philip; Edwards, Kimberly J; Kozlowski, Paul; Backer, Marina V; Backer, Joseph M; Lewis, Jason S

2016-11-01

Vascular endothelial growth factor-A (VEGF-A) acts via 2 vascular endothelial growth factor receptors, VEGFR-1 and VEGFR-2, that play important and distinct roles in tumor biology. We reasoned that selective imaging of these receptors could provide unique information for diagnostics and for monitoring and optimizing responses to anticancer therapy, including antiangiogenic therapy. Herein, we report the development of 2 first-in-class 89 Zr-labeled PET tracers that enable the selective imaging of VEGFR-1 and VEGFR-2. Functionally active mutants of scVEGF (an engineered single-chain version of pan-receptor VEGF-A with an N-terminal cysteine-containing tag for site-specific conjugation), named scVR1 and scVR2 with enhanced affinity to, respectively, VEGFR-1 and VEGFR-2, were constructed. Parental scVEGF and its receptor-specific mutants were site-specifically derivatized with the 89 Zr chelator desferroxamine B via a 3.4-kDa PEG linker. 89 Zr labeling of the desferroxamine B conjugates furnished scV/Zr, scVR1/Zr, and scVR2/Zr tracers with high radiochemical yield (>87%), high specific activity (≥9.8 MBq/nmol), and purity (>99%). Tracers were tested in an orthotopic breast cancer model using 4T1luc-bearing syngeneic BALB/c mice. For testing tracer specificity, tracers were coinjected with an excess of cold proteins of the same or opposite receptor specificity or pan-receptor scVEGF. PET imaging, biodistribution, and dosimetry studies in mice, as well as immunohistochemical analysis of harvested tumors, were performed. All tracers rapidly accumulated in orthotopic 4T1luc tumors, allowing for the successful PET imaging of the tumors as early as 2 h after injection. Blocking experiments with an excess of pan-receptor or receptor-specific cold proteins indicated that more than 80% of tracer tumor uptake is VEGFR-mediated, whereas uptake in all major organs is not affected by blocking within the margin of error. Critically, blocking experiments indicated that VEGFR-mediated tumor uptake of scVR1/Zr and scVR2/Zr was mediated exclusively by the corresponding receptor, VEGFR-1 or VEGFR-2, respectively. In contrast, uptake of pan-receptor scV/Zr was mediated by both VEGFR-1 and VEGFR-2 at an approximately 2:1 ratio. First-in-class selective PET tracers for imaging VEGFR-1 and VEGFR-2 were constructed and successfully validated in an orthotopic murine tumor model. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

The effect of PI3K inhibitor LY294002 and gemcitabine hydrochloride combined with ionizing radiation on the formation of vasculogenic mimicry of Panc-1 cells in vitro and in vivo.

PubMed

Bai, R; Ding, T; Zhao, J; Liu, S; Zhang, L; Lan, X; Yu, Y; Yin, L

2016-01-01

This research's purpose was to explore the existence of vasculogenic mimicry (VM) in both 3-D matrices of Panc-1 cells in vitro and orthotopic Panc-1 xenografts in vivo and to test the hypothesis that PI3K inhibitor LY294002 and gemcitabine hydrochloride would offer clear treatment benefit when integrated into ionizing radiation (IR) therapeutic regimens for treatment of pancreatic cancer. We explored the existence of VM in both 3-D matrices of Panc-1 cells and orthotopic Panc-1 xenografts. We subsequently investigated the activation of the PI3K/MMPs/Ln-5γ2 signaling pathway in response to IR. LY294002 and gemcitabine hydrochloride were then evaluated for their radiosensitizing effect solely and in combination. We found that VM existed in both 3-D matrices of Panc-1 cells in vitro and orthotopic Panc-1 xenografts in vivo. The expressions of p-Akt and MMP- 2 were found to increase in response to IR. LY294002 and gemcitabine hydrochloride combined with IR better inhibited cell migration, VM formation and MMP-2 mRNA expression of Panc-1 cells in vitro, and we also proved that the novel therapeutic regimen better inhibited tumor growth, tumor metastasis and VM formation of orthotopic Panc-1 xenografts by suppressing the PI3K/MMPs/Ln-5γ2 signaling pathway in vivo. Our present study is among the first to prove the VM formation in orthotopic Panc-1 xenografts. Furthermore, our current study is also among the first to provide preliminary evidence for the use of the novel therapeutic regimen LY294002 and gemcitabine hydrochloride combined with IR for treatment of pancreatic cancer.

A novel method for RNA extraction from FFPE samples reveals significant differences in biomarker expression between orthotopic and subcutaneous pancreatic cancer patient-derived xenografts.

PubMed

Hoover, Malachia; Adamian, Yvess; Brown, Mark; Maawy, Ali; Chang, Alexander; Lee, Jacqueline; Gharibi, Armen; Katz, Matthew H; Fleming, Jason; Hoffman, Robert M; Bouvet, Michael; Doebler, Robert; Kelber, Jonathan A

2017-01-24

Next-generation sequencing (NGS) can identify and validate new biomarkers of cancer onset, progression and therapy resistance. Substantial archives of formalin-fixed, paraffin-embedded (FFPE) cancer samples from patients represent a rich resource for linking molecular signatures to clinical data. However, performing NGS on FFPE samples is limited by poor RNA purification methods. To address this hurdle, we developed an improved methodology for extracting high-quality RNA from FFPE samples. By briefly integrating a newly-designed micro-homogenizing (mH) tool with commercially available FFPE RNA extraction protocols, RNA recovery is increased by approximately 3-fold while maintaining standard A260/A280 ratios and RNA quality index (RQI) values. Furthermore, we demonstrate that the mH-purified FFPE RNAs are longer and of higher integrity. Previous studies have suggested that pancreatic ductal adenocarcinoma (PDAC) gene expression signatures vary significantly under in vitro versus in vivo and in vivo subcutaneous versus orthotopic conditions. By using our improved mH-based method, we were able to preserve established expression patterns of KRas-dependency genes within these three unique microenvironments. Finally, expression analysis of novel biomarkers in KRas mutant PDAC samples revealed that PEAK1 decreases and MST1R increases by over 100-fold in orthotopic versus subcutaneous microenvironments. Interestingly, however, only PEAK1 levels remain elevated in orthotopically grown KRas wild-type PDAC cells. These results demonstrate the critical nature of the orthotopic tumor microenvironment when evaluating the clinical relevance of new biomarkers in cells or patient-derived samples. Furthermore, this new mH-based FFPE RNA extraction method has the potential to enhance and expand future FFPE-RNA-NGS cancer biomarker studies.

Comparison of a chimeric anti-carcinoembryonic antigen antibody conjugated with visible or near-infrared fluorescent dyes for imaging pancreatic cancer in orthotopic nude mouse models

NASA Astrophysics Data System (ADS)

Maawy, Ali A.; Hiroshima, Yukihiko; Kaushal, Sharmeela; Luiken, George A.; Hoffman, Robert M.; Bouvet, Michael

2013-12-01

The aim of this study was to evaluate a set of visible and near-infrared dyes conjugated to a tumor-specific chimeric antibody for high-resolution tumor imaging in orthotopic models of pancreatic cancer. BxPC-3 human pancreatic cancer was orthotopically implanted into pancreata of nude mice. Mice received a single intravenous injection of a chimeric anti-carcinoembryonic antigen antibody conjugated to one of the following fluorophores: 488-nm group (Alexa Fluor 488 or DyLight 488); 550-nm group (Alexa Fluor 555 or DyLight 550); 650-nm group (Alexa Fluor 660 or DyLight 650), or the 750-nm group (Alexa Fluor 750 or DyLight 755). After 24 h, the Olympus OV100 small-animal imaging system was used for noninvasive and intravital fluorescence imaging of mice. Dyes were compared with respect to depth of imaging, resolution, tumor-to-background ratio (TBR), photobleaching, and hemoglobin quenching. The longer wavelength dyes had increased depth of penetration and ability to detect the smallest tumor deposits and provided the highest TBRs, resistance to hemoglobin quenching, and specificity. The shorter wavelength dyes were more photostable. This study showed unique advantages of each dye for specific cancer imaging in a clinically relevant orthotopic model.

Fluorescence-Raman Dual Modal Endoscopic System for Multiplexed Molecular Diagnostics

NASA Astrophysics Data System (ADS)

Jeong, Sinyoung; Kim, Yong-Il; Kang, Homan; Kim, Gunsung; Cha, Myeong Geun; Chang, Hyejin; Jung, Kyung Oh; Kim, Young-Hwa; Jun, Bong-Hyun; Hwang, Do Won; Lee, Yun-Sang; Youn, Hyewon; Lee, Yoon-Sik; Kang, Keon Wook; Lee, Dong Soo; Jeong, Dae Hong

2015-03-01

Optical endoscopic imaging, which was recently equipped with bioluminescence, fluorescence, and Raman scattering, allows minimally invasive real-time detection of pathologies on the surface of hollow organs. To characterize pathologic lesions in a multiplexed way, we developed a dual modal fluorescence-Raman endomicroscopic system (FRES), which used fluorescence and surface-enhanced Raman scattering nanoprobes (F-SERS dots). Real-time, in vivo, and multiple target detection of a specific cancer was successful, based on the fast imaging capability of fluorescence signals and the multiplex capability of simultaneously detected SERS signals using an optical fiber bundle for intraoperative endoscopic system. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) on the breast cancer xenografts in a mouse orthotopic model were successfully detected in a multiplexed way, illustrating the potential of FRES as a molecular diagnostic instrument that enables real-time tumor characterization of receptors during routine endoscopic procedures.

Vascular and micro-environmental influences on MSC-coral hydroxyapatite construct-based bone tissue engineering.

PubMed

Cai, Lei; Wang, Qian; Gu, Congmin; Wu, Jingguo; Wang, Jian; Kang, Ning; Hu, Jiewei; Xie, Fang; Yan, Li; Liu, Xia; Cao, Yilin; Xiao, Ran

2011-11-01

Bone tissue engineering (BTE) has been demonstrated an effective approach to generate bone tissue and repair bone defect in ectopic and orthotopic sites. The strategy of using a prevascularized tissue-engineered bone grafts (TEBG) fabricated ectopically to repair bone defects, which is called live bone graft surgery, has not been reported. And the quantitative advantages of vascularization and osteogenic environment in promoting engineered bone formation have not been defined yet. In the current study we generated a tissue engineered bone flap with a vascular pedicle of saphenous arteriovenous in which an organized vascular network was observed after 4 weeks implantation, and followed by a successful repaire of fibular defect in beagle dogs. Besides, after a 9 months long term observation of engineered bone formation in ectopic and orthotopic sites, four CHA (coral hydroxyapatite) scaffold groups were evaluated by CT (computed tomography) analysis. By the comparison of bone formation and scaffold degradation between different groups, the influences of vascularization and micro-environment on tissue engineered bone were quantitatively analyzed. The results showed that in the first 3 months vascularization improved engineered bone formation by 2 times of non-vascular group and bone defect micro-environment improved it by 3 times of ectopic group, and the CHA-scaffold degradation was accelerated as well. Copyright © 2011 Elsevier Ltd. All rights reserved.

The Role of Lymphangiogenesis in Orthotopic Prostatic Tumor-Environment on Regional and Systemic Metastasis

DTIC Science & Technology

2008-01-01

expressing Renilla luciferase and VEGF-C shRNA or irrelevant firefly luciferase shRNA (Ctrl) were implanted orthotopically as before. To determine the...on metastasis in Pten knockout model (Month 10-24): a) Generate Ubc/sVEGFR-3 and Ubc/ Renilla luciferase (RL) lentiviral vectors by subcloning...progression (month 10-12) c) Monitor efficiency of Ubc/lentiviral transduction and expression in Pten (-/-) prostate using optical imaging of Renilla

Infections After Orthotopic Liver Transplantation

PubMed Central

Pedersen, Mark; Seetharam, Anil

2014-01-01

Opportunistic infections are a leading cause of morbidity and mortality after orthotopic liver transplantation. Systemic immunosuppression renders the liver recipient susceptible to de novo infection with bacteria, viruses and fungi post-transplantation as well to reactivation of pre-existing, latent disease. Pathogens are also transmissible via the donor organ. The time from transplantation and degree of immunosuppression may guide the differential diagnosis of potential infectious agents. However, typical systemic signs and symptoms of infection are often absent or blunted after transplant and a high index of suspicion is needed. Invasive procedures are often required to procure tissue for culture and guide antimicrobial therapy. Antimicrobial prophylaxis reduces the incidence of opportunistic infections and is routinely employed in the care of patients after liver transplant. In this review, we survey common bacterial, fungal, and viral infections after orthotopic liver transplantation and highlight recent developments in their diagnosis and management. PMID:25755581

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maleux, Geert; Pirenne, Jacques; Vaninbroukx, Johan

Our purpose was to assess the feasibility of orthotopic liver transplantation (OLT) in patients priorly having undergone transjugular intrahepatic portosystemic shunt (TIPS) with an expanded tetrafluoroethylene (e-PTFE)-covered endoprosthesis. In 48 patients an e- PTFE-covered endoprosthesis was inserted to treat severe complications of portal hypertension. In 36 patients the endoprosthesis was inserted during TIPS creation (de novo TIPS); in the other 12 patients the endoprosthesis was placed to repermeabilize the previously created, but occluded bare stent (revision TIPS). Eight of them (5 de novo and 3 revision cases) later underwent an OLT. The hospital records of these patients were reviewed frommore » initial admission, through TIPS, the pre-OLT period, and OLT to current postoperative status. Five de novo and 3 revision cases underwent OLT 4-279 days (mean delay: 80.8 days) after TIPS procedure. All OLT's were performed under veno-venous bypass surgery. De visu surgical inspection confirmed correct positioning of the fully patent stent graft, starting in the portal vein and ending at the junction of the hepatic vein to the inferior caval vein. No surgical difficulty was observed during proximal or distal clamping or during resection of the diseased liver. Correctly positioned e-PTFE-covered nitinol endoprostheses do not interfere with a later OLT and may not be considered as a contraindication in patients who need a TIPS as a bridge to OLT.« less

Solving the Mystery: Hyalinized cyst wall containing organism- like structures in a Lung Transplant Donor.

PubMed

Bini Viotti, Julia; Loebe, Matthias; Brozzi, Nicolas; Pinto, Andre; Simkins, Jacques; Cloke, Christina M; Camargo, Jose F; Salama, Sam; Abbo, Lilian M

2018-06-05

A 59-year-old man with non-ischemic cardiomyopathy underwent orthotopic heart transplantation. The donor, a 31-year-old male declared brain dead after a gunshot wound to the head, was considered high risk due to history of incarceration, illicit drug use and sex with a HIV positive partner. At organ procurement, the heart, kidneys, pancreas and liver looked grossly normal. A small right lower lobe nodule was noticed, and lung biopsy was performed. Bronchoscopy showed purulent secretions in the right lower lobe. Images from pathology are presented. Lung biopsy confirmed the presence of hyalinized cyst wall containing organism- like structures. A combination of culture, microscopic morphology, and gene sequencing was used to identify the causative organism. The patient and all other organ recipients received appropriate antifungal prophylaxis and remain asymptomatic six months post- transplant. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Antitumor immune activity by chemokine CX3CL1 in an orthotopic implantation of lung cancer model in vivo.

PubMed

Kee, Ji-Ye; Arita, Yoshihisa; Shinohara, Kanna; Ohashi, Yasukata; Sakurai, Hiroaki; Saiki, Ikuo; Koizumi, Keiichi

2013-01-01

Due to their chemoattractant properties stimulating the accumulation of infiltrating immune cells in tumors, chemokines are known to have antitumor effects. Fractalkine, a unique CX3C chemokine, is expressed in activated endothelial cells, while its receptor, CX3CR1, is expressed in cytolytic immune cells, such as natural killer cells, monocytes and some CD8 + T cells. The biological properties of cancer cells are affected by the implantation organ and differences in immune systems, requiring cancer implantation in orthotopic organs in an in vivo experiment. To develop new therapy strategies for lung cancer, an animal model reflecting the clinical features of lung cancer was previously established. This study aimed to determine whether CX3CL1-induced biological functions should be used for immune cell-based gene therapy of lung cancer in the orthotopic implantation model. An orthotopic intrapulmonary implantation of CX3CL1-stable expression in mouse lung cancer (LLC-CX3CL1) was performed to analyze growth. Results showed a significant decrease in tumor growth in the lung compared to the control cells (LLC-mock). Furthermore, the antitumor effects of CX3CL1 were derived from natural killer cell activities in the depletion experiment in vivo . Therefore, CX3CL1 has the potential of a useful therapeutic target in lung cancer.

Total Artificial Heart as Rescue Therapy for Primary Graft Failure in an Infant.

PubMed

Ziegler, Luke A; Sainathan, Sandeep; Morell, Victor O; Sharma, Mahesh S

2018-04-01

An infant unable to be weaned from cardiopulmonary bypass after orthotopic heart transplantation was cannulated for extracorporeal membrane oxygenation. During the next 3 days, allograft failure and intracardiac thrombosis necessitated cardiectomy. To provide acute mechanical circulatory support, artificial atrial chambers were constructed with Gore-Tex conduits and PediMag centrifugal pumps were connected to each by Berlin Heart EXCOR cannulae. The PediMag pumps were subsequently exchanged for 10-mL Berlin Heart EXCOR pumps. After 60 days of support by total artificial heart, the patient was bridged successfully to a second heart transplant. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

PubMed Central

Antonello, ZA; Nucera, C

2015-01-01

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research. PMID:24362526

Analysis of Stroma Labeling During Multiple Passage of a Sarcoma Imageable Patient-Derived Orthotopic Xenograft (iPDOX) in Red Fluorescent Protein Transgenic Nude Mice.

PubMed

Kiyuna, Tasuku; Murakami, Takashi; Tome, Yasunori; Kawaguchi, Kei; Igarashi, Kentaro; Miyake, Kentaro; Kanaya, Fuminori; Singh, Arun; Eilber, Fritz C; Hoffman, Robert M

2017-10-01

A patient-derived orthotopic xenograft (PDOX) model of undifferentiated pleomorphic sarcoma (UPS) was previously established that acquired red fluorescent protein (RFP)-expressing stroma by growth in an RFP transgenic nude mouse. In the present study, an imageable PDOX model (iPDOX) of UPS was established by orthotopic implantation in the biceps femoris of transgenic RFP nude mice. After the tumors grew to a diameter of 10 mm, they were harvested and the brightest portion of the tumors were subsequently orthotopically transplanted to both RFP and non-colored nude mice. The UPS PDOX tumor was again transplanted to RFP transgenic and non-colored nude mice, and finally a 3rd passage was made in the same manner. Five UPS tumors from each passage in both RFP and non-colored mouse models were harvested. The FV1,000 confocal microscope was used to visualize and quantitate the RFP area of the resected tumors. The average percent fluorescent area in the first passage of RFP mice was 34 ± 22%; in the second passage, 34 ± 20%; and 36 ± 11% in the third passage of RFP transgenic nude mice. The average tumor RFP area in the first passage from RFP mice to non-colored mice was 20 ± 7%; in the second passage, 28 ± 11%; in the third passage was 27 ± 13%. The present results demonstrate the extensive and stable acquisition of stroma by the UPS-tumor growing orthotopically in transgenic RFP nude mice (iPDOX). This model can be used for screening for effective drugs for individual patients and drug discovery. J. Cell. Biochem. 118: 3367-3371, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Virotherapy of the Malignant U87 Human Glioblastoma in the Orthotopic Xenotransplantation Mouse SCID Model.

PubMed

Shchelkunov, S N; Razumov, I A; Kolosova, I V; Romashchenko, A V; Zavjalov, E L

2018-01-01

The possibility of glioblastoma virotherapy at intravenous injection of the LIVP-GFP recombinant virus was studied in experimental model of orthotopic xenotransplantation of human glioblastoma cell line U87 to SCID laboratory mice. The LIVP-GFP recombinant virus deficient for thymidine kinase exhibited a significantly greater oncolytic capacity than the original LIVP virus, and an intravenous injection of LIVP-GFP at the early stages of tumorigenesis in mouse brain in most cases resulted in the lysis of the tumor.

The role of cryopreservation for women prior to treatment of malignancy.

PubMed

Donnez, Jacques; Dolmans, Marie-Madeleine; Martinez-Madrid, Belen; Demylle, Dominique; Van Langendonckt, Anne

2005-08-01

The purpose of this review is to investigate recent advances in xenografting, as well as in orthotopic and heterotopic autotransplantation of human cryopreserved ovarian tissue. The first livebirth after orthotopic transplantation of cryopreserved ovarian tissue was reported recently. We discuss this case and other cases of reimplantation of cryopreserved ovarian tissue, bearing in mind that many questions remain. Finally, we report the latest developments in research on the transplantation of an intact ovary and the reimplantation of isolated follicles.

Molecularly Targeted Dose-Enhancement Radiotherapy Using Gold and Luminescent Nanoparticles in an Orthotopic Human Prostate Cancer Rat Model

DTIC Science & Technology

2013-10-01

cell lines, such as cervix cancer cell line (HeLa) and breast cancer cell line (MDA-MB-231), were also employed. The experiments with other cell lines...breast cancer cell line (MDA-MB- 231), and cervix cancer cell line (HeLa). Different from our hypothesis, prostate cancer cell lines did not present...Radiotherapy Using Gold and Luminescent Nanoparticles in an Orthotopic Human Prostate Cancer Rat Model PRINCIPAL INVESTIGATOR: Kwang Song

Infections Complicating Orthotopic Liver Transplantation

PubMed Central

Schröter, Gerhard P. J.; Hoelscher, Manfred; Putnam, Charles W.; Porter, Kendrick A.; Hansbrough, John F.; Starzl, Thomas E.

2011-01-01

In 93 recipients of 102 orthotopic liver homografts, the incidence of bacteremia or fungemia exceeded 70%. The graft itself was usually an entry site for systemic infection after both immunologic and nonimmunologic parenchymal injury, especially if there was defective biliary drainage. The role of the homograft itself as the special infectious risk factor has prompted increased use of defunctionalized jejunal Roux limbs to reduce graft contamination. It has also stimulated very aggressive postoperative diagnostic efforts to rule out remedial mechanical complications of the transplant. PMID:793568

GIT2 Gene: Androgenic Regulation of White Adipose Tissue-Prostate Cancer Interactions

DTIC Science & Technology

2014-05-01

survival of growth factor–expressing ASCs, which enter the systemic circulation and promote PCa progression. An important note is that the prostate...surgical castration and systemic GLIPR1-ΔTM in vivo using VCaP xenograft model: 1. Generate orthotopic VCaP tumors in athymic nude male mice and...effects of systemic GLIPR1-ΔTM on orthotopic VCaP tumor growth and ASCs infiltration profiles ± surgical castration at acute (3d), intermediate (14d

Inhibition of PI3K suppresses propagation of drug-tolerant cancer cell subpopulations enriched by 5-fluorouracil.

PubMed

Ishida, Kaoru; Ito, Chie; Ohmori, Yukimi; Kume, Kohei; Sato, Kei A; Koizumi, Yuka; Konta, Akari; Iwaya, Takeshi; Nukatsuka, Mamoru; Kobunai, Takashi; Takechi, Teiji; Nishizuka, Satoshi S

2017-05-23

Drug-tolerant cancer cell subpopulations are responsible for relapse after chemotherapy. By continuously exposing the gastric cancer cell line MKN45 to 5-FU for >100 passages, we established a 5-fluorouracil (5-FU)-tolerant line, MKN45/5FU. Orthotopic xenografts of MKN45/5FU cells in the stomach of nude mice revealed that these cells had a high potential to metastasize to sites such as the liver. Levels of phosphorylated phosphatidylinositide 3-kinase (PI3K) increased both in 5-FU-tolerant subpopulations according to the 5-FU dose, and in gastric submucosal orthotopic xenografts of MKN45/5FU cells. Sequential administration of 5-FU and a PI3K inhibitor, GDC-0941, targeted the downstream ribosomal S6 kinase phosphorylation to significantly suppress 5-FU-tolerant subpopulations and tumor propagation of orthotopic MKN45/5FU xenografts. These results suggest that administration of 5-FU followed by GDC-0941 may suppress disease relapse after 5-FU-based gastric cancer chemotherapy.

Perfluorocarbon emulsions radiosensitise brain tumors in carbogen breathing mice with orthotopic GL261 gliomas

PubMed Central

Feldman, Lisa A.; Fabre, Marie-Sophie; Grasso, Carole; Reid, Dana; Broaddus, William C.; Lanza, Gregory M.; Spiess, Bruce D.; Garbow, Joel R.; McConnell, Melanie J.

2017-01-01

Background Tumour hypoxia limits the effectiveness of radiation therapy. Delivering normobaric or hyperbaric oxygen therapy elevates pO2 in both tumour and normal brain tissue. However, pO2 levels return to baseline within 15 minutes of stopping therapy. Aim To investigate the effect of perfluorocarbon (PFC) emulsions on hypoxia in subcutaneous and intracranial mouse gliomas and their radiosensitising effect in orthotopic gliomas in mice breathing carbogen (95%O2 and 5%CO2). Results PFC emulsions completely abrogated hypoxia in both subcutaneous and intracranial GL261 models and conferred a significant survival advantage orthotopically (Mantel Cox: p = 0.048) in carbogen breathing mice injected intravenously (IV) with PFC emulsions before radiation versus mice receiving radiation alone. Carbogen alone decreased hypoxia levels substantially and conferred a smaller but not statistically significant survival advantage over and above radiation alone. Conclusion IV injections of PFC emulsions followed by 1h carbogen breathing, radiosensitises GL261 intracranial tumors. PMID:28873460

Density-tunable conjugation of cyclic RGD ligands with polyion complex vesicles for the neovascular imaging of orthotopic glioblastomas

NASA Astrophysics Data System (ADS)

Kawamura, Wataru; Miura, Yutaka; Kokuryo, Daisuke; Toh, Kazuko; Yamada, Naoki; Nomoto, Takahiro; Matsumoto, Yu; Sueyoshi, Daiki; Liu, Xueying; Aoki, Ichio; Kano, Mitsunobu R.; Nishiyama, Nobuhiro; Saga, Tsuneo; Kishimura, Akihiro; Kataoka, Kazunori

2015-06-01

Introduction of ligands into 100 nm scaled hollow capsules has great potential for diagnostic and therapeutic applications in drug delivery systems. Polyethylene glycol-conjugated (PEGylated) polyion complex vesicles (PICsomes) are promising hollow nano-capsules that can survive for long periods in the blood circulation and can be used to deliver water-soluble macromolecules to target tissues. In this study, cyclic RGD (cRGD) peptide, which is specifically recognized by αVβ3 and αvβ5 integrins that are expressed at high levels in the neovascular system, was conjugated onto the distal end of PEG strands on PICsomes for active neovascular targeting. Density-tunable cRGD-conjugation was achieved using PICsomes with definite fraction of end-functionalized PEG, to substitute 20, 40, and 100% of PEG distal end of the PICsomes to cRGD moieties. Compared with control-PICsomes without cRGD, cRGD-PICsomes exhibited increased uptake into human umbilical vein endothelial cells. Intravital confocal laser scanning microscopy revealed that the 40%-cRGD-PICsomes accumulated mainly in the tumor neovasculature and remained in the perivascular region even after 24 h. Furthermore, we prepared superparamagnetic iron oxide (SPIO)-loaded cRGD-PICsomes for magnetic resonance imaging (MRI) and successfully visualized the neovasculature in an orthotopic glioblastoma model, which suggests that SPIO-loaded cRGD-PICsomes might be useful as a MRI contrast reagent for imaging of the tumor microenvironment, including neovascular regions that overexpress αVβ3 integrins.

In vivo imaging of tumor vascular endothelial cells

NASA Astrophysics Data System (ADS)

Zhao, Dawen; Stafford, Jason H.; Zhou, Heling; Thorpe, Philip E.

2013-02-01

Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable (non-apoptotic) endothelial cells in tumor blood vessels, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we optically imaged exposed PS on tumor vasculature in vivo using PGN635, a novel human monoclonal antibody that targets PS. PGN635 F(ab')2 was labeled with the near infrared (NIR) dye, IRDye 800CW. Human glioma U87 cells or breast cancer MDA-MB-231 cells were implanted subcutaneously or orthotopically into nude mice. When the tumors reached ~5 mm in diameter, 800CW- PGN635 was injected via a tail vein and in vivo dynamic NIR imaging was performed. For U87 gliomas, NIR imaging allowed clear detection of tumors as early as 4 h later, which improved over time to give a maximal tumor/normal ratio (TNR = 2.9 +/- 0.5) 24 h later. Similar results were observed for orthotopic MDA-MB-231 breast tumors. Localization of 800CW-PGN635 to tumors was antigen specific since 800CW-Aurexis, a control probe of irrelevant specificity, did not localize to the tumors, and pre-administration of unlabeled PGN635 blocked the uptake of 800CW-PGN635. Fluorescence microscopy confirmed that 800CW-PGN635 was binding to PS-positive tumor vascular endothelium. Our studies suggest that tumor vasculature can be successfully imaged in vivo to provide sensitive tumor detection.

MicroRNAs Associated with Epithelial-Mesenchymal Transition Can Be Targeted to Inhibit Peritoneal Dissemination of Human Scirrhous Gastric Cancers.

PubMed

Takei, Yoshifumi; Shen, Guodong; Morita-Kondo, Ayami; Hara, Toshifumi; Mihara, Keichiro; Yanagihara, Kazuyoshi

2018-05-30

Scirrhous gastric cancers grow rapidly, and frequently invade the peritoneum. Such peritoneal dissemination properties markedly reduce patient survival. Thus, an effective means for inhibiting peritoneal dissemination is urgently required. We previously established a cell line, HSC-58, from a scirrhous gastric cancer patient, and further successfully isolated a metastatic line, 58As9, in nude mice upon orthotopic inoculation. Using the lines, we examined the mechanism underlying peritoneal dissemination from the viewpoint of microRNA (miRNA) expression. miRNA array and qRT-PCR analysis showed that the expressions of epithelial-mesenchymal transition (EMT)-associated miRNAs such as miR-200c and miR-141 were significantly low in 58As9. Using 58As9 with stably overexpressing miR-200c, miR-141, or both, together with a luciferase reporter assay, we found that miR-200c targeted zinc finger E-box-binding homeobox 1 (ZEB1) and miR-141 targeted ZEB2. The overexpressed lines reversed the EMT status from mesenchymal to epithelial in 58As9, and significantly reduced the invasion activity and peritoneal dissemination for a significant prolongation of survival in the orthotopic tumor models in nude mice. EMT-associated miRNAs such as miR-200c and miR-141 and their target genes ZEB1/ZEB2 have good potential for antiperitoneal dissemination therapy in patients with scirrhous gastric cancers. © 2018 S. Karger AG, Basel.

Maintenance of airway epithelium in acutely rejected orthotopic vascularized mouse lung transplants.

PubMed

Okazaki, Mikio; Gelman, Andrew E; Tietjens, Jeremy R; Ibricevic, Aida; Kornfeld, Christopher G; Huang, Howard J; Richardson, Steven B; Lai, Jiaming; Garbow, Joel R; Patterson, G Alexander; Krupnick, Alexander S; Brody, Steven L; Kreisel, Daniel

2007-12-01

Lung transplantation remains the only therapeutic option for many patients suffering from end-stage pulmonary disease. Long-term success after lung transplantation is severely limited by the development of bronchiolitis obliterans. The murine heterotopic tracheal transplantation model has been widely used for studies investigating pathogenesis of obliterative airway disease and immunosuppressive strategies to prevent its development. Despite its utility, this model employs proximal airway that lacks airflow and is not vascularized. We have developed a novel model of orthotopic vascularized lung transplantation in the mouse, which leads to severe vascular rejection in allogeneic strain combinations. Here we characterize differences in the fate of airway epithelial cells in nonimmunosuppressed heterotopic tracheal and vascularized lung allograft models over 28 days. Up-regulation of growth factors that are thought to be critical for the development of airway fibrosis and interstitial collagen deposition were similar in both models. However, while loss of airway epithelial cells occurred in the tracheal model, airway epithelium remained intact and fully differentiated in lung allografts, despite profound vascular rejection. Moreover, we demonstrate expression of the anti-apoptotic protein Bcl-2 in airway epithelial cells of acutely rejected lung allografts. These findings suggest that in addition to alloimmune responses, other stimuli may be required for the destruction of airway epithelial cells. Thus, the model of vascularized mouse lung transplantation may provide a new and more physiologic experimental tool to study the interaction between immune and nonimmune mechanisms affecting airway pathology in lung allografts.

Perioperative and mid-term oncologic outcomes of robotic assisted radical cystectomy with totally intracorporeal neobladder: Results of a propensity score matched comparison with open cohort from a single-centre series.

PubMed

Simone, Giuseppe; Tuderti, Gabriele; Misuraca, Leonardo; Anceschi, Umberto; Ferriero, Mariaconsiglia; Minisola, Francesco; Guaglianone, Salvatore; Gallucci, Michele

2018-04-17

In this study, we compared perioperative and oncologic outcomes of patients treated with either open or robot-assisted radical cystectomy and intracorporeal neobladder at a tertiary care center. The institutional prospective bladder cancer database was queried for "cystectomy with curative intent" and "neobladder". All patients underwent robot-assisted radical cystectomy and intracorporeal neobladder or open radical cystectomy and orthotopic neobladder for high-grade non-muscle invasive bladder cancer or muscle invasive bladder cancer with a follow-up length ≥2 years were included. A 1:1 propensity score matching analysis was used. Kaplan-Meier method was performed to compare oncologic outcomes of selected cohorts. Survival rates were computed at 1,2,3 and 4 years after surgery and the log rank test was applied to assess statistical significance between the matched groups. Overall, 363 patients (299 open and 64 robotic) were included. Open radical cystectomy patients were more frequently male (p = 0.08), with higher pT stages (p = 0.003), lower incidence of urothelial histologies (p = 0.05) and lesser adoption of neoadjuvant chemotherapy (<0.001). After applying the propensity score matching, 64 robot-assisted radical cystectomy patients were matched with 46 open radical cystectomy cases (all p ≥ 0.22). Open cohort showed a higher rate of perioperative overall complications (91.3% vs 42.2%, p 0.001). At Kaplan-Meier analysis robotic and open cohorts displayed comparable disease-free survival (log-rank p = 0.746), cancer-specific survival (p = 0.753) and overall-survival rates (p = 0.909). Robot-assisted radical cystectomy and intracorporeal neobladder provides comparable oncologic outcomes of open radical cystectomy and orthotopic neobladder at intermediate term survival analysis. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Health-related Quality of Life After Radical Cystectomy: A Cross-sectional Study With Matched-pair Analysis on Ileal Conduit vs Ileal Orthotopic Neobladder Diversion.

PubMed

Cerruto, Maria Angela; D'Elia, Carolina; Siracusano, Salvatore; Saleh, Omar; Gacci, Mauro; Cacciamani, Giovanni; De Marco, Vincenzo; Porcaro, Antonio Benito; Balzarro, Matteo; Niero, Mauro; Lonardi, Cristina; Iafrate, Massimo; Bassi, Pierfrancesco; Imbimbo, Ciro; Racioppi, Marco; Talamini, Renato; Ciciliato, Stefano; Serni, Sergio; Carini, Marco; Verze, Paolo; Artibani, Walter

2017-10-01

To examine the different and health-related quality of life (HR-QoL) outcomes between ileal conduit (IC) and ileal orthotopic neobladder (IONB) in patients who underwent radical cystectomy (RC), by using validated self-reported cancer-specific instruments. This retrospective, cross-sectional, multicenter cohort study included 148 and 171 patients with either IC or IONB. HR-QoL was evaluated with Quality of Life Core Questionnaire and bladder module (BLM)-30 European Organisation for Research and Treatment of Cancer questionnaires. Baseline HR-QoL scores were dichotomized at the median to give "good" or "poor" score profiles. A matched-pair analysis compared HR-QoL aspects between 79 IC patients and 79 IONB patients. At univariate analysis IONB resulted favorable for physical functioning, emotional functioning, cognitive functioning (CF), fatigue, dyspnea, appetite loss, constipation (CO), and abdominal bloating flatulence (AB). At multivariate analyses, IONB showed better scores for emotional functioning (85 vs 79, P = .023), CF (93 vs 85, P <.001), CO (16 vs 31, P <.001), and AB (12 vs 25, P <.001). A significant worsening of sexual and urinary function was observed for IONB patients in the long-term. At matched-pair analysis, global health status was similar (65 vs 62, P = .385). Significantly better scores were observed in the IONB group for the following items: CF (P = .007), fatigue (P = .003), pain (P = .019), dyspnea (P = .016), CO (P = .001), and AB (P = .00). IONB and IC after RC were similar in terms of global health status. IONB provides better results in some aspects of HR-QoL related to bowel function, but a worsening of urinary and sexual functions. Further randomized controlled trials are needed to confirm these data. Copyright © 2017 Elsevier Inc. All rights reserved.

Our Experiences with Robot-Assisted Laparoscopic Radical Cystectomy: Orthotopic Neobladder by the Suprapubic Incision Method

PubMed Central

Cho, Byung Chul; Jung, Ha Bum; Cho, Sung Tae; Kim, Ki Kyung; Han, Jun Hyun; Lee, Yong Seong

2012-01-01

Purpose To report our technique for and experience with robot-assisted laparoscopic radical cystectomy (RARC) with orthotopic neobladder (ON) formation in a cohort of bladder cancer patients. Materials and Methods Between December 2007 and December 2011, a total of 35 patients underwent RARC. The patients' mean age was 63.3 years and their mean body mass index was 23.7 kg/m2. Thirty patients had a clinical stage of T2 or higher. Postoperative mean follow-up duration was 25.5 months. In 5 patients, a 4-cm midline infraumbilical skin incision was made for an ileal conduit (IC) and the stoma formation was similar to the open procedure. In 30 patients undergoing the ON procedure, the skin for specimen removal and extracorporeal enterocystoplasty was incised infraumbilically in the early 5 cases with redocking (ON-I) and suprapubically in the latter 25 cases without redocking (ON-S). Results The mean operative times of the IC, ON-I, and ON-S groups were 442.5, 646.0, and 531.3 minutes, respectively (p=0.001). Mean console and lymph node dissection time were not significantly different between the groups. Mean urinary diversion times in each group were 68.8, 125.0, and 118.8 minutes, respectively (p=0.001). In the comparison between the ON-I and ON-S group, only operative time was significant. Four patients required a blood transfusion. We had no cases of intraabdominal organ injury or open conversion. Thiry-three patients (94.2%) had a pathologic stage of T2 or higher. Two patients (5.7%) had lymph node-positive disease. Postoperative complications included ileus (n=4), stricture in the uretero-ileal junction (n=2), and vesicovaginal fistula (n=1). Conclusions Our robotic neobladder-suprapubic incision without redocking procedure is easier and more rapid than that of infraumbilical incision with redocking. PMID:23185668

Experience With Cardiac Implantable Electrical Device Explantation After Cardiac Transplantation: A Report of 16 Cases From a Single Center in a Period of 5 Years.

PubMed

Çiftci, Orçun; Yılmaz, Kerem Can; Sezgin, Atilla; Özin, Mehmet Bülent; Müderrisoğlu, İbrahim Haldun; Haberal, Mehmet

2018-03-01

Cardiac implantable electrical devices are widely used for patients with advanced heart failure and are usually explanted during orthotopic heart transplant. However, lead fragments and the pulse generator are sometimes left after the procedure. Given the concerns of infectious and thromboembolic complications, their removal is recommended. Herein, we report our experience with cardiac implantable electrical device explantation after orthotopic heart transplant. We included recipients of heart transplants performed at Başkent University Faculty of Medicine, Department of Cardiovascular Surgery, who underwent lead and pulse generator explantation by manual traction between January 2012 and June 2017. We analyzed patient demographic, clinical, biochemical, and treatment properties. Sixteen patients (11 males, 5 females) with a median age of 45 years (range, 18-52 y) were included. Two patients (12.5%) died during follow-up but not secondary to device explantation. All patients were using immunosuppressives and 50% were receiving antiplatelet/anticoagulant agents. All pulse generators were located at the left prepectoral area, with tips of lead fragments in the superior vena cava or left subclavian vein. No procedural complications were observed. Aspirin was continued uninterrupted perioperatively, warfarin was stopped 2 days before the procedure, and low-molecular-weight heparins were skipped on the morning and evening of the procedure. One patient (6.3%) complained of postoperative pain, and another (6.3%) developed a pocket hematoma, which was treated conservatively. No patient developed fever, clinical infection, or major bleeding. Preoperative and postoperative levels of hemoglobin, white blood cells, and C-reactive protein were similar. No demographic, procedural, or biochemical variable was significantly correlated with postprocedural complications. In our cohort, explantation of lead fragments and pulse generators of cardiac implantable electrical devices was safe after heart transplant. It appears that neither antiplatelet/anticoagulant agents nor immunosuppressives seem to put patients at increased risk of postoperative complications.

Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.

PubMed

Yoshiji, Hitoshi; Kuriyama, Shigeki; Noguchi, Ryuichi; Yoshii, Junichi; Ikenaka, Yasuhide; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Akahane, Takemi; Asada, Kiyoshi; Tsujimoto, Tatsuhito; Uemura, Masahito; Fukui, Hiroshi

2006-01-01

Recent studies have revealed that angiogenesis plays a pivotal role in carcinogenesis and tumor growth. We previously reported that the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) exerted potent anti-angiogenic activities. The aim of our current study was to examine the combination effect of VK and ACE-I on hepatocarcinogenesis induced by diethyl-nitrosamine, and orthotopic hepatocellular carcinoma (HCC) growth in rats. When used individually, both VK and ACE-I at clinically comparable low doses exerted significant inhibitory effects on tumor development in the liver. A combination treatment of VK and ACE-I showed a more potent suppressive effect against hepatocarcinogenesis. Neovascularization increased during hepatocarcinogenesis, and VK and ACE-I significantly attenuated angiogenesis in the tumor. In orthotopic HCC transplantation, VK and ACE-I also showed marked suppressive effects against HCC development similar to those against hepatocarcinogenesis. In both experiments, the suppressive effects of VK and ACE-I against angiogenesis were similar in magnitude to their inhibitory effects against hepatocarcinogenesis and orthotopic HCC development. In the orthotopic model, VK and ACE-I treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. Since both VK and ACE-I are widely used in clinical practice without serious side effects, this combination therapy may be an effective new therapeutic strategy against hepatocarcinogenesis and HCC growth in the future.

Fluorescence imaging of angiogenesis in green fluorescent protein-expressing tumors

NASA Astrophysics Data System (ADS)

Yang, Meng; Baranov, Eugene; Jiang, Ping; Li, Xiao-Ming; Wang, Jin W.; Li, Lingna; Yagi, Shigeo; Moossa, A. R.; Hoffman, Robert M.

2002-05-01

The development of therapeutics for the control of tumor angiogenesis requires a simple, reliable in vivo assay for tumor-induced vascularization. For this purpose, we have adapted the orthotopic implantation model of angiogenesis by using human and rodent tumors genetically tagged with Aequorea victoria green fluorescent protein (GFP) for grafting into nude mice. Genetically-fluorescent tumors can be readily imaged in vivo. The non-luminous induced capillaries are clearly visible against the bright tumor fluorescence examined either intravitally or by whole-body luminance in real time. Fluorescence shadowing replaces the laborious histological techniques for determining blood vessel density. High-level GFP-expressing tumor cell lines made it possible to acquire the high-resolution real-time fluorescent optical images of angiogenesis in both primary tumors and their metastatic lesions in various human and rodent tumor models by means of a light-based imaging system. Intravital images of angiogenesis onset and development were acquired and quantified from a GFP- expressing orthotopically-growing human prostate tumor over a 19-day period. Whole-body optical imaging visualized vessel density increasing linearly over a 20-week period in orthotopically-growing, GFP-expressing human breast tumor MDA-MB-435. Vessels in an orthotopically-growing GFP- expressing Lewis lung carcinoma tumor were visualized through the chest wall via a reversible skin flap. These clinically-relevant angiogenesis mouse models can be used for real-time in vivo evaluation of agents inhibiting or promoting tumor angiogenesis in physiological micro- environments.

A deimmunized bispecific ligand directed toxin that shows an impressive anti-pancreatic cancer effect in a systemic nude mouse orthotopic model

PubMed Central

Oh, Seunguk; Todhunter, Deborah A.; Panoskaltsis-Mortari, Angela; Buchsbaum, Donald J.; Toma, Shoko; Vallera, Daniel A.

2011-01-01

Objective The objective was to test a bispecific ligand directed toxin (BLT), with reduced immunogenicity for enhanced efficacy in targeting orthotopic pancreatic cancer in vivo. Method A new BLT was created in which both human EGF and IL-4 cytokines were cloned onto the same single chain molecule with deimmunized pseudomonas exotoxin (dEGF4KDEL). Key amino acids dictating B cell generation of neutralizing anti-toxin antibodies were mutated. Bioassays were used to determine whether mutation reduced potency, and ELISA studies were performed to determine whether anti-toxin antibodies were reduced. A genetically altered luciferase MIA PaCa-2 xenograft model was used to image in real time and determine affects on systemic malignant human cancer. BLTs targeting B cells were used as specificity controls. Results dEGF4KDEL was significantly effective following systemic injection against established orthotopic MIA PaCa-2 pancreatic cancer and selectively prevented metastasis. Mutagenesis significantly reduced anti-toxin levels in vivo with no apparent activity loss in vitro. The drug was effective against three human pancreatic cancer lines in vitro, MIA PaCa-2, SW1990, and S2VP10. Conclusions Despite the metastatic nature of the MIA PaCa-2 orthotopic tumor xenografted in nude mice, high percentages of tumors responded to extended dEGFKDEL treatment resulting in significant anti-cancer effects and disease-free survivors. PMID:22258068

Vascular invasion is a prognostic indicator in hepatoblastoma.

PubMed

Shi, Yan; Commander, Sarah J; Masand, Prakash M; Heczey, Andras; Goss, John A; Vasudevan, Sanjeev A

2017-06-01

The data regarding vascular invasion as a prognostic factor in hepatoblastoma (HB) are conflicted. The purpose of this study is to examine the relationship between vascular invasion and outcomes. This is a retrospective review of patients <18 years old who underwent resection for hepatoblastoma from 1998 to 2015. Pathology reports were used to identify patients who had pathologic vascular invasion (VI), and those who did not (NVI). Sixty-six children were identified with a median age at diagnosis of 21months (interquartile range: 10-33months). Pathologic vascular invasion was present in 42/66 (64%) patients. A significant difference (P=0.02) in 3-year overall survival (3YOS) was detected between NVI (95%) and VI (61%). Recurrent disease was present in 8/66 (12%) patients. A marginally significant difference (P=0.08) was found in 3-year recurrence free survival (3YRFS) between NVI (94%) and the VI (76%) groups. Patients with NVI had no metastatic disease, had a lower recurrence rate, universally responded to neoadjuvant chemotherapy, and were less likely to have small cell undifferentiated histology. Twenty-one children underwent orthotopic liver transplant (OLT), with no difference in 3YROS or 3YRFS. Pathologic vascular invasion is associated with significantly worse 3YOS in HB, and lack of vascular invasion was associated with more favorable disease characteristics. The presence of pathologic vascular invasion did not confer a worse outcome in patients treated with liver transplantation in this cohort of patients. Retrospective review. Level III. Copyright © 2017 Elsevier Inc. All rights reserved.

Cardio-hepatic risk assessment by CMR imaging in liver transplant candidates.

PubMed

Reddy, Sahadev T; Thai, Ngoc L; Oliva, Jose; Tom, Kusum B; Dishart, Michael K; Doyle, Mark; Yamrozik, June A; Williams, Ronald B; Shah, Moneal; Wani, Adil; Singh, Anil; Maheswary, Rishi; Biederman, Robert W W

2018-03-02

The preoperative workup of orthotopic liver transplantation (OLT) patients is practically complex given the need for multiple imaging modalities. We recently demonstrated in our proof-of-concept study the value of a one-stop-shop approach using cardiovascular MRI (CMR) to address this complex problem. However, this approach requires further validation in a larger cohort, as detection of hepatocellular carcinoma (HCC) as well as cardiovascular risk assessment is critically important in these patients. We hypothesized that coronary risk assessment and HCC detectability is acceptable using the one-stop-shop CMR approach. In this observational study, patients underwent CMRI evaluation including cardiac function, stress CMR, thoracoabdominal MRA, and abdominal MRI on a standard MRI scanner in one examination. Over 8 years, 252 OLT candidates underwent evaluation in the cardiac MRI suit. The completion rates for each segment of the CMR examination were 99% for function, 95% completed stress CMR, 93% completed LGE for viability, 85% for liver MRI, and 87% for MRA. A negative CMR stress examination had 100% CAD event-free survival at 12 months. A total of 63 (29%) patients proceeded to OLT. Explant pathology confirmed detection/exclusion of HCC. This study further defines the population suitable for the one-stop-shop CMR concept for preop evaluation of OLT candidates providing a road map for integrated testing in this complex patient population for evaluation of cardiac risk and detection of HCC lesions. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Submandibular ectopic thyroid with normally located thyroid gland.

PubMed

Yılmaz, Mahmut Sinan; Aytürk, Semra; Güven, Mehmet; Dilek, Fatma Hüsniye

2014-01-01

Ectopic thyroid is a rare developmental anomaly of the thyroid gland which is defined as the presence of thyroid tissue at a site other than the pretracheal area. Nearly 1 to 3% of all ectopic thyroids are located in the lateral neck. Simultaneous submandibular ectopic thyroid tissue presenting with a functional orthotopic thyroid gland is extremely rare. In this article, we report a 37-year-old female case admitted to our clinic with a complaint of swollen neck in whom ultrasonography revealed submandibular ectopic thyroid tissue presenting with an orthotopic thyroid gland.

Metastatic adenocarcinoma of mammary-like glands of the vulva successfully treated with surgery and hormonal therapy.

PubMed

Benito, Virginia; Arribas, Sara; Martínez, David; Medina, Norberto; Lubrano, Amina; Arencibia, Octavio

2013-01-01

Vulvar cancer is a rare malignancy; most tumors are squamous cell type while adenocarcinomas are rare. Primary adenocarcinomas of the vulva predominantly include extramammary Paget's disease and sweat gland carcinomas. Greene first described a rare form of adenocarcinoma in 1936, which was called adenocarcinoma of mammary-like glands of the vulva because of its morphologic and immunohistochemical resemblance to breast adenocarcinomas. In the management of this entity, varying combinations of surgery, radiation therapy, systemic chemotherapy and/or hormonal therapy may be used, as in patients with orthotopic breast carcinoma. However, hormonal therapy leads the way in patients with positive hormonal receptors, where other therapies cannot be used due to comorbidities or advanced age. We present the first reported case of an elderly patient with metastatic vulvar adenocarcinoma arising from mammary-like glands, successfully treated with a combination of surgery and hormonal therapy. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

Colonic stenting as a bridge to surgery for obstructive colorectal cancer: advantages and disadvantages.

PubMed

Haraguchi, Naotsugu; Ikeda, Masataka; Miyake, Masakazu; Yamada, Takuya; Sakakibara, Yuko; Mita, Eiji; Doki, Yuichiro; Mori, Masaki; Sekimoto, Mitsugu

2016-11-01

To clarify the advantages and disadvantages of stenting as a bridge to surgery (BTS) by comparing the clinical features and outcomes of patients who underwent BTS with those of patients who underwent emergency surgery (ES). We assessed technical success, clinical success, surgical procedures, stoma formation, complications, clinicopathological features, and Onodera's prognostic nutritional index (OPNI) in patients who underwent BTS and those who underwent ES. Twenty-six patients underwent stenting, which was successful in 22 (BTS group). The remaining four patients with unsuccessful stenting underwent emergency surgery. A total of 22 patients underwent emergency surgery (ES group). The rates of technical and clinical success were 85.0 and 81.0 %, respectively. The proportion of patients able to be treated by laparoscopic surgery (P = 0.0001) and avoid colostomy (P = 0.0042) was significantly higher in the BTS group. Although the incidence of anastomotic leakage in the two groups was not significantly different, it was significantly reduced by colonoscopic evaluation of obstructive colitis (P = 0.0251). The mean number of harvested lymph nodes (P = 0.0056) and the proportion of D3 lymphadenectomy (P = 0.0241) were significantly greater in the BTS group. Perineural invasion (PNI) was noted in 59.1 and 18.2 % of the BTS group and ES group patients, respectively (P = 0.0053). OPNI and serum albumin decreased significantly after stenting (P = 0.0084). The advantages of stenting as a BTS were that it avoided colostomy and allowed for laparoscopic surgery and lymphadenectomy, whereas its disadvantage lay in the decreased PNI and OPNI levels. A larger study including an analysis of prognosis is warranted.

Alveolar graft in the cleft lip and palate patient: Review of 104 cases

PubMed Central

Tobella-Camps, María L.; Rivera-Baró, Alejandro

2014-01-01

Introduction: Alveolar bone grafting is a vital part of the rehabilitation of cleft patients. The factors that have been most frequently associated with the success of the graft are the age at grafting and the pre-grafting orthodontic treatment. Objectives: 1) Describe the cases of alveolar bone grafts performed at the Maxilofacial Unit of Hospital Sant Joan de Déu, Barcelona (HSJD); and 2) Analyze the success/failure of alveolar grafts and related variables. Material and Methods: Descriptive retrospective study using a sample of 104 patients who underwent a secondary alveolar graft at the Craniofacial Unit of HSJD between 1998 and 2012. The graft was done by the same surgeon in all patients using bone from the iliac crest. Results: 70% of the patients underwent the procedure before the age of 15 (median 14.45 years); 70% of the graft patients underwent pre-graft maxillary expansion. A total of 100 cases were recorded as successful (median age of 14.58 years, 68 underwent pre-graft expansion) and only 4 were recorded as failures (median age of 17.62 years, 3 underwent pre-graft expansion). We did not find statistically significant differences in age at the time of grafting or pre-surgical expansion when comparing the success and failure groups. We found the success rate of the graft to be 96.2%. Conclusions: The number of failures was too small to establish a statistically significant conclusion in our sample regarding the age at grafting and pre-grafting expansion. The use of alveolar bone grafting from the iliac crest has a very high success rate with a very low incidence of complications. Existing controversies regarding secondary bone grafting and the wide range of success rates found in the literature suggest that it is necessary to establish a specific treatment protocol that ensures the success of this procedure. Key words:Alveolar graft, cleft lip and palate, alveolar cleft, alveolar defect. PMID:24880440

Preoperative Transcatheter Selective Arterial Chemoembolization in Treatment of Unresectable Hepatoblastoma in Infants and Children

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li Jiaping; Chu Jianping, E-mail: truechu@hotmail.com; Yang Jianyong

2008-11-15

The purpose of this study was to evaluate the clinical feasibility and efficacy of transcatheter selective arterial chemoembolization (TACE) for unresectable hepatoblastoma in infants and children. The study was performed with the approval of our institutional review board. Sixteen patients (13 boys, 3 girls) with unresectable hepatoblastoma were treated one to three times with preoperative TACE in an effort to improve the surgical and clinical outcome. Their ages ranged from 50 days to 60 months, with a mean age of 20.4 months. All cases were pathologically proved hepatoblastoma by fine-needle biopsy. After an intra-arterial catheter was selectively inserted into themore » main feeding artery of the tumor, cycles of cisplatin (40 to 50 mg/m{sup 2}) and adriamycin (20 to 30 mg/m{sup 2}) mixed with lipiodol were given, followed by gelatin foam particles or stainless-steel coils. Tumor response was evaluated according to tumor shrinkage, {alpha}-fetoprotein (AFP) levels, and pathological findings. TACE procedure was performed one to three times, depending on the patient's response. Surgical resection was carried out when the tumor volume appeared sufficiently reduced to allow safe resection by either lobectomy or extended lobectomy. A marked reduction in tumor size associated with decreased AFP level occurred after treatment. According to paired-samples test, tumor shrinkage ranged from 19.0% to 82.0%, with a mean value of 59.2%. AFP levels decreased 99.0% to 29.0% from initial levels, with a mean decrease of 60.0%. TACE allowed subsequent complete surgical resection in 13 cases and the other 3 cases underwent partial resection. One patient underwent successful orthotopic liver transplantation after receiving TACE therapy. Pathological examination showed that the mean percentage of necrotic area in the surgical specimens was 87%. Overall survival rate at 1, 3, and 5 years was 87.5%, 68.7%, and 50%, respectively. Correspondingly, event-free survival rate was 75%, 62.5%, and 43.7%, respectively. In addition, there was no marked chemotherapeutic agent-induced toxicity noted during the observation period. We conclude that TACE is feasible, well tolerated, and effective in inducing surgical resectability of hepatoblastoma in pediatric patients, which has become an independent palliative or curative therapeutic option, especially for patients without distant metastasis.« less

Screening of the residual normal ovarian tissue adjacent to orthotopic epithelial ovarian carcinomas in nude mice.

PubMed

Zhu, G H; Wang, S T; Yao, M Z; Cai, J H; Chen, C Y; Yang, Z X; Hong, L; Yang, S Y

2014-04-16

The objective of this study was to explore the feasibility and methods of screening the residual normal ovarian tissue adjacent to orthotopic ovarian carcinomas in nude mice. Human epithelial ovarian cancer cells (OVCAR3) were subcutaneously implanted for a tumor source and ovarian orthotopic transplantation. The cancer tissue, proximal paraneoplastic tissue, middle paraneoplastic tissue, remote paraneoplastic tissue, and normal ovarian tissue were removed. CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was detected by reverse transcription polymerase chain reaction. We obtained 35 paraneoplastic residual ovarian tissues with normal biopsies from 40 cases of an orthotopic epithelial ovarian carcinoma model (87.5%). CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was lower in proximal paraneoplastic tissue than in cancer tissue (P < 0.05) and higher than in middle and remote paraneoplastic tissue (P < 0.01). There was no statistically significant difference between the expression of these genes in middle and proximal paraneoplastic tissue as well as among residual normal ovarian tissues with different severity (P > 0.05). In ovarian tissues of 20 normal nude mice, the expression of CK- 7, CA125, p53, survivin, MMP-2, and TIMP-2 was negative. Overall, the expression levels of CK-7, CA125, p53, survivin, MMP-2, TIMP-2, and other molecular markers showed a decreasing trend in the non-cancer tissue direction. The expression levels can be used as standards to screen residual normal ovarian tissue. We can obtain relatively safe normal ovarian tissues adjacent to epithelial ovarian cancer.

Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma.

PubMed

Laramy, Janice K; Kim, Minjee; Gupta, Shiv K; Parrish, Karen E; Zhang, Shuangling; Bakken, Katrina K; Carlson, Brett L; Mladek, Ann C; Ma, Daniel J; Sarkaria, Jann N; Elmquist, William F

2017-11-01

This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC 50 ). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Trehalose Liposomes Suppress the Growth of Tumors on Human Lung Carcinoma-bearing Mice by Induction of Apoptosis In Vivo.

PubMed

Ichihara, Hideaki; Kuwabara, Keiji; Matsumoto, Yoko

2017-11-01

Previous evidence demonstrates that trehalose liposomes (DMTreC14) composed of L-α-dimyristoylphosphatidylcholine (DMPC) and α-D-glycopyranosyl-α-D-glucopyranoside monomyristate (TreC14) inhibit proliferation and invasion on lung carcinoma (A549 cells) in vitro. Here, we aimed to investigate suppressive effects of DMTreC14 on the growth of tumor on human lung carcinoma bearing mice. DMTreC14 composed of 30 mol% DMPC and 70 mol% TreC14 were prepared by the sonication method. Anti-tumor activities of DMTreC14 using the subcutaneous and orthotopic graft-bearing mice of A549 cells were investigated in vivo. The remarkable reduction of volume and weight in subcutaneous tumors on subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were obtained. Apoptotic-positive cells in the subcutaneous tumor slice of subcutaneous lung carcinoma-bearing mice topically administrated with DMTreC14 were observed using TUNEL staining. Lung weights on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 were markedly decreased compared to those of the control group. Remarkable decrease in dimensions of tumor area of lung on the orthotopic graft-bearing mice of lung carcinoma intravenously administrated with DMTreC14 was obtained in histological analysis using the hematoxylin and eosin staining. Remarkably high anti-tumor activities of DMTreC14 for the subcutaneous and orthotopic graft-bearing mice of lung carcinoma accompanied with apoptosis were revealed for the first time in vivo. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging.

PubMed

Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

2017-11-01

We have established an orthotopic nude-mouse model of gastric cancer carcinomatosis peritonitis, a recalcitrant disease in human patients. Human MKN45 poorly-differentiated human gastric cancer cells developed carcinomatosis peritonitis upon orthotopic transplantation in nude mice. The MKN45 cells expressed the fluorescent ubiquitination-based cell cycle indicator (FUCCI) that color codes the phases of the cell cycle. The intra-peritoneal tumors and ascites contained mostly quiescent G 1 /G o cancer cells visualized as red by FUCCI imaging. Cisplatinum (CDDP) treatment did not reduce bloody ascites, and larger tumors formed in the peritoneal cavity after CDDP treatment in an early-stage carcinomatosis peritonitis orthotopic mouse model. Paclitaxel-treated mice had reduced ascites, but also had large tumor masses in the peritonium after treatment with cancer cells mostly in G 0 /G 1 , visualized by FUCCI red. In contrast, OBP-301 telomerase-dependent adenovirus-treated mice had no ascites and only small tumor nodules consisting of cancer cells mostly in S/G 2 phases in the early-stage carcinomatosis peritonitis model, visualized by FUCCI green. Furthermore, OBP-301 significantly reduced the size of tumors (P < 0.01) and ascites even in a late-stage carcinomatosis peritonitis model. These results suggest that quiescent peritoneally-disseminated gastric cancer cells are resistant to conventional chemotherapy, but OBP-301 significantly reduced the weight of the tumors and increased survival, suggesting clinical potential. J. Cell. Biochem. 118: 3635-3642, 2017. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Is Health-Related Quality of Life after Radical Cystectomy Using Validated Questionnaires Really Better in Patients with Ileal Orthotopic Neobladder Compared to Ileal Conduit: A Meta-Analysis of Retrospective Comparative Studies.

PubMed

Cerruto, Maria A; D'Elia, Carolina; Siracusano, Salvatore; Porcaro, Antonio B; Cacciamani, Giovanni; De Marchi, Davide; Niero, Mauro; Lonardi, Cristina; Iafrate, Massimo; Bassi, Pierfrancesco; Belgrano, Emanuele; Imbimbo, Ciro; Racioppi, Marco; Talamini, Renato; Ciciliato, Stefano; Toffoli, Laura; Rizzo, Michele; Visalli, Francesco; Verze, Paolo; Artibani, Walter

2017-07-01

From the most recent systematic revision of the literature, an orthotopic neobladder would seem to show marginally better health related quality of life (HR-QoL) scores compared with an ileal conduit. The aim of this study was to review all relevant published studies about the comparison between ileal orthotopic neobladder (IONB) and ileal conduit using validated HR-QoL questionnaires. Studies were identified by searching multiple literature databases. Data were synthesized using meta-analytic methods conformed to the PRISMA statement. The literature search identified 10 papers; pooled effect sizes of combined quality of life outcomes for ileal conduit versus IONB showed a significantly better HR-QoL in patients with IONB (Hedges' g = 0.278; p = 0.000);. The present study has an important limitation due to the type of the analyzed comparative studies, all retrospective and not randomized. This meta-analysis of not-randomized, retrospective comparative studies on the impact of ileal conduit versus IONB on HR-QoL showed a significant advantage of IONB subgroups.

Human pancreatic cancer xenografts recapitulate key aspects of cancer cachexia.

PubMed

Delitto, Daniel; Judge, Sarah M; Delitto, Andrea E; Nosacka, Rachel L; Rocha, Fernanda G; DiVita, Bayli B; Gerber, Michael H; George, Thomas J; Behrns, Kevin E; Hughes, Steven J; Wallet, Shannon M; Judge, Andrew R; Trevino, Jose G

2017-01-03

Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

Quality of life in women undergoing urinary diversion for bladder cancer: results of a multicenter study among long-term disease-free survivors.

PubMed

Gacci, Mauro; Saleh, Omar; Cai, Tommaso; Gore, John L; D'Elia, Carolina; Minervini, Andrea; Masieri, Lorenzo; Giannessi, Claudia; Lanciotti, Michele; Varca, Virginia; Simonato, Alchiede; Serni, Sergio; Carmignani, Giorgio; Carini, Marco

2013-03-12

Women undergoing radical cystectomy (RC) and urinary diversion for bladder cancer experience substantial limitations in health-related quality of life (HRQOL). However, the level of discomfort caused by different urinary diversion has been never evaluated in long term survivors. The aim of this multicenter study is to evaluate differences in HRQOL among recurrence-free women undergoing cutaneous ureterostomy (CUS), Bricker's ileal conduit (BK-IC) and Orthotopic neobladder VIP (ONB-VIP) in disease-free females treated with radical cystectomy (RC), with long-term follow up (mean 60.1 months; range 36-122 months). All consecutively treated female patients from two urological institutions who underwent RC and urinary diversion from January 2000 to December 2008, with no evidence of tumor recurrence at a minimum follow up of 36 months, were included. Patients received the European Organisation for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and bladder cancer-specific instruments (QLQ-BLM30) and the Functional Assessment of Cancer Therapy for Bladder Cancer (FACT-BL). Clinical data and questionnaire results were analyzed in order to evaluate the HRQOL differences among diversion groups. We identified 37 females (median age: 68, range 45-82 years), including 12 status-post CUS, 16 who underwent BK-IC, and 9 who underwent ONB-VIP. Most were healthy (24/37 with no comorbidities, 4/37 Charlson 1-2, 9/37 Charlson 3 or greater - we didn't considered bladder cancer in Charlson evaluation because bladder cancer was the main inclusion criteria). Women undergoing CUS endorsed worse FACT-BL scores compared with BK-IC and ONB-VIP patients, worse HRQOL regarding physical and emotional well-being (p=0.008 and p=0.02, respectively), and a trend toward worse EORTC QLQ-C30 scores for appetite loss and fatigue (p=0.05 for both). In our study long-term disease-free females treated with CUS endorsed worse HRQOL compared with women who underwent BK-IC or ONB-VIP, mostly due to worse physical and emotional perception of their body image.

Intravital imaging of a spheroid-based orthotopic model of melanoma in the mouse ear skin

PubMed Central

Chan, Keefe T.; Jones, Stephen W.; Brighton, Hailey E.; Bo, Tao; Cochran, Shelly D.; Sharpless, Norman E.; Bear, James E.

2017-01-01

Multiphoton microscopy is a powerful tool that enables the visualization of fluorescently tagged tumor cells and their stromal interactions within tissues in vivo. We have developed an orthotopic model of implanting multicellular melanoma tumor spheroids into the dermis of the mouse ear skin without the requirement for invasive surgery. Here, we demonstrate the utility of this approach to observe the primary tumor, single cell actin dynamics, and tumor-associated vasculature. These methods can be broadly applied to investigate an array of biological questions regarding tumor cell behavior in vivo. PMID:28748125

Orthotopic neo- bladder in women.

PubMed

Schettini, Manlio

2010-12-01

Radical cystectomy is the most effective treatment madality for high grade urinary bladder carcinoma and orthotopic reconstruction is the better urinary diversion modality also in women. From 2002 to 2007 we performed 14 radical cystectomies followed by orthotopic reconstruction in women aged between 47 and 68 years (mean age 56) affected by urinary bladder carcinoma. Our reconstructive technique requires the preparation of two strips of the recti muscles fascia, the sectioning of the bladder neck and, when the uterus is present, hysteroannessiectomy and cystectomy en block leaving intact the lateral and inferior vaginal walls. The pelvic floor is stabilized by a colposacropexis with a prosthesis and placing an omental flap over the prosthesis. The orthotopic reconstruction is achieved via a neobladder according to the Padovana technique. The ureters are anastomized to the neobladder and splinted with single J stents. The pathological examination demonstrated in all patients the presence of a high grade carcinoma (G3): more specifically 4 patients had a full thickness intramural infiltration (T2), 2 patients had involvment of the perivescical fat (T3) ad 8 patients were in T1 stage. Lymphnodes were negative for tumour (NO). In 8 patients blood transfusions were necessary to treat post surgical anemia. No significant intra-, peri- or post operative complications were noted. The mean follow-up was 45 months: a patient died for diffuse metastatic disease after 11 months. The remaining patients are still alive and report normal lifestyle: 10 with normal micturition and 4 with urinary retention treated with intermittent self-catetherization. Two patients report nocturnal incontinence treated with hourly micturition and one pad. The five patients who had normal preoperative sexual intercourse resumed a normal sexual activity. The possibility to orthotopically recontruct the female urinary bladder has been established long time after the introduction of orthotopic neobladder in males, when became obvious that bladder reconstruction had to be done in conjunction with the reconstruction of the pelvic floor, in order to assure a satisfactory function at the new bladder. To avoid a posterior slippage of the vaginal stump we inserted the vaginal stump into a prolene tube which was then anchored posteriorly to the sacral periostium. We covered the prolene net with a flap of omentum pedicled down from the transverse colon and brought into the pelvis through the right colic space. This solid, stable and well protected support was able to accept the new bladder. We use the Padovana technique to facilitate the anastomosis of the bladder neck to the urethra. In the patients affected by urethral ipermotility we shaped a sub urethral sling using the recti muscles fascia pedicled by the pyramidal muscles. With this modality of reconstruction female pelvic anatomy is preserved as demonstrated by recovery of sexual activity.

The effect of the sequential therapy in end-stage heart failure (ESHF)--from ECMO, through the use of implantable pump for a pneumatic heart assist system, Religa Heart EXT, as a bridge for orthotopic heart transplant (OHT). Case study.

PubMed

Religa, Grzegorz; Jasińska, Małgorzata; Czyżewski, Łukasz; Torba, Krzysztof; Różański, Jacek

2014-10-21

Modern Polish medicine offers patients various treatments for end-stage treatment-resistant heart failure. Methods applied at the right time before the occurrence of irreversible changes in organs give a chance for survival and prolong life. Here, we report on the safety and efficacy of the sequential use of the above treatments in a 58-year old patient with heart failure in dilatative cardiomyopathy (DCM). A 7-day mechanical blood circulatory support and extracorporeal membrane oxygenation of blood (ECMO), followed by a 13-day implantation of a left ventricular assist device, Religa Heart EXT, was used as a bridge to a successful orthotopic heart transplant (OHT). On Day 40 after OHT, the patient was discharged home with stable function of the circulatory system. We describe our experiences with the qualification, preparation, and procedure of sequential ECMO, Religa Heart EXT, and OHT. Application of short-term ECMO as a bridge-to-bridge helped save the patient from severe cardiogenic shock caused by increased left ventricular afterload. The experimental implantation of an innovative Religa Heart EXT prosthesis was a safe and efficacious bridge to transplantation. Too short time of Religa Heart EXT implantation in the discussed patient prevented the possibility to evaluate the occurrence of thromboembolic complications and infections compared to the documented complications of POLVAD implanted until now. OHT is a safe and efficacious method of treatment of patients previously supported by ECMO and Religa Heart EXT.

Successful immunosuppressant-free heterotopic transplantation of tracheal allografts in the pig.

PubMed

De Wolf, Julien; Brieu, Mathias; Zawadzki, Christophe; Ung, Alexandre; Kipnis, Eric; Jashari, Ramadan; Hubert, Thomas; Fayoux, Pierre; Mariette, Christophe; Copin, Marie-Christine; Wurtz, Alain

2017-08-01

It has been demonstrated that both heterotopic and orthotopic transplants of epithelium-denuded cryopreserved tracheal allografts are feasible in immunosuppressant-free rabbits. Validation of these results in large animals is required before considering clinical applications. We evaluated the viability, immune tolerance and strain properties of such tracheal allografts heterotopically transplanted in a pig model. Ten tracheal segments, 5 short (5 rings) and 5 long (10 rings), were obtained from male Landrace pigs. The tracheal segments were surgically denuded of their epithelium, then cryopreserved and stored in a tissue bank for 33 to 232 days. After thawing, tracheal segments stented with a silicone tube were wrapped in the omentum in 2 groups of 5 female recipients. The animals did not receive any immunosuppressive drugs. The animals were euthanized from Day 6 to Day 90 in both groups. An effective revascularization of allografts regardless of length was observed. Lymphocyte infiltrate was shown in the early postoperative period and became non-significant after 30 days. Allografts displayed high levels of neoangiogenesis and viable cartilage rings with islets of calcification. Biomechanical measurements demonstrated strain properties similar to those of a fresh tracheal segment from Day 58. Our results demonstrate the acceptability and satisfactory stiffness of epithelium-denuded cryopreserved tracheal allografts implanted in the omentum, despite the absence of immunosuppressive drugs. Since the omentum has the capability to reach the tracheal region, this approach should be investigated in the setting of orthotopic transplants in a pig model before considering clinical applications. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer.

PubMed

Gao, Duo; Gao, Liquan; Zhang, Chenran; Liu, Hao; Jia, Bing; Zhu, Zhaohui; Wang, Fan; Liu, Zhaofei

2015-06-01

Integrin αvβ6 is widely upregulated in variant malignant cancers but is undetectable in normal organs, making it a promising target for cancer diagnostic imaging and therapy. Using streptavidin-biotin chemistry, we synthesized an integrin αvβ6-targeted near-infrared phthalocyanine dye-labeled agent, termed Dye-SA-B-HK, and investigated whether it could be used for cancer imaging, optical imaging-guided surgery, and phototherapy in pancreatic cancer mouse models. Dye-SA-B-HK specifically bound to integrin αvβ6 in vitro and in vivo with high receptor binding affinity. Using small-animal optical imaging, we detected subcutaneous and orthotopic BxPC-3 human pancreatic cancer xenografts in vivo. Upon optical image-guidance, the orthotopically growing pancreatic cancer lesions could be successfully removed by surgery. Using light irradiation, Dye-SA-B-HK manifested remarkable antitumor effects both in vitro and in vivo. (18)F-FDG positron emission tomography (PET) imaging and ex vivo fluorescence staining validated the observed decrease in proliferation of treated tumors by Dye-DA-B-HK phototherapy. Tissue microarray results revealed overexpression of integrin αvβ6 in over 95% cases of human pancreatic cancer, indicating that theranostic application of Dye-DA-B-HK has clear translational potential. Overall, the results of this study demonstrated that integrin αvβ6-specific Dye-SA-B-HK is a promising theranostic agent for the management of pancreatic cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Optimization of high grade glioma cell culture from surgical specimens for use in clinically relevant animal models and 3D immunochemistry.

PubMed

Hasselbach, Laura A; Irtenkauf, Susan M; Lemke, Nancy W; Nelson, Kevin K; Berezovsky, Artem D; Carlton, Enoch T; Transou, Andrea D; Mikkelsen, Tom; deCarvalho, Ana C

2014-01-07

Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor. Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies.

Optimization of High Grade Glioma Cell Culture from Surgical Specimens for Use in Clinically Relevant Animal Models and 3D Immunochemistry

PubMed Central

Hasselbach, Laura A.; Irtenkauf, Susan M.; Lemke, Nancy W.; Nelson, Kevin K.; Berezovsky, Artem D.; Carlton, Enoch T.; Transou, Andrea D.; Mikkelsen, Tom; deCarvalho, Ana C.

2014-01-01

Glioblastomas, the most common and aggressive form of astrocytoma, are refractory to therapy, and molecularly heterogeneous. The ability to establish cell cultures that preserve the genomic profile of the parental tumors, for use in patient specific in vitro and in vivo models, has the potential to revolutionize the preclinical development of new treatments for glioblastoma tailored to the molecular characteristics of each tumor. Starting with fresh high grade astrocytoma tumors dissociated into single cells, we use the neurosphere assay as an enrichment method for cells presenting cancer stem cell phenotype, including expression of neural stem cell markers, long term self-renewal in vitro, and the ability to form orthotopic xenograft tumors. This method has been previously proposed, and is now in use by several investigators. Based on our experience of dissociating and culturing 125 glioblastoma specimens, we arrived at the detailed protocol we present here, suitable for routine neurosphere culturing of high grade astrocytomas and large scale expansion of tumorigenic cells for preclinical studies. We report on the efficiency of successful long term cultures using this protocol and suggest affordable alternatives for culturing dissociated glioblastoma cells that fail to grow as neurospheres. We also describe in detail a protocol for preserving the neurospheres 3D architecture for immunohistochemistry. Cell cultures enriched in CSCs, capable of generating orthotopic xenograft models that preserve the molecular signatures and heterogeneity of GBMs, are becoming increasingly popular for the study of the biology of GBMs and for the improved design of preclinical testing of potential therapies. PMID:24429465

Hypoxia-inducible factor-targeting prodrug TOP3 combined with gemcitabine or TS-1 improves pancreatic cancer survival in an orthotopic model.

PubMed

Hoang, Ngoc Thi Hong; Kadonosono, Tetsuya; Kuchimaru, Takahiro; Kizaka-Kondoh, Shinae

2016-08-01

Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers. TAT-ODD-procaspase-3 (TOP3) is a protein prodrug that is specifically processed and activated in hypoxia-inducible factor-active cells in cancers, leading to cell death. Here, we report combination therapies in which TOP3 was combined with gemcitabine or TS-1. As monotherapy, gemcitabine and TS-1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co-treatment with TOP3 successfully overcame this limitation in vitro. Furthermore, combination therapies of TOP3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line SUIT-2. Overall, our study indicates that the combination of TOP3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Side-to-side cavocavostomy with an endovascular stapler: Rescue technique for severe hepatic vein and/or inferior vena cava outflow obstruction after liver transplantation using the piggyback technique.

PubMed

Quintini, Cristiano; Miller, Charles M; Hashimoto, Koji; Philip, Ding; Uso, Teresa Diago; Aucejo, Federico; Kelly, Dympna; Winans, Charles; Eghtesad, Bijan; Vogt, David; Fung, John

2009-01-01

Venous outflow obstruction is a rare but potentially lethal complication after orthotopic liver transplantation (OLT) with the "piggyback" technique. Therapeutic options include angioplasty with or without stent placement, surgical reconstruction of the venous anastomosis, and retransplantation. Surgical options are technically very challenging and the outcomes discouraging. We describe here two cases of venous outflow obstruction in recipients of piggyback liver grafts, one involving both the vena cava and hepatic veins and the other affecting only hepatic vein outflow. Both patients were treated successfully with side-to-side cavo-cavostomy using an endovascular (endo-GIA) stapler. This novel technique is fast and effective in resolving the outflow obstruction. Copyright 2008 AASLD.

Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities.

PubMed

Wang, Xingyu; Gronchi, Fabrizio; Bensimon, Michael; Mercier, Thomas; Decosterd, Laurent Arthur; Wagnières, Georges; Debefve, Elodie; Ris, Hans-Beat; Letovanec, Igor; Peters, Solange; Perentes, Jean Yannis

2015-12-01

Low-dose, Visudyne®-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin®) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities. Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne®, 10 J/cm(2) ) followed by IV administration of Lipoplatin® (5 mg/kg) and the other half received Lipoplatin® without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne®; 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin® administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin® immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin® and VATS pleural biopsies but no photo-induction (controls). Lipoplatin® concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry. Photo-induction selectively increased Lipoplatin® uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin® concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin® was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin® concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 ± 0.7 vs. 1.37 ± 0.7 ng/mg, P  < 0.001). Visudyne®-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin® in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Gene Therapy Using Therapeutic and Diagnostic Recombinant Oncolytic Vaccinia Virus GLV-1h153 for Management of Colorectal Peritoneal Carcinomatosis

PubMed Central

Eveno, Clarisse; Mojica, Kelly; Ady, Justin W.; Thorek, Daniel L.J.; Longo, Valerie; Belin, Laurence J.; Gholami, Sepideh; Johnsen, Clark; Zanzonico, Pat; Chen, Nanhai; Yu, Tony; Szalay, Aladar A.; Fong, Yuman

2015-01-01

Background Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive surgery and chemotherapy, coupled with the inability to reliably track disease progression using established diagnostic methods make this a deadly disease. This paper examines the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) can provide both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC). Methods Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in-vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice, and subsequently administered GLV-1h153 intraperitoneally. Reduction of tumor burden was assessed by mass. Orthotopic tumors were visualized by SPECT/CT after Iodine (131I) administration and by fluorescence optical imaging. Results GLV-1h153 infected and killed CRC cells in a time and concentration dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a significant reduction of tumor burden. Infection of orthotopic xenografts was both therapeutic and facilitated monitoring by 131I-SPECT/CT via expression of hNIS in infected tissue. Conclusions GLV-1h153 effectively kills CRC in-vitro and dramatically reduces tumor burden in-vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in-vivo. These findings indicate that GLV-1h153 has significant potential for use as theragnostic agent in the treatment of CRPC. PMID:25616946

Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery

PubMed Central

Thisgaard, Helge; Halle, Bo; Aaberg-Jessen, Charlotte; Olsen, Birgitte Brinkmann; Therkelsen, Anne Sofie Nautrup; Dam, Johan Hygum; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne Winther

2016-01-01

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [125I]5-Iodo-2'-deoxyuridine (125I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy. PMID:27924163

Highly Effective Auger-Electron Therapy in an Orthotopic Glioblastoma Xenograft Model using Convection-Enhanced Delivery.

PubMed

Thisgaard, Helge; Halle, Bo; Aaberg-Jessen, Charlotte; Olsen, Birgitte Brinkmann; Therkelsen, Anne Sofie Nautrup; Dam, Johan Hygum; Langkjær, Niels; Munthe, Sune; Någren, Kjell; Høilund-Carlsen, Poul Flemming; Kristensen, Bjarne Winther

2016-01-01

Glioblastoma, the most common and malignant primary brain tumor, always recurs after standard treatment. Therefore, promising new therapeutic approaches are needed. Short-range Auger-electron-emitters carry the ability of causing highly damaging radiation effects in cells. The aim of this study was to test the effect of [ 125 I]5-Iodo-2'-deoxyuridine ( 125 I-UdR, a radioactive Auger-electron-emitting thymidine analogue) Auger-therapy on immature glioblastoma spheroid cultures and orthotopic xenografted glioblastoma-bearing rats, the latter by means of convection-enhanced delivery (CED). Moreover, we aimed to determine if the therapeutic effect could be enhanced when combining 125 I-UdR therapy with the currently used first-line chemotherapeutic agent temozolomide. 125 I-UdR significantly decreased glioblastoma cell viability and migration in vitro and the cell viability was further decreased by co-treatment with methotrexate and/or temozolomide. Intratumoral CED of methotrexate and 125 I-UdR with and without concomitant systemic temozolomide chemotherapy significantly reduced the tumor burden in orthotopically xenografted glioblastoma-bearing nude rats. Thus, 100% (8/8) of the animals survived the entire observation period of 180 days when subjected to the combined Auger-chemotherapy while 57% (4/7) survived after the Auger-therapy alone. No animals (0/8) treated with temozolomide alone survived longer than 50 days. Blood samples and post-mortem histology showed no signs of dose-limiting adverse effects. In conclusion, the multidrug approach consisting of CED of methotrexate and 125 I-UdR with concomitant systemic temozolomide was safe and very effective leading to 100% survival in an orthotopic xenograft glioblastoma model. Therefore, this therapeutic strategy may be a promising option for future glioblastoma therapy.

Post-operative infection and prophylactic antibiotic administration after radical cystectomy with orthotopic neobladder urinary diversion.

PubMed

Shigemura, Katsumi; Tanaka, Kazushi; Matsumoto, Minori; Nakano, Yuzo; Shirakawa, Toshiro; Miyata, Masahiro; Yamashita, Masuo; Arakawa, Soichi; Fujisawa, Masato

2012-08-01

The purpose of this study was to investigate the association between prophylactic antibiotic administration (PAA) and post-operative infection in radical cystectomy with orthotopic neobladder urinary diversion carried out for patients with bladder cancer. Fifty-seven consecutive cases were analyzed retrospectively. Post-operative infections were categorized as urinary tract, wound, and remote infections. We used the antibiotics tazobactam/piperacillin (TAZ/PIPC), sulbactam/ampicillin (SBT/ABPC), flomoxef (FMOX), cefazolin (CEZ), cefotiam (CTM), and cefmetazole (CMZ). Twenty-five (43.9%) patients had post-operative infections. Five of these (8.77%) patients had wound infections, 22 (38.6%) patients had urinary tract infections, and 2 (3.51%) had remote infections. Our statistical analysis demonstrated that the patients with TAZ/PIPC used for PAA (5/18: 27.8%) had a significantly lower post-operative infection rate than patients with other antibiotics (24/39: 61.5%) (p = 0.0442). In addition, the patients with a shorter-duration PAA (within 72 h after the operation (48-72 h)) had a significantly lower rate of post-operative infections (12/33: 36.4%) than those with longer-duration PAA (longer than 72-96 h after the operation) (16/24: 66.7%) (p = 0.0239). Taken together, these results suggest that TAZ/PIPC with shorter PAA duration (within 72 h) might lead to a lower rate of post-operative infections. In conclusion, our data showed that PAA with TAZ/PIPC with a shorter duration PAA (within 72 h) might be recommended for radical cystectomy with orthotopic neobladder reconstruction. A prospective study based on our data is desirable to establish or revise guidelines for prophylactic medication for preventing post-operative infection after radical cystectomy with orthotopic neobladder urinary diversion.

Marine Collagen Scaffolds for Nasal Cartilage Repair: Prevention of Nasal Septal Perforations in a New Orthotopic Rat Model Using Tissue Engineering Techniques

PubMed Central

Bermueller, Christian; Elsaesser, Alexander F.; Sewing, Judith; Baur, Nina; von Bomhard, Achim; Scheithauer, Marc; Notbohm, Holger; Rotter, Nicole

2013-01-01

Autologous grafts are frequently needed for nasal septum reconstruction. Because they are only available in limited amounts, there is a need for new cartilage replacement strategies. Tissue engineering based on the use of autologous chondrocytes and resorbable matrices might be a suitable option. So far, an optimal material for nasal septum reconstruction has not been identified. The aim of our study was to provide the first evaluation of marine collagen for use in nasal cartilage repair. First, we studied the suitability of marine collagen as a cartilage replacement matrix in the context of in vitro three dimensional cultures by analyzing cell migration, cytotoxicity, and extracellular matrix formation using human and rat nasal septal chondrocytes. Second, we worked toward developing a suitable orthotopic animal model for nasal septum repair, while simultaneously evaluating the biocompatibility of marine collagen. Seeded and unseeded scaffolds were transplanted into nasal septum defects in an orthotopic rat model for 1, 4, and 12 weeks. Explanted scaffolds were histologically and immunohistochemically evaluated. Scaffolds did not induce any cytotoxic reactions in vitro. Chondrocytes were able to adhere to marine collagen and produce cartilaginous matrix proteins, such as collagen type II. Treating septal cartilage defects in vivo with seeded and unseeded scaffolds led to a significant reduction in the number of nasal septum perforations compared to no replacement. In summary, we demonstrated that marine collagen matrices provide excellent properties for cartilage tissue engineering. Marine collagen scaffolds are able to prevent septal perforations in an autologous, orthotopic rat model. This newly described experimental surgical procedure is a suitable way to evaluate new scaffold materials for their applicability in the context of nasal cartilage repair. PMID:23621795

Using Dual Fluorescence Reporting Genes to Establish an In Vivo Imaging Model of Orthotopic Lung Adenocarcinoma in Mice.

PubMed

Lai, Cheng-Wei; Chen, Hsiao-Ling; Yen, Chih-Ching; Wang, Jiun-Long; Yang, Shang-Hsun; Chen, Chuan-Mu

2016-12-01

Lung adenocarcinoma is characterized by a poor prognosis and high mortality worldwide. In this study, we purposed to use the live imaging techniques and a reporter gene that generates highly penetrative near-infrared (NIR) fluorescence to establish a preclinical animal model that allows in vivo monitoring of lung cancer development and provides a non-invasive tool for the research on lung cancer pathogenesis and therapeutic efficacy. A human lung adenocarcinoma cell line (A549), which stably expressed the dual fluorescence reporting gene (pCAG-iRFP-2A-Venus), was used to generate subcutaneous or orthotopic lung cancer in nude mice. Cancer development was evaluated by live imaging via the NIR fluorescent signals from iRFP, and the signals were verified ex vivo by the green fluorescence of Venus from the gross lung. The tumor-bearing mice received miR-16 nucleic acid therapy by intranasal administration to demonstrate therapeutic efficacy in this live imaging system. For the subcutaneous xenografts, the detection of iRFP fluorescent signals revealed delicate changes occurring during tumor growth that are not distinguishable by conventional methods of tumor measurement. For the orthotopic xenografts, the positive correlation between the in vivo iRFP signal from mice chests and the ex vivo green fluorescent signal from gross lung tumors and the results of the suppressed tumorigenesis by miR-16 treatment indicated that lung tumor size can be accurately quantified by the emission of NIR fluorescence. In addition, orthotopic lung tumor localization can be accurately visualized using iRFP fluorescence tomography in vivo, thus revealing the trafficking of lung tumor cells. We introduced a novel dual fluorescence lung cancer model that provides a non-invasive option for preclinical research via the use of NIR fluorescence in live imaging of lung.

Porphyrin lipid nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model

NASA Astrophysics Data System (ADS)

MacLaughlin, Christina M.; Ding, Lili; Jin, Cheng; Cao, Pingjiang; Siddiqui, Iram; Hwang, David M.; Chen, Juan; Wilson, Brian C.; Zheng, Gang; Hedley, David W.

2016-03-01

Local disease control is a major problem in the treatment of pancreatic cancer, because curative-intent surgery is only possible in a minority of patients, and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for ablation of pancreatic tumors, this approach remains under investigated. Using photothermal sensitizers in combination with laser light for PTT can result in more efficient conversion of light energy to heat, and confinement of thermal destruction to the tumor, thus sparing adjacent organs and vasculature. Porphyrins have been previously employed as photosensitizers for PDT and PTT, however their incorporation in to "porphysomes", lipid-based nanoparticles each containing ~80,000 porphyrins through conjugation of pyropheophorbide to phospholipids, carries two distinct advantages: 1) high-density porphyrin packing imparts the nanoparticles with enhanced photonic properties for imaging and phototherapy; 2) the enhanced permeability and retention effect may be exploited for optimal delivery of porphysomes to the tumor region thus high payload porphyrin delivery. The feasibility of porphysome-enhanced PTT for pancreatic cancer treatment was investigated using a patient-derived orthotopic pancreas xenograft tumor model. Uptake of porphysomes at the orthotopic tumor site was validated using ex vivo fluorescence imaging of intact organs of interest. The accumulation of porphysomes in orthotopic tumor microstructure was also confirmed by fluorescence imaging of excised tissue slices. PTT progress was monitored as changes in tumor surface temperature using IR optical imaging. Histological analyses were conducted to examine microstructure changes in tissue morphology, and the viability of remaining tumor tissues following exposure to heat. These studies may also provide insight as to the contribution of heat sink in application of thermal therapies to highly vascularized pancreatic tumors.

Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model.

PubMed

Dai, Bailing; Qi, Na; Li, Junchao; Zhang, Guilong

2018-07-02

Temozolomide (TMZ) is the most frequent adjuvant chemotherapy drug in gliomas. PDL1 expresses on various tumors, including gliomas, and anti-PD-1 antibodies have been approved for treating some tumors by FDA. This study was to evaluate the therapeutical potential of combined TMZ with anti-PD-1 antibody therapy for mouse orthotopic glioma model. We performed C57BL/6 mouse orthotopic glioma model by stereotactic intracranial implantation of glioma cell line GL261, mice were randomly divided into four groups: (1) control group; (2) TMZ group; (3) anti-PD-1 antibody group; (4) TMZ combined with anti-PD-1 antibody group. Then the volume or size of tumor was assessed by 7.0 T MRI and immunohistochemistry, and the number of CD4 and CD8 infiltrating cells in brain tumor and spleen was evaluated by immunohistochemistry. Western blot was used to evaluate the expression of PDL1. Furthermore, Overall survival of each group mice was also evaluated. Overall survival was significantly improved in combined group compared to other groups (χ2 = 32.043, p < 0.01). The volume or size of tumor was significantly decreased in combined group compared with other groups (F = 42.771, P < 0.01). And the number of CD4 and CD8 infiltrating cells in brain tumor was also obviously increased in combined group (CD4 F = 45.67, P < 0.01; CD8 F = 53.75, P < 0.01). Anti-PD1 antibody combined with TMZ therapy for orthotopic mouse glioma model could significantly improve the survival time of tumor-bear mice. Thus, this study provides the effective preclinical evidence for support clinical chemotherapy combined with immunotherapy for glioma patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system

PubMed Central

Parrish, Karen E.; Cen, Ling; Murray, James; Calligaris, David; Kizilbash, Sani; Mittapalli, Rajendar K.; Carlson, Brett L.; Schroeder, Mark A.; Sludden, Julieann; Boddy, Alan V.; Agar, Nathalie Y.R.; Curtin, Nicola J.; Elmquist, William F.; Sarkaria, Jann N.

2015-01-01

Poly (ADP-ribose) polymerase (PARP) inhibition can enhance the efficacy of temozolomide (TMZ) and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with TMZ and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with TMZ was highly effective in vitro in short-term explant cultures derived from GBM12, and similarly, the combination of rucaparib and TMZ (dosed for 5 days every 28 days × 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of TMZ in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b−/−Bcrp1−/− knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared to normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with TMZ in GBM. PMID:26438157

The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma.

PubMed

Pokorny, Jenny L; Calligaris, David; Gupta, Shiv K; Iyekegbe, Dennis O; Mueller, Dustin; Bakken, Katrina K; Carlson, Brett L; Schroeder, Mark A; Evans, Debra L; Lou, Zhenkun; Decker, Paul A; Eckel-Passow, Jeanette E; Pucci, Vincenzo; Ma, Bennett; Shumway, Stuart D; Elmquist, William F; Agar, Nathalie Y R; Sarkaria, Jann N

2015-04-15

Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide. In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging. GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors. Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. ©2015 American Association for Cancer Research.

Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.

PubMed

Parrish, Karen E; Cen, Ling; Murray, James; Calligaris, David; Kizilbash, Sani; Mittapalli, Rajendar K; Carlson, Brett L; Schroeder, Mark A; Sludden, Julieann; Boddy, Alan V; Agar, Nathalie Y R; Curtin, Nicola J; Elmquist, William F; Sarkaria, Jann N

2015-12-01

PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM. ©2015 American Association for Cancer Research.

The efficacy of the Wee1 inhibitor MK-1775 combined with temozolomide is limited by heterogeneous distribution across the blood-brain barrier in glioblastoma

PubMed Central

Pokorny, Jenny L.; Calligaris, David; Gupta, Shiv K.; Iyekegbe, Dennis O.; Mueller, Dustin; Bakken, Katrina K.; Carlson, Brett L.; Schroeder, Mark A.; Evans, Debra L.; Lou, Zhenkun; Decker, Paul A.; Eckel-Passow, Jeanette E.; Pucci, Vincenzo; Ma, Bennett; Shumway, Stuart D.; Elmquist, William; Agar, Nathalie Y.; Sarkaria, Jann N.

2015-01-01

Purpose Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in GBM xenograft models alone and in combination with radiation and/or temozolomide (TMZ). Experimental design In vitro MK-1775 efficacy alone and in combination with TMZ, and the impact on DNA damage was analyzed by western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI) -MS imaging. Results GBM22 (IC50 = 68 nM) was significantly more sensitive to MK-1775 compared to 5 other GBM xenograft lines including GBM6 (IC50 >300 nM), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with TMZ in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with TMZ, while in a flank model of GBM22, MK-1775 exhibited both single agent and combinatorial activity with TMZ. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared to heterotopic GBM22 tumors. Conclusions Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. PMID:25609063

Liver Stiffness Measurements Using Acoustic Radiation Force Impulse in Recipients of Living-Donor and Deceased-Donor Orthotopic Liver Transplant.

PubMed

Haberal, Kemal Murat; Turnaoğlu, Hale; Özdemir, Adnan; Uslu, Nihal; Haberal Reyhan, Asuman Nihan; Moray, Gökhan; Haberal, Mehmet

2017-08-24

The aim of this study was to evaluate the diagnostic efficiency of the acoustic radiation force impulse (Siemens Medical Solutions, Erlangen, Germany) elastography in assessment of fibrosis in orthotopic liver transplant patients. We enrolled 28 orthotopic liver transplant patients (deceased and living donors), whose biopsy decision had been prospectively given clinically. Ten acoustic radiation force impulse elastographic measurements were applied before the biopsy or within 3 days after the biopsy by 2 radiologists. After the core tissue needle biopsy, specimens of all patients were analyzed according to the modified Ishak scoring system. Measurements of acoustic radiation force impulse elastography and pathology specimen results were compared. From 28 biopsies, fibrosis scores of 4 biopsies were evaluated as F0 (14.3%), 16 as F1 (57.1%), 4 as F2 (14.3%), and 4 as F3 (14.3%). Mean results of acoustic radiation force impulse measurements were calculated as 1.4 ± 0.07 in F0, 1.74 ± 0.57 in F1, 2.19 ± 0.7 in F2, and 2.18 ± 0.35 in F3. There were no significant correlations of mean acoustic radiation force impulse values between the F0 versus F1 (P = .956) and F0 versus F2 stages (P = .234). A statistically significant correlation of mean acoustic radiation force impulse values was found between the F0 and F3 fibrosis stages (P = .046). Acoustic radiation force impulse imaging is a promising screening test for detecting significant liver fibrosis (≥ F3 in modified Ishak) in living-donor or deceased-donor orthotopic liver transplant recipients.

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity

PubMed Central

Garcia, Emmanuel; Becker, Veronika G. C.; McCullough, Danielle J.; Stabley, John N.; Gittemeier, Elizabeth M.; Opoku-Acheampong, Alexander B.; Sieman, Dietmar W.

2016-01-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10−9 to 10−4 M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. PMID:27125846

Micro-positron emission tomography/contrast-enhanced computed tomography imaging of orthotopic pancreatic tumor-bearing mice using the αvβ₃ integrin tracer ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄.

PubMed

Aung, Winn; Jin, Zhao-Hui; Furukawa, Takako; Claron, Michael; Boturyn, Didier; Sogawa, Chizuru; Tsuji, Atsushi B; Wakizaka, Hidekatsu; Fukumura, Toshimitsu; Fujibayashi, Yasuhisa; Dumy, Pascal; Saga, Tsuneo

2013-09-01

The purpose of this study was to develop a clinically relevant orthotopic xenotransplantation model of pancreatic cancer and to perform a preclinical evaluation of a new positron emission tomography (PET) imaging probe, ⁶⁴Cu-labeled cyclam-RAFT-c(-RGDfK-)₄ peptide (⁶⁴Cu-RAFT-RGD), using this model. Varying degrees of αvβ₃ integrin expression in several human pancreatic cancer cell lines were examined by flow cytometry and Western blotting. The cell line BxPC-3, which is stably transfected with a red fluorescence protein (RFP), was used for surgical orthotopic implantation. Orthotopic xenograft was established in the pancreas of recipient nude mice. An in vivo probe biodistribution and receptor blocking study, preclinical PET imaging coregistered with contrast-enhanced computed tomography (CECT) comparing ⁶⁴Cu-RAFT-RGD and ¹⁸F-fluoro-2-deoxy-d-glucose (¹⁸F-FDG) accumulation in tumor, postimaging autoradiography, and histologic and immunohistochemical examinations were done. Biodistribution evaluation with a blocking study confirmed that efficient binding of probe to tumor is highly αvβ₃ integrin specific. ⁶⁴Cu-RAFT-RGD PET combined with CECT provided for precise and easy detection of cancer lesions. Autoradiography, histologic, and immunohistochemical examinations confirmed the accumulation of ⁶⁴Cu-RAFT-RGD in tumor versus nontumor tissues. In comparative PET studies, ⁶⁴Cu-RAFT-RGD accumulation provided better tumor contrast to background than ¹⁸F-FDG. Our results suggest that ⁶⁴Cu-RAFT-RGD PET imaging is potentially applicable for the diagnosis of αvβ₃ integrin-expressing pancreatic tumors.

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

PubMed

Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

2016-07-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

Impact on postoperative bleeding and cost of recombinant activated factor VII in patients undergoing heart transplantation.

PubMed

Hollis, Allison L; Lowery, Ashleigh V; Pajoumand, Mehrnaz; Pham, Si M; Slejko, Julia F; Tanaka, Kenichi A; Mazzeffi, Michael

2016-01-01

Cardiac transplantation can be complicated by refractory hemorrhage particularly in cases where explantation of a ventricular assist device is necessary. Recombinant activated factor VII (rFVIIa) has been used to treat refractory bleeding in cardiac surgery patients, but little information is available on its efficacy or cost in heart transplant patients. Patients who had orthotopic heart transplantation between January 2009 and December 2014 at a single center were reviewed. Postoperative bleeding and the total costs of hemostatic therapies were compared between patients who received rFVIIa and those who did not. Propensity scores were created and used to control for the likelihood of receiving rFVIIa in order to reduce bias in our risk estimates. Seventy-six patients underwent heart transplantation during the study period. Twenty-one patients (27.6%) received rFVIIa for refractory intraoperative bleeding. There was no difference in postoperative red blood cell transfusion, chest tube output, or surgical re-exploration between patients who received rFVIIa and those who did not, even after adjusting with the propensity score (P = 0.94, P = 0.60, and P = 0.10, respectively). The total cost for hemostatic therapies was significantly higher in the rFVIIa group (median $10,819 vs. $1,985; P < 0.0001). Subgroup analysis of patients who underwent redo-sternotomy with left ventricular assist device explantation did not show any benefit for rFVIIa either. In this relatively small cohort, rFVIIa use was not associated with decreased postoperative bleeding in patients undergoing heart transplantation; however, it led to significantly higher cost.

Thyroid storm complicated by fulminant hepatic failure: case report and literature review.

PubMed

Hambleton, Catherine; Buell, Joseph; Saggi, Bob; Balart, Luis; Shores, Nathan J; Kandil, Emad

2013-11-01

Thyroid storm is a presentation of severe thyrotoxicosis that has a mortality rate of up to 20% to 30%. Fulminant hepatic failure (FHF) entails encephalopathy with severe coagulopathy in the setting of liver disease. It carries a high mortality rate, with an approximately 60% rate of overall survival for patients who undergo orthotopic liver transplantation (OLT). Fulminant hepatic failure is a rare but serious complication of thyroid storm. There have been only 6 previously reported cases of FHF with thyroid storm. We present a patient from our institution with thyroid storm and FHF. A literature review was performed to analyze the outcomes of the 6 additional cases of concomitant thyroid storm and FHF. Our patient underwent thyroidectomy followed by OLT. Her serum levels of thyroid-stimulating hormone, triiodothyronine, thyroxine, and transaminase normalized, and she was ready for discharge within 10 days of surgery. She has survived without complication. There is a 40% mortality rate for the reported patients treated medically with these conditions. Of the 7 total cases of reported FHF and thyroid storm, 2 patients died. Only 2 of the 7 patients underwent thyroidectomy and OLT--both at our institution. Both patients survived without complications. Thyroid storm and FHF each independently carry high mortality rates, and managing patients with both conditions simultaneously is an extraordinary challenge. These cases should compel clinicians to investigate liver function in hyperthyroid patients and to be wary of its rapid decline in patients who present in thyroid storm with symptoms of liver dysfunction. Patients with rapidly progressing thyroid storm and FHF should be considered for total thyroidectomy and OLT.

Diagnostic Value of Anti-Hepatitis C Virus (HCV) Core Immunoglobulin M in Recurrence of HCV Infection after Orthotopic Liver Transplantation†

PubMed Central

Casino, Carmela; Lilli, Daniela; Rivanera, Daniela; Comanducci, Antonella; Rossi, Massimo; Casciaro, Giovanni; Pecorella, Irene; Alfani, Dario; Mancini, Carlo

1999-01-01

The significance of anti-hepatitis C virus (HCV) core immunoglobulin M (IgM) and its relationship with genotypes, alanine aminotransferase abnormality, and histological data were studied for 18 patients who had undergone orthotopic liver transplantation due to HCV-related end-stage disease. During follow-up, IgM response seemed to be associated with the recurrence of HCV infection but did not correlate with abnormal alanine aminotransferase levels and histological data. In addition, the results of this study indicated that the detection of HCV RNA is critical for diagnosis of reinfection in liver transplantation. PMID:10405433

Is Health-Related Quality of Life after Radical Cystectomy Using Validated Questionnaires Really Better in Patients with Ileal Orthotopic Neobladder Compared to Ileal Conduit: A Meta-Analysis of Retrospective Comparative Studies

PubMed Central

Cerruto, Maria A.; D'Elia, Carolina; Siracusano, Salvatore; Porcaro, Antonio B.; Cacciamani, Giovanni; De Marchi, Davide; Niero, Mauro; Lonardi, Cristina; Iafrate, Massimo; Bassi, Pierfrancesco; Belgrano, Emanuele; Imbimbo, Ciro; Racioppi, Marco; Talamini, Renato; Ciciliato, Stefano; Toffoli, Laura; Rizzo, Michele; Visalli, Francesco; Verze, Paolo; Artibani, Walter

2017-01-01

Introduction From the most recent systematic revision of the literature, an orthotopic neobladder would seem to show marginally better health related quality of life (HR-QoL) scores compared with an ileal conduit. The aim of this study was to review all relevant published studies about the comparison between ileal orthotopic neobladder (IONB) and ileal conduit using validated HR-QoL questionnaires. Materials and Methods Studies were identified by searching multiple literature databases. Data were synthesized using meta-analytic methods conformed to the PRISMA statement. Results The literature search identified 10 papers; pooled effect sizes of combined quality of life outcomes for ileal conduit versus IONB showed a significantly better HR-QoL in patients with IONB (Hedges' g = 0.278; p = 0.000);. The present study has an important limitation due to the type of the analyzed comparative studies, all retrospective and not randomized. Conclusion This meta-analysis of not-randomized, retrospective comparative studies on the impact of ileal conduit versus IONB on HR-QoL showed a significant advantage of IONB subgroups. PMID:28785189

Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer.

PubMed

Kochall, Susan; Thepkaysone, May-Linn; García, Sebastián A; Betzler, Alexander M; Weitz, Jürgen; Reissfelder, Christoph; Schölch, Sebastian

2017-07-18

Despite the advantages of easy applicability and cost-effectiveness, subcutaneous mouse models have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Orthotopic mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in hollow organs such as the large bowel. In order to produce uniform tumors which reliably grow and metastasize, standardized techniques of tumor cell preparation and injection are critical. We have developed an orthotopic mouse model of colorectal cancer (CRC) which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor cells from either primary tumors, 2-dimensional (2D) cell lines or 3-dimensional (3D) organoids are injected into the cecum and, depending on the metastatic potential of the injected tumor cells, form highly metastatic tumors. In addition, CTCs can be found regularly. We here describe the technique of tumor cell preparation from both 2D cell lines and 3D organoids as well as primary tumor tissue, the surgical and injection techniques as well as the isolation of CTCs from the tumor-bearing mice, and present tips for troubleshooting.

Orthotopic lung cancer murine model by nonoperative transbronchial approach.

PubMed

Nakajima, Takahiro; Anayama, Takashi; Matsuda, Yasushi; Hwang, David M; McVeigh, Patrick Z; Wilson, Brian C; Zheng, Gang; Keshavjee, Shaf; Yasufuku, Kazuhiro

2014-05-01

The aim of this work was to establish a novel orthotopic human non-small cell lung cancer (NSCLC) murine xenograft model by a nonsurgical, transbronchial approach. Male athymic nude mice and human NSCLC cell lines, including A549, H460, and H520 were used. Under direct visualization of the vocal cords, a 23-gauge blunt-tip slightly curved metal catheter was introduced into the trachea to the bronchus, and 2.5×10(5) tumor cells mixed with Matrigel (BD Biosciences, Mississauga, Ontario, Canada) were administered into the lung. Mice were monitored using weekly microcomputed tomography scans for tumor formation. When the tumor size reached more than 4 mm in diameter, the animals were euthanized, and the tumor tissue was evaluated histopathologically. Of 37 mice studied, 34 were confirmed to have tumor formation: 29 developed solitary tumors and 5 had multifocal lesions. There was no evidence of extrapleural dissemination or effusion. Transbronchial delivery of tumor cells enabled the establishment of a novel orthotopic human NSCLC murine xenograft model. This clinically relevant preclinical model bearing a solitary nodule is of value for a variety of in vivo research studies. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

[To the issue of postreperfusion syndrome predictors in orthotopic liver transplantation (OLT)].

PubMed

Kiseleva, E A; Ushakova, I A; Kim, E F; Matveev, G P; Biriulina, N Iu; Vabishchevich, A V

2012-01-01

The aim of the study is revelation of postperfusion syndrome (pPS) predictors in orthotopic liver transplantation (OLT). Was conducted a retrospective analysis of anesthesia maintainance protocols during orthotopic liver transplantation in 261 patients aged from 6 months to 60 years. Investigated the effect of various factors on the development of PPS by the application of methods of non-parametric statistics. Significantly more frequent development of the PPS is noted in the age group from 3 to 18 years (up to 30% of patients). In recipients older than 18 years the frequency of the development of the PPS does not depend on age, with an average of 14%. The development of the PPS does not depend on the recipient sex, the nature of the pathology which served as an indication to the OTP, the initial severity of the state, type of OTP (living related donor or cadaveric transplantation, primary or re-transplantation), the transplant warm ischemia duration, use, or the lack of venous-venous bypass, metabolic status of the patient. The obtained results do not contradict to the data of foreign publications. Among parameters available for screening, predictor of PPS was not detected.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer.

PubMed

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-06-07

To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI ( P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites ( P = 0.009), liver metastasis ( P = 0.035), and decreased survival time ( P = 0.022). N-syndecan expression was significantly associated with tumor size ( P = 0.025), but not with survival time ( P = 0.539). High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

Predictors of successful external cephalic version and assessment of success for vaginal delivery.

PubMed

Salzer, Liat; Nagar, Ran; Melamed, Nir; Wiznitzer, Arnon; Peled, Yoav; Yogev, Yariv

2015-01-01

To identify predictors of successful external cephalic version (ECV) and to compare delivery outcome between women who had a successful ECV and women with spontaneous vertex presentation. A retrospective cohort study of all women who underwent ECV in a single tertiary medical center between 2007 and 2011. Delivery outcome was compared between women who underwent a trial of vaginal delivery following successful ECV with that of a control group in a 2:1 ratio. Multivariate analysis was used to identify predictors of successful ECV. Overall 287 were eligible for the study group. Of these 130 (45.3%) had a successful ECV. Polyhydramnios was the strongest factor associated with successful ECV (OR=3.1, 95%-CI 1.4-7.2), followed by transverse lie (versus breech presentation, OR=2.6, 95%-CI 1.2-6.7) and a posterior placenta (OR=1.7, 95%-CI 1.1-3.9), while nulliparity was associated with a lower likelihood of successful ECV (OR=0.4, 95%-CI 0.2-0.6). Women who had a successful ECV and underwent a trial of labor were more likely to deliver by operative vaginal delivery (OVD) (OR=1.8, 95%-CI 1.2-3.6), mainly due to a higher rate of prolonged 2nd, but were not at an increased risk for CS (OR=0.9, 95%-CI 0.4-2.4). Counselling to women prior to ECV should address the likelihood of success based on the predicting factors described above, as well as the increased risk for OVD in the case of successful ECV.

Radiofrequency catheter ablation in patients with symptomatic atrial flutter/tachycardia after orthotopic heart transplantation.

PubMed

Li, Yi-gang; Grönefeld, Gerian; Israel, Carsten; Lu, Shang-biao; Wang, Qun-shan; Hohnloser, Stefan H

2006-12-20

Atrial tachycardia or flutter is common in patients after orthotopic heart transplantation. Radiofrequency catheter ablation to treat this arrhythmia has not been well defined in this setting. This study was conducted to assess the incidence of various symptomatic atrial arrhythmias and the efficacy and safety of radiofrequency catheter ablation in these patients. Electrophysiological study and catheter ablation were performed in patients with symptomatic tachyarrhythmia. One Halo catheter with 20 poles was positioned around the tricuspid annulus of the donor right atrium, or positioned around the surgical anastomosis when it is necessary. Three quadripolar electrode catheters were inserted via the right or left femoral vein and positioned in the recipient atrium, the bundle of His position, the coronary sinus. Programmed atrial stimulation and burst pacing were performed to prove electrical conduction between the recipient and the donor atria and to induce atrial arrhythmias. Out of 55 consecutive heart transplantation patients, 6 males [(58 +/- 12) years] developed symptomatic tachycardias at a mean of (5 +/- 4) years after heart transplantation. Electrical propagation through the suture line between the recipient and the donor atrium was demonstrated during atrial flutter or during recipient atrium and donor atrium pacing in 2 patients. By mapping around the suture line, the earliest fragmented electrogram of donor atrium was assessed. This electrical connection was successfully ablated in the anterior lateral atrium in both patients. There was no electrical propagation through the suture line in the other 4 patients. Two had typical atrial flutter in the donor atrium which was successfully ablated by completing a linear ablation between the tricuspid annulus and the inferior vena cava. Two patients had atrial tachycardia which was ablated in the anterior septal and lateral donor atrium. There were no procedure-related complications. Patients were free of recurrent atrial tachyarrhythmias after a follow-up of (8 +/- 7) months. Four electrophysiological mechanisms have been found to contribute to the occurrence of symptomatic supraventricular arrhythmias following heart transplantation. Radiofrequency catheter ablation in patients with atrial flutter/tachycardia is feasible and safe after heart transplantation.

Pre-transplant depression as a predictor of adherence and morbidities after orthotopic heart transplantation.

PubMed

Delibasic, Maja; Mohamedali, Burhan; Dobrilovic, Nikola; Raman, Jaishankar

2017-07-25

Psychosocial factors are useful predictors of adverse outcomes after solid organ transplantation. Although depression is a known predictor of poor outcomes in patients who undergo orthotopic heart transplantation (OHT) and is actively screened for during pre-transplant evaluation, the effects of early identification of this entity on post-transplant outcomes are not clearly understood. The purpose of this study was to evaluate the impact of pre-transplant depression on outcomes after OHT. In this retrospective study, 51 patients that underwent psychosocial evaluation performed by a social worker prior to the transplant and followed up in our center post-transplant were enrolled. Patients were stratified by the presence/absence of depression during the initial encounter. Primary end-points were overall survival, 1st-year hospitalizations, overall hospitalizations, rejections, and compliance with medications and outpatient appointments. Depressed patients were 3.5 times more likely to be non-compliant with medications; RR = 3.5, 95% CI (1.2,10.2), p = 0.046 and had higher incidence of first year hospitalizations (4.7 ± 3.1 vs. 2.2 ± 1.9, p = 0.046), shorter time to first hospitalization 25 days (IQR 17-39) vs. 100 days (IQR 37-229), p = 0.001. Patients with depression also had higher overall hospitalizations (8.3 ± 4.4 vs. 4.6 ± 4.2, p = 0.025,) and higher number of admissions for infections (2.8 ± 1.3 vs. 1.5 ± 1.4, p = 0.018) compared to patients without depression. There were no statistically significant differences in total number of rejections or compliance with outpatient appointments. Kaplan-Meier survival analysis did not reveal differences between the two groups (mean 3705 vs. 3764 days, log-rank p = 0.52). Depression was a strong predictor of poor medication compliance and higher rates of hospitalization in transplant recipients. No difference in survival between depressed and non-depressed patients after OHT was noted.

Implantability, Complications, and Follow-Up After Transjugular Intrahepatic Portosystemic Stent-Shunt Creation With the 6F Self-Expanding Sinus-SuperFlex-Visual Stent.

PubMed

Spira, Daniel; Wiskirchen, Jakub; Lauer, Ulrich; Ketelsen, Dominik; Nikolaou, Konstantin; Wiesinger, Benjamin

2016-07-01

The transjugular intrahepatic portosystemic stent-shunt (TIPSS) builds a shortcut between the portal vein and a liver vein, and represents a sophisticated alternative to open surgery in the management of portal hypertension or its complications. To describe clinical experiences with a low-profile nitinol stent system in TIPSS creation, and to assess primary and long-term success. Twenty-six patients (5 females, 21 males; mean age 54.6 years) were treated using a low-profile 6F self-expanding sinus-SuperFlex-Visual stent system. The indication for TIPSS creation was refractory bleeding in 9 of the 26 patients, refractory ascites in 18 patients, and acute thrombosis of the portal vein confluence in one patient. Portosystemic pressure gradients before and after TIPSS, periprocedural and long-term complications, and the time to orthotopic liver transplantation (OLT) or death were recorded. The portosystemic pressure gradient was significantly reduced, from 20.9 ± 6.3 mmHg before to 8.2 ± 2.3 mmHg after TIPSS creation (P < 0.001). Procedure-related complications included acute tract occlusion (n = 2), liver hematoma (n = 1), hepatic encephalopathy (n = 1), and cardiac failure (n = 1). Three of the 26 patients had late-onset TIPSS occlusion (at 12, 12, and 39 months after TIPSS creation). Three patients died within one week after the procedure due to their poor general condition (multiorgan failure, acute respiratory distress syndrome, necrotizing pancreatitis, and aspiration pneumonia). Another four patients succumbed to their underlying advanced liver disease within one year after TIPSS insertion. Seven patients underwent OLT at a mean time of 9.4 months after TIPSS creation. The sinus-SuperFlex-Visual stent system can be safely deployed as a TIPSS device. The pressure gradient reduction was clinically sufficient to treat the patients' symptoms, and periprocedural complications were due to the TIPSS procedure per se rather than to the particular stent system employed in this study.

Direct visual internal urethrotomy for isolated, post-urethroplasty strictures: a retrospective analysis.

PubMed

Brown, Elizabeth Timbrook; Mock, Stephen; Dmochowski, Roger; Reynolds, W Stuart; Milam, Douglas; Kaufman, Melissa R

2017-02-01

Urethroplasty is often successful for the treatment of male urethral stricture disease, but limited data exists on recurrence management. Our goal was to evaluate direct visual internal urethrotomy (DVIU) as a treatment option for isolated, recurrent strictures after urethroplasty. We retrospectively identified male patients who underwent urethroplasty from 1999 to 2013 and developed an isolated, recurrent stricture at the urethroplasty site treated with DVIU. Success was defined as lack of symptomatology and no subsequent intervention. Comparative analysis identified characteristics and stricture properties associated with success. A total of 436 urethroplasties were performed in 401 patients at our institution between 1999 and 2013. Stricture recurrence was noted in 64 (16%) patients. Of these, 47 (73%) underwent a DVIU. A total of 37 patients met inclusion criteria and underwent 50 DVIU procedures at the urethroplasty site. A single DVIU was successful in 13 of 37 patients (35%). A total of 4 of 6 patients required a second DVIU (67%). Overall, 17 of 43 (40%) of the total DVIUs were successful after urethroplasty. Success did not differ by age, stricture length or location, surgical technique, radiation history, prior urethroplasty or DVIU, time to failure, or etiology. Post-urethroplasty DVIU for isolated, recurrent strictures may be offered as a minimally invasive treatment option. Approximately 40% of patients were spared further intervention.

Effect of rebamipide ophthalmic suspension on the success of lacrimal stent intubation.

PubMed

Mimura, Masashi; Ueki, Mari; Oku, Hidehiro; Sato, Bunpei; Ikeda, Tsunehiko

2016-02-01

To evaluate the effect of the postoperative administration of rebamipide ophthalmic suspension on the success rate of lacrimal stent intubation (LSI) for the treatment of primary acquired nasolacrimal duct obstruction (PANDO). This comparative interventional cohort study investigated 110 consecutive patients with PANDO who were treated with LSI and followed up for 12 months postoperatively at one institution. LSI was performed by one surgeon, and all patients received identical postoperative care. Among the total 110 patients, 71 underwent LSI with postoperative administration of rebamipide ophthalmic suspension, and 39 underwent LSI without administration of the suspension. Data related to patient age, gender, laterality, and postoperative administration of rebamipide ophthalmic suspension were collected and used as independent variables, and logistic regression analyses were performed to compare the anatomical success rate at 12 months postoperatively between patients with and without postoperative administration of the suspension. The anatomical success rate of LSI in patients with and without postoperative administration of rebamipide ophthalmic suspension was 90.1 and 69.2 %, respectively. A comparison of these success rates showed statistical significance, in that the rate of treatment success was higher in PANDO patients who underwent LSI with postoperative administration of the suspension [odds ratio (OR), 3.37; P < 0.05]. The findings of this study show that postoperative administration of rebamipide ophthalmic suspension increases the rate of anatomical success in patients who undergo LSI for the treatment of PANDO.

Cyclodextrin and Polyethylenimine Functionalized Mesoporous Silica Nanoparticles for Delivery of siRNA Cancer Therapeutics

PubMed Central

Shen, Jianliang; Kim, Han-Cheon; Su, Hua; Wang, Feng; Wolfram, Joy; Kirui, Dickson; Mai, Junhua; Mu, Chaofeng; Ji, Liang-Nian; Mao, Zong-Wan; Shen, Haifa

2014-01-01

Effective delivery holds the key to successful in vivo application of therapeutic small interfering RNA (siRNA). In this work, we have developed a universal siRNA carrier consisting of a mesoporous silica nanoparticle (MSNP) functionalized with cyclodextrin-grafted polyethylenimine (CP). CP provides positive charge for loading of siRNA through electrostatic interaction and enables effective endosomal escape of siRNA. Using intravital microscopy we were able to monitor tumor enrichment of CP-MSNP/siRNA particles in live mice bearing orthotopic MDA-MB-231 xenograft tumors. CP-MSNP delivery of siRNA targeting the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) resulted in effective knockdown of gene expression in vitro and in vivo. Suppression of PKM2 led to inhibition of tumor cell growth, invasion, and migration. PMID:24672582

The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.

PubMed

Murakami, Takashi; Kiyuna, Tasuku; Kawaguchi, Kei; Igarashi, Kentaro; Singh, Arun S; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Miyake, Kentaro; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; DeLong, Jonathan C; Lwin, Thinzar M; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2017-06-03

William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P < 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.

The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago

PubMed Central

Murakami, Takashi; Kiyuna, Tasuku; Kawaguchi, Kei; Igarashi, Kentaro; Singh, Arun S.; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Nelson, Scott D.; Dry, Sarah M.; Li, Yunfeng; DeLong, Jonathan C.; Lwin, Thinzar M.; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Hoffman, Robert M.

2017-01-01

ABSTRACT William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P < 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley. PMID:28296559

Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.

PubMed

Solorzano, C C; Baker, C H; Tsan, R; Traxler, P; Cohen, P; Buchdunger, E; Killion, J J; Fidler, I J

2001-08-01

We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.

[Orthotopic liver transplantation in adult patients with cadaveric grafts. Experience of the Fundeni Center of General Surgery and Liver Transplantation].

PubMed

Popescu, I; Ionescu, M; Tulbure, D; Ciurea, S; Băilă, S; Braşoveanu, V; Hrehoreţ, D; Sârbu-Boeţi, P; Pietrăreanu, D; Alexandrescu, S; Dorobanţu, B; Gheorghe, L; Gheorghe, C; Mihăilă, M; Boroş, M; Croitoru, M; Herlea, V

2005-01-01

We analyze the experience of the Center of General Surgery and Liver Transplantation from the Fundeni Clinical Institute (Bucharest, Romania) regarding orthotopic liver transplantation (OLT) in adult recipients, with whole liver grafts from cadaveric donors, between April 2000 (when the first successful LT was performed in Romania) and December 2004. This series includes 37 OLTs in adult recipients (16 women and 21 men, aged between 29-57 years--average 46 years). Other two LT with whole liver cadaveric grafts and two reduced-size LT were performed in children; also, in the same period, due to the acute organ shortage, other methods of LT were performed in 28 patients (21 living donor LT, 6 split LT and one "do mino" LT), that were not included in the present series. The indications for OLT were HBV cirrhosis--10, HBV+HDV cirrhosis--4, HCV cirrhosis--11, HBV+HCV cirrhosis--2, biliary cirrhosis--5, Wilson disease--2, alcoholic cirrhosis--1, non-alcoholic liver disease--1, autoimmune cirrhosis--1. With three exceptions, in which the classical transplantation technique was used, the liver was grafted following the technique described by Belghiti. Local postoperative complications occurred in 15 patients (41%) and general complications in 17 (46%); late complications were registered in 18 patients (49%) and recurrence of the initial disease in 6 patients (16%). Intrao- and postoperative mortality was 8% (3/37). There were two patients (5%) who died because of immunosuppressive drug neurotoxicity at more than 30 days following LT. Four patients (11%) died lately because of PTLD, liver venoocclusive disease, recurrent autoimmune hepatitis and liver venoocclusive disease, myocardial infarction, respectively. Thirty-four patients survived the postoperative period (92%); according to Kaplan-Meier analysis, actuarial patient-survival rate at month 31 was 75%.

Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics.

PubMed

Lin, Chun-Jui; Kuan, Chen-Hsiang; Wang, Li-Wen; Wu, Hsi-Chin; Chen, Yunching; Chang, Chien-Wen; Huang, Rih-Yang; Wang, Tzu-Wei

2016-06-01

Ovarian cancers are the leading cause for mortality among gynecologic malignancies with five-year survival rate less than 30%. The purpose of this study is to develop a redox and pH-sensitive self-assembling hyaluronic acid nanoparticle with active targeting peptide for anticancer drug delivery. Anti-cancer drug is grafted onto hyaluronic acid (HA) via cis-aconityl linkage and disulfide bond to possess pH sensitivity and redox property, respectively. This conjugate is amphiphilic and can self-assemble into nanoparticle (NP) in aqueous solution. The results show that the nanoconjugate is successfully developed and the grafting ratio of cystamine (cys) is 17.8% with drug loading amount about 6.2% calculated by (1)H NMR spectra. The particle size is approximately 229.0 nm using dynamic light scatting measurement, and the morphology of nanoparticles is observed as spherical shape by transmission electron microscope. The pH and redox sensitivities are evaluated by changing either pH value or concentration of dithiothreitol in the medium. It is proved that the drug carrier is capable of achieving sustained controlled release of anti-cancer drug to 95% within 150 h. The intracellular uptake is observed by fluorescent microscope and the images show that conjugating luteinizing hormone-releasing hormone (LHRH) peptide can enhance specific uptake of nanoparticles by OVCAR-3 cancer cells; thus, resulting in inhibitory cell growth to less than 20% in 72 h in vitro. Orthotopic ovarian tumor model is also established to evaluate the therapeutic and diagnostic efficacy using non-invasive in vivo imaging system. The representative results demonstrate that LHRH-conjugated NPs possess a preferable tumor imaging capability and an excellent antitumor ability to almost 30% of original size in 20 days. Copyright © 2016 Elsevier Ltd. All rights reserved.

Intracranial tuberculoma in a liver transplant patient: first reported case and review of the literature.

PubMed

Henderson, Corey; Meyers, Burt; Humayun Gultekin, S; Liu, Bin; Zhang, David Y

2003-01-01

A 66-year-old female who had undergone an orthotopic liver transplant two years before admission was admitted with fever and neurological symptoms of several days' duration. Following an extensive work-up, which revealed positive intracranial lesions on computed typography and magnetic resonance imaging, the patient was begun on broad spectrum antimicrobials including corticosteroids. The patient responded though the etiology of infection remained unclear. After a stereotactic biopsy was performed revealing granulomas and acid-fast bacilli, the patient was started on antituberculous medications. A review of the literature reveals that the rare occurrence of intracranial tuberculoma should be considered in an orthotopic liver transplant (OLT) patient with central nervous system pathology.

Clinical features and surgical procedures of congenital vaginal atresia-A retrospective study of 67 patients.

PubMed

Xie, Zhihong; Zhang, Xiaoping; Zhang, Ningzhi; Xiao, Hong; Liu, Yongying; Liu, Jiandong; Chen, Lili; Li, Liang; Zhang, Linlin; Zhang, Youguo

2017-10-01

To explore the characteristics of congenital vaginal atresia, further improve its classification, and therefore help the clinical diagnosis and treatment of congenital vaginal atresia. This was a retrospective study of 67 patients with congenital vaginal atresia (from March 1984 to March 2015). Clinical and surgical characteristics were analyzed. For lower vaginal atresia, 25 patients successfully underwent vaginoplasty at the lower portion of the vagina. For complete vagina atresia, 25 patients with type i cervical atresia were treated with artificial vaginoplasty+tracheloplasty, and all showed no dysmenorrhea within six months after surgery. Four patients with type ii cervical atresia and two patients with type iii cervical atresia successfully underwent hysterectomy+artificialvaginoplasty. Two patients with type iv cervical atresia underwent combined abdominoperineal artificial vaginoplasty+tracheloplasty. One patient with upper vaginal atresia successfully underwent hysterectomy via the narrow segment of the cervix. Three patients with top vaginal atresia had no dysmenorrhea after transvaginaltracheloplasty. This study suggests two new categories of vaginal atresia (upper vaginal atresia and top vaginal atresia), which could be used as a reference for treatment of this condition. Appropriate treatments were performed using a personalized approach and satisfactory results were achieved. Copyright © 2017. Published by Elsevier B.V.

Evaluation of Nonradiative Clinical Imaging Techniques for the Longitudinal Assessment of Tumour Growth in Murine CT26 Colon Carcinoma

PubMed Central

Doan, Bich-Thuy; Latorre Ossa, Heldmuth; Jugé, Lauriane; Gennisson, Jean-Luc; Tanter, Mickaël; Scherman, Daniel; Chabot, Guy G.; Mignet, Nathalie

2013-01-01

Background and Objectives. To determine the most appropriate technique for tumour followup in experimental therapeutics, we compared ultrasound (US) and magnetic resonance imaging (MRI) to characterize ectopic and orthotopic colon carcinoma models. Methods. CT26 tumours were implanted subcutaneously (s.c.) in Balb/c mice for the ectopic model or into the caecum for the orthotopic model. Tumours were evaluated by histology, spectrofluorescence, MRI, and US. Results. Histology of CT26 tumour showed homogeneously dispersed cancer cells and blood vessels. The visualization of the vascular network using labelled albumin showed that CT26 tumours were highly vascularized and disorganized. MRI allowed high-resolution and accurate 3D tumour measurements and provided additional anatomical and functional information. Noninvasive US imaging allowed good delineation of tumours despite an hypoechogenic signal. Monitoring of tumour growth with US could be accomplished as early as 5 days after implantation with a shorter acquisition time (<5 min) compared to MRI. Conclusion. MRI and US afforded excellent noninvasive imaging techniques to accurately follow tumour growth of ectopic and orthotopic CT26 tumours. These two techniques can be appropriately used for tumour treatment followup, with a preference for US imaging, due to its short acquisition time and simplicity of use. PMID:23936648

A New Cone-Shaped Aortic Valve Prosthesis for Orthotopic Position: An Experimental Study in Swine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sochman, Jan, E-mail: jan.sochman@medicon.c; Peregrin, Jan H.; Pulda, Zdenek

The aim of this experimental study was to evaluate a newly designed cone-shaped aortic valve prosthesis (CAVP) for one-step transcatheter placement in an orthotopic position. The study was conducted in 15 swine using either the transcarotid (11 animals) or the transfemoral (4 animals) artery approach. A 12- or 13-Fr sheath was inserted via arterial cutdown. The CAVP was deployed under fluoroscopic control and its struts, by design, induced significant native valve insufficiency. CAVP function was evaluated by aortography and aortic pressure curve tracing. In 11 of 15 swine the CAVP was properly deployed and functioned well throughout the scheduled periodmore » of 2-3 h. In three swine the CAVPs were placed lower than intended, however, they were functional even in the left ventricular outflow tract position. One swine expired due to inadvertent low CAVP placement that caused both aortic regurgitation and immobilization of the anterior mitral valve leaflet by the valve struts. We conclude that this design of CAVP is relatively easy to deploy, works well throughout a short time period (2-3 h), and, moreover, seems to be reliable even in a lower-than-orthotopic position (e.g., infra-annulary space). Longer-term studies are needed for its further evaluation.« less

Radiation dose uncertainty and correction for a mouse orthotopic and xenograft irradiation model.

PubMed

Gan, Gregory N; Altunbas, Cem; Morton, John J; Eagles, Justin; Backus, Jennifer; Dzingle, Wayne; Raben, David; Jimeno, Antonio

2016-01-01

In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification. Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source. Entrance dose was evaluated using optically-stimulated luminescence dosimeters (OSLD) and exit dose was assessed using radiochromic film dosimetry. Tumor position within the irradiation field was validated using external fiducial markers. The average entrance dose in orthotopic tumors from 10 OSLDs placed on two different animal irradiation days was 514 ± 37 cGy (range: 437-545). Exit dose measurements taken from seven radiochromic films on two separate days were 341 ± 21 cGy (a 34% attenuation). Flank tumor irradiation doses measured by OSLD were 368 ± 9 cGy compared to exit doses of 330 cGy measured by radiochromic film. Variations related to the irradiation model can lead to significant under or overdosing in vivo which can affect tumor control and/or biologic endpoints that are dose-dependent. We recommend that dose measurements be determined empirically based on the mouse model and irradiator used and dose compensation adjustments performed to ensure correct and appropriate doses.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer

PubMed Central

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-01-01

AIM To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. RESULTS The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer. PMID:28638231

"Passing loop" technique: a new modification of the piggyback technique tailored to voluminous liver grafts--case report.

PubMed

Eldeen, F Z; Lee, C-F; Lee, C-S; Chan, K-M; Lee, W-C

2013-03-01

The modified piggyback technique with side-to-side cavocavostomy decreases the risk of outflow obstruction compared with the standard piggyback method. However, this modification is not ideal for recipients who receive a graft that is voluminous or bears an enlarged caudate lobe. We modified the inferior vena cava (IVC) preservation technique against deleterious complications of compression by using a passing loop. A 49-year-old woman, who underwent orthotopic liver transplantation for hepatic failure, was allocated a large-size liver. In anticipation of serious caval compression due to the voluminous grafts, we kept the suprahepatic or infrahepatic donor caval cuffs open for an anastomosis. The first anastomosis was performed between suprahepatic donor IVC cuff and recipient middle-left hepatic vein common channel; the second anastomosis was a terminolateral cavocavostomy between infrahepatic donor IVC cuff and the anterior wall of the recipient's IVC. When the liver circulation was restored, the donor retrohepatic vena cava served as a passing loop for both hepatic venous outflow and infra-diaphragmatic venous return to bypass possible IVC compression. Our technique may solve a dilemna for patients receiving voluminous liver grafts. Copyright © 2013 Elsevier Inc. All rights reserved.

Salvage with a Secondary Infrahepatic Cavocavostomy of the Occluded Modified Piggyback Anastomosis during Split Liver Transplantation: A Case Report.

PubMed

Kinaci, Erdem; Kayaalp, Cuneyt; Yilmaz, Sezai; Otan, Emrah

2014-01-01

Hepatic venous outflow obstruction following liver transplantation is rare but disastrous. Here we described a 14-year-old boy who underwent a split right lobe liver transplantation with modified (side-to-side) piggyback technique which resulted in hepatic venous outflow obstruction. When the liver graft was lifted up, the outflow drainage returned to normal but when it was placed back into the abdomen, the outflow obstruction recurred. Because reanastomosis would have resulted in hepatic reischemia, alternatively, a second infrahepatic cavocavostomy was planned without requiring hepatic reischemia. During this procedure, the first assistant hung the liver up to provide sufficient outflow and the portal inflow of the graft continued as well. We only clamped the recipient's infrahepatic vena cava and the caudal cuff of the graft cava. After the second end-to-side cavocaval anastomosis, the graft was placed in its orthotopic position and there was no outflow problem anymore. The patient tolerated the procedure well and there were no problems after three months of follow-up. A second cavocavostomy can provide an extra bypass for some hepatic venous outflow problems after piggyback anastomosis by avoiding hepatic reischemia.

Salvage with a Secondary Infrahepatic Cavocavostomy of the Occluded Modified Piggyback Anastomosis during Split Liver Transplantation: A Case Report

PubMed Central

Kinaci, Erdem; Kayaalp, Cuneyt; Yilmaz, Sezai; Otan, Emrah

2014-01-01

Hepatic venous outflow obstruction following liver transplantation is rare but disastrous. Here we described a 14-year-old boy who underwent a split right lobe liver transplantation with modified (side-to-side) piggyback technique which resulted in hepatic venous outflow obstruction. When the liver graft was lifted up, the outflow drainage returned to normal but when it was placed back into the abdomen, the outflow obstruction recurred. Because reanastomosis would have resulted in hepatic reischemia, alternatively, a second infrahepatic cavocavostomy was planned without requiring hepatic reischemia. During this procedure, the first assistant hung the liver up to provide sufficient outflow and the portal inflow of the graft continued as well. We only clamped the recipient's infrahepatic vena cava and the caudal cuff of the graft cava. After the second end-to-side cavocaval anastomosis, the graft was placed in its orthotopic position and there was no outflow problem anymore. The patient tolerated the procedure well and there were no problems after three months of follow-up. A second cavocavostomy can provide an extra bypass for some hepatic venous outflow problems after piggyback anastomosis by avoiding hepatic reischemia. PMID:24959369

Longitudinal Assessment of Lung Cancer Progression in Mice Using the Sodium Iodide Symporter Reporter Gene and SPECT/CT Imaging.

PubMed

Price, Dominique N; McBride, Amber A; Anton, Martina; Kusewitt, Donna F; Norenberg, Jeffrey P; MacKenzie, Debra A; Thompson, Todd A; Muttil, Pavan

2016-01-01

Lung cancer has the highest mortality rate of any tissue-specific cancer in both men and women. Research continues to investigate novel drugs and therapies to mitigate poor treatment efficacy, but the lack of a good descriptive lung cancer animal model for preclinical drug evaluation remains an obstacle. Here we describe the development of an orthotopic lung cancer animal model which utilizes the human sodium iodide symporter gene (hNIS; SLC5A5) as an imaging reporter gene for the purpose of non-invasive, longitudinal tumor quantification. hNIS is a glycoprotein that naturally transports iodide (I-) into thyroid cells and has the ability to symport the radiotracer 99mTc-pertechnetate (99mTcO4-). A549 lung adenocarcinoma cells were genetically modified with plasmid or lentiviral vectors to express hNIS. Modified cells were implanted into athymic nude mice to develop two tumor models: a subcutaneous and an orthotopic xenograft tumor model. Tumor progression was longitudinally imaged using SPECT/CT and quantified by SPECT voxel analysis. hNIS expression in lung tumors was analyzed by quantitative real-time PCR. Additionally, hematoxylin and eosin staining and visual inspection of pulmonary tumors was performed. We observed that lentiviral transduction provided enhanced and stable hNIS expression in A549 cells. Furthermore, 99mTcO4- uptake and accumulation was observed within lung tumors allowing for imaging and quantification of tumor mass at two-time points. This study illustrates the development of an orthotopic lung cancer model that can be longitudinally imaged throughout the experimental timeline thus avoiding inter-animal variability and leading to a reduction in total animal numbers. Furthermore, our orthotopic lung cancer animal model is clinically relevant and the genetic modification of cells for SPECT/CT imaging can be translated to other tissue-specific tumor animal models.

Longitudinal Assessment of Lung Cancer Progression in Mice Using the Sodium Iodide Symporter Reporter Gene and SPECT/CT Imaging

PubMed Central

Anton, Martina; Kusewitt, Donna F.; Norenberg, Jeffrey P.; MacKenzie, Debra A.; Thompson, Todd A.; Muttil, Pavan

2016-01-01

Lung cancer has the highest mortality rate of any tissue-specific cancer in both men and women. Research continues to investigate novel drugs and therapies to mitigate poor treatment efficacy, but the lack of a good descriptive lung cancer animal model for preclinical drug evaluation remains an obstacle. Here we describe the development of an orthotopic lung cancer animal model which utilizes the human sodium iodide symporter gene (hNIS; SLC5A5) as an imaging reporter gene for the purpose of non-invasive, longitudinal tumor quantification. hNIS is a glycoprotein that naturally transports iodide (I-) into thyroid cells and has the ability to symport the radiotracer 99mTc-pertechnetate (99mTcO4-). A549 lung adenocarcinoma cells were genetically modified with plasmid or lentiviral vectors to express hNIS. Modified cells were implanted into athymic nude mice to develop two tumor models: a subcutaneous and an orthotopic xenograft tumor model. Tumor progression was longitudinally imaged using SPECT/CT and quantified by SPECT voxel analysis. hNIS expression in lung tumors was analyzed by quantitative real-time PCR. Additionally, hematoxylin and eosin staining and visual inspection of pulmonary tumors was performed. We observed that lentiviral transduction provided enhanced and stable hNIS expression in A549 cells. Furthermore, 99mTcO4- uptake and accumulation was observed within lung tumors allowing for imaging and quantification of tumor mass at two-time points. This study illustrates the development of an orthotopic lung cancer model that can be longitudinally imaged throughout the experimental timeline thus avoiding inter-animal variability and leading to a reduction in total animal numbers. Furthermore, our orthotopic lung cancer animal model is clinically relevant and the genetic modification of cells for SPECT/CT imaging can be translated to other tissue-specific tumor animal models. PMID:28036366

Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors.

PubMed

Marin-Valencia, Isaac; Cho, Steve K; Rakheja, Dinesh; Hatanpaa, Kimmo J; Kapur, Payal; Mashimo, Tomoyuki; Jindal, Ashish; Vemireddy, Vamsidhara; Good, Levi B; Raisanen, Jack; Sun, Xiankai; Mickey, Bruce; Choi, Changho; Takahashi, Masaya; Togao, Osamu; Pascual, Juan M; Deberardinis, Ralph J; Maher, Elizabeth A; Malloy, Craig R; Bachoo, Robert M

2012-10-01

It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-(13) C(2) ]glucose. The [3-(13) C]lactate/[2,3-(13) C(2) ]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197 ± 0.011 and 0.195 ± 0.033, respectively (p = 1); metastasis: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, (13) C-(13) C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, (13) C multiplets of γ-aminobutyric acid (GABA) differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient's primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that (13) C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy. Copyright © 2012 John Wiley & Sons, Ltd.

The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAFV600E-Positive Papillary and Anaplastic Thyroid Carcinoma

PubMed Central

Vanden Borre, Pierre; McFadden, David G.; Gunda, Viswanath; Sadow, Peter M.; Varmeh, Shohreh; Bernasconi, Maria; Jacks, Tyler

2014-01-01

Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient mice. Genetically engineered models of papillary and undifferentiated (anaplastic) thyroid carcinoma (PTC and ATC) are immunocompetent; however, slow and stochastic tumor development hinders high-throughput testing. Novel models of PTC and ATC in which tumors arise rapidly and synchronously in immunocompetent mice would facilitate the investigation of novel therapeutics and approaches. Methods: We characterized and utilized mouse cell lines derived from PTC and ATC tumors arising in genetically engineered mice with thyroid-specific expression of endogenous BrafV600E/WT and deletion of either Trp53 (p53) or Pten. These murine thyroid cancer cells were transduced with luciferase- and GFP-expressing lentivirus and implanted into the thyroid glands of immunocompetent syngeneic B6129SF1/J mice in which the growth characteristics were assessed. Results: Large locally aggressive thyroid tumors form within one week of implantation. Tumors recapitulate their histologic subtype, including well-differentiated PTC and ATC, and exhibit CD3+, CD8+, B220+, and CD163+ immune cell infiltration. Tumor progression can be followed in vivo using luciferase and ex vivo using GFP. Metastatic spread is not detected at early time points. Conclusions: We describe the development of the next generation of murine orthotopic thyroid cancer models. The implantation of genetically defined murine BRAF-mutated PTC and ATC cell lines into syngeneic mice results in rapid and synchronous tumor formation. This model allows for preclinical investigation of novel therapeutics and/or therapeutic combinations in the context of a functional immune system. PMID:24295207

In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models.

PubMed

Asadzadeh, Fatemeh; Ferrucci, Veronica; DE Antonellis, Pasqualino; Zollo, Massimo

2017-03-01

Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub-groups with a higher predictive value. Here we show how this technology should be applied with hopes on generations of new treatments to be applied then in human.

Orthotopic Esophageal Cancers: Intraesophageal Hyperthermia-enhanced Direct Chemotherapy in Rats

PubMed Central

Shi, Yaoping; Zhang, Feng; Bai, Zhibin; Wang, Jianfeng; Qiu, Longhua; Li, Yonggang; Meng, Yanfeng; Valji, Karim

2017-01-01

Purpose To determine the feasibility of using intraesophageal radiofrequency (RF) hyperthermia to enhance local chemotherapy in a rat model with orthotopic esophageal squamous cancers. Materials and Methods The animal protocol was approved by the institutional animal care and use committee and the institutional review board. Human esophageal squamous cancer cells were transduced with luciferase lentiviral particles. Cancer cells, mice with subcutaneous cancer esophageal xenografts, and nude rats with orthotopic esophageal cancers in four study groups of six animals per group were treated with (a) combination therapy of magnetic resonance imaging heating guidewire–mediated RF hyperthermia (42°C) plus local chemotherapy (cisplatin and 5-fluorouracil), (b) chemotherapy alone, (c) RF hyperthermia alone, and (d) phosphate-buffered saline. Bioluminescent optical imaging and transcutaneous ultrasonographic imaging were used to observe bioluminescence signal and changes in tumor size among the groups over 2 weeks, which were correlated with subsequent histologic results. The nonparametric Mann-Whitney U test was used for comparisons of variables. Results Compared with chemotherapy alone, RF hyperthermia alone, and phosphate-buffered saline, combination therapy with RF hyperthermia and chemotherapy induced the lowest cell proliferation (relative absorbance of formazan: 23.4% ± 7, 44.6% ± 7.5, 95.8% ± 2, 100%, respectively; P < .0001), rendered the smallest relative tumor volume (0.65 mm3 ± 0.15, P < .0001) and relative bioluminescence optical imaging photon signal (0.57 × 107 photons per second per square millimeter ± 0.15, P < .001) of mice with esophageal cancer xenografts, as well as the smallest relative tumor volume (0.68 mm3 ± 0.13, P < .05) and relative photon signal (0.56 × 107 photons per second per square millimeter ± 0.11. P < .001) of rat orthotopic esophageal cancers. Conclusion Intraesophageal RF hyperthermia can enhance the effect of chemotherapy on esophageal squamous cell cancers. © RSNA, 2016 PMID:27404050

Development of a Preclinical Orthotopic Xenograft Model of Ewing Sarcoma and Other Human Malignant Bone Disease Using Advanced In Vivo Imaging

PubMed Central

Batey, Michael A.; Almeida, Gilberto S.; Wilson, Ian; Dildey, Petra; Sharma, Abhishek; Blair, Helen; Hide, I. Geoff; Heidenreich, Olaf; Vormoor, Josef; Maxwell, Ross J.; Bacon, Chris M.

2014-01-01

Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG) and Rag2−/−/γc−/− mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000–5000) injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised “malignant” bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which resemble the human disease. We have shown the utility of small animal bioimaging for tracking disease progression, making this model a useful assay for preclinical drug testing. PMID:24409320

Health information quality on the internet for bladder cancer and urinary diversion: a multi-lingual analysis.

PubMed

Corfield, Julia M; Abouassaly, Robert; Lawrentschuk, Nathan

2018-04-01

Bladder cancer patients undergoing radical cystectomy and urinary diversion are faced with difficult decisions regarding mode of urinary diversion. Although these patients may use the Internet as a guide to diagnosis and treatment options, online resources remain largely unregulated leading to a great variation in quality of medical information. Further variation in quality is seen between languages. Fortunately, tools such as an automated toolbar developed by the World Health Organization Health on the Net (HON) Foundation exist to assist physicians in recommending quality online health information to patients. We set out to compare and assess the quality of bladder cancer, ileal conduit and orthotopic neobladder web sites in 2016 on the basis of the HON principles for English language. The Google search engine imbedded with the HON toolbar was used to assess 1350 Web sites using the keywords "bladder cancer", "ileal conduit" and "orthotopic neobladder" in English, Italian and Spanish. The first 150 results of each search were identified and screened. A further analysis was completed comparing results between 2009 and 2016. Less than 20% of English, Italian and Spanish "bladder cancer" and urinary diversion ("ileal conduit" and "orthotopic neobladder") web sites are HON-accredited. HON-accredited web sites featured preferentially in the first 50 search results for bladder cancer (P=0.0001) and ileal conduit (P=0.03) web sites. Comparing 2016 results to 2009, percentage of HON-accreditation has not shown statistically significant change (-13%, P=0.23), while overall number of search results has increased (+44%). A lack of validation of bladder cancer sites is present, which is consistent across modes of urinary diversion (orthotopic neobladder and ileal conduit) and languages. It is important that physicians involved in the care of bladder cancer patients undergoing radical cystectomy and urinary diversion participate in the development of informative, ethical, and reliable health Web sites and direct patients to them.

Bufalin attenuates the stage and metastatic potential of hepatocellular carcinoma in nude mice

PubMed Central

2014-01-01

Background Advanced hepatocellular carcinoma (HCC) patients undergo significant tumor growth and metastasis. Here, we investigated bufalin for treating HCC, which exhibits anti-tumor activities in many tumor cell lines. Method In our experiment, HCCLM3-R cells were injected into nude mice to form subcutaneous human HCC tumors that were implanted into the liver to establish orthotopic transplantation tumor models. Bufalin was injected intraperitoneally at 1 or 1.5 mg/kg. LY294002 (100 mg/kg), a potent inhibitor of Akt which reduced the levels of pAkt in HCCLM3 cell lines, was injected intraperitoneally into one group thrice weekly. The control was injected with an equal volume of saline. Morphological alterations were evaluated in the liver and lung by stereomicroscopy, the apoptotic rate was measured by TUNEL staining, and expression of AKT/GSK3β/β-catenin/E-cadherin signaling pathway-related proteins was detected by immunohistochemistry (IHC) and western blot analysis. Results These results suggested that the sizes and qualities of orthotopic transplanted tumors as well as pulmonary metastasis decreased markedly at the highest bufalin dose compared with that in the control. Orthotopic transplanted tumor tissues were necrotic in bufalin-treated groups and the apoptotic cell number was markedly higher at the highest bufalin dose compared with that in the control. Certain changes of expression of AKT/GSK3β/β-catenin/E-cadherin signaling pathway-related proteins were in tumor tissues, which were related to the bufalin dose. Similar results were observed in the LY294002-treated group. Conclusion Based on the above, one can draw conclusions that bufalin has significant anti-tumor activities and reduces the metastatic potential in an orthotopic transplantation tumor model of human HCC. Inhibition of AKT/GSK3β/β-catenin/E-cadherin signaling pathways by bufalin may show therapeutic effects in advanced HCC patients. PMID:24581171

In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2'-deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models.

PubMed

Russell, James; Pillarsetty, Nagavarakishore; Kramer, Robin M; Romesser, Paul B; Desai, Pooja; Haimovitz-Friedman, Adriana; Lowery, Maeve A; Humm, John L

2017-12-01

Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug. [ 18 F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [ 14 C]gemcitabine and [ 18 F]FAC were mapped with autoradiography. The inter-tumor correlation between [ 14 C]gemcitabine and [ 18 F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [ 3 H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [ 18 F]FAC and [ 14 C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [ 14 C]gemcitabine and [ 18 F]FAC were largely co-localized. In the lines examined here, [ 18 F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [ 18 F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.

In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2′-deoxy-2′-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models

PubMed Central

Russell, James; Pillarsetty, Nagavarakishore; Kramer, Robin M; Romesser, Paul B; Desai, Pooja; Haimovitz-Friedman, Adriana; Lowery, Maeve A; Humm, John L

2017-01-01

Purpose Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2′-deoxy-2′-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug. Procedures [18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized. Conclusions In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors. PMID:28349292

Direct visual internal urethrotomy for isolated, post-urethroplasty strictures: a retrospective analysis

PubMed Central

Brown, Elizabeth Timbrook; Mock, Stephen; Dmochowski, Roger; Reynolds, W. Stuart; Milam, Douglas; Kaufman, Melissa R.

2016-01-01

Background: Urethroplasty is often successful for the treatment of male urethral stricture disease, but limited data exists on recurrence management. Our goal was to evaluate direct visual internal urethrotomy (DVIU) as a treatment option for isolated, recurrent strictures after urethroplasty. Methods: We retrospectively identified male patients who underwent urethroplasty from 1999 to 2013 and developed an isolated, recurrent stricture at the urethroplasty site treated with DVIU. Success was defined as lack of symptomatology and no subsequent intervention. Comparative analysis identified characteristics and stricture properties associated with success. Results: A total of 436 urethroplasties were performed in 401 patients at our institution between 1999 and 2013. Stricture recurrence was noted in 64 (16%) patients. Of these, 47 (73%) underwent a DVIU. A total of 37 patients met inclusion criteria and underwent 50 DVIU procedures at the urethroplasty site. A single DVIU was successful in 13 of 37 patients (35%). A total of 4 of 6 patients required a second DVIU (67%). Overall, 17 of 43 (40%) of the total DVIUs were successful after urethroplasty. Success did not differ by age, stricture length or location, surgical technique, radiation history, prior urethroplasty or DVIU, time to failure, or etiology. Conclusions: Post-urethroplasty DVIU for isolated, recurrent strictures may be offered as a minimally invasive treatment option. Approximately 40% of patients were spared further intervention. PMID:28203286

Urinary tract infections following radical cystectomy and urinary diversion: a review of 1133 patients.

PubMed

Clifford, Thomas G; Katebian, Behrod; Van Horn, Christine M; Bazargani, Soroush T; Cai, Jie; Miranda, Gus; Daneshmand, Siamak; Djaladat, Hooman

2018-05-01

To investigate the incidence and microbiology of urinary tract infection (UTI) within 90 days following radical cystectomy (RC) and urinary diversion. We reviewed 1133 patients who underwent RC for bladder cancer at our institution between 2003 and 2013; 815 patients (72%) underwent orthotopic diversion, 274 (24%) ileal conduit, and 44 (4%) continent cutaneous diversion. 90-day postoperative UTI incidence, culture results, antibiotic sensitivity/resistance and treatment were recorded through retrospective review. Fisher's exact test, Kruskal-Wallis test, and multivariable analysis were performed. A total of 151 urinary tract infections were recorded in 123 patients (11%) during the first 90 days postoperatively. 21/123 (17%) had multiple infections and 25 (20%) had urosepsis in this time span. Gram-negative rods were the most common etiology (54% of positive cultures). 52% of UTI episodes led to readmission. There was no significant difference in UTI rate, etiologic microbiology (Gram-negative rods, Gram-positive cocci, fungi), or antibiotic sensitivity and resistance patterns between diversion groups. Resistance to quinolones was evident in 87.5% of Gram-positive and 35% of Gram-negative bacteria. In multivariable analysis, Charlson Comorbidity Index > 2 was associated with higher 90-day UTI rate (OR = 1.8, 95% CI 1.1-2.9, p = 0.05) and Candida UTI (OR 5.6, 95% CI 1.6-26.5, p = 0.04). UTI is a common complication and cause of readmission following radical cystectomy and urinary diversion. These infections are commonly caused by Gram-negative rods. High comorbidity index is an independent risk factor for postoperative UTI, but diversion type is not.

Magnetically-Responsive Nanoparticles for Vectored Delivery of Cancer Therapeutics

NASA Astrophysics Data System (ADS)

Klostergaard, Jim; Bankson, James; Woodward, Wendy; Gibson, Don; Seeney, Charles

2010-12-01

We propose that physical targeting of therapeutics to tumors using magnetically-responsive nanoparticles (MNPs) will enhance intratumoral drug levels compared to free drugs in an effort to overcome tumor resistance. We evaluated the feasibility of magnetic enhancement of tumor extravasation of systemically-administered MNPs in human xenografts implanted in the mammary fatpads of nude mice. Mice with orthotopic tumors were injected systemically with MNPs, with a focused magnetic field juxtaposed over the tumor. Magnetic resonance imaging and scanning electron microscopy both indicated successful tumor localization of MNPs. Next, MNPs were modified with poly-ethylene-glycol (PEG) and their clearance compared by estimating signal attenuation in liver due to iron accumulation. The results suggested that PEG substitution could retard the rate of MNP plasma clearance, which may allow greater magnetically-enhanced tumor localization. We propose that this technology is clinically scalable to many types of both superficial as well as some viscerable tumors with existing magnetic technology.

[Combined heart-kidney transplantation in Mexic].

PubMed

Careaga-Reyna, Guillermo; Zetina-Tun, Hugo Jesús; Lezama-Urtecho, Carlos Alberto; Hernández-Domínguez, José Mariano; Santos-Caballero, Marlene

In our country, heart and kidney transplantation is a novel option for treatment of combined terminal heart and kidney failure. This program began in 2012 for selected patients with documented terminal heart failure and structural kidney damage with renal failure. Description of cases: Between January 1, 2012 and April 30, 2016, we made 92 orthotopic heart transplantations. In five of these cases the heart transplantation was combined with kidney transplantation. There were three male and two female patients with a mean age 25.6 ± 5.2 years (range, 17-29). The patients improved their renal function and the heart transplantation was successful with an improved quality of life. One patient died from abdominal sepsis. The other patients are doing well. The combined heart-kidney transplantation is a safe and efficient procedure for patients with structural kidney and heart damage as a cause of terminal failure.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation

PubMed Central

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-01-01

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. PMID:28951512

Combined en bloc liver/pancreas transplantation in two different patients

PubMed Central

Chen, Zhi-Shui; Meng, Fan-Ying; Chen, Xiao-Ping; Liu, Dun-Gui; Wei, Lai; Jiang, Ji-Pin; Du, Dun-Feng; Zhang, Wei-Jie; Ming, Chang-Sheng; Gong, Nian-Qiao

2009-01-01

Combined en bloc liver/pancreas transplantation (CLPT) was used primarily in the treatment of otherwise non-resectable upper abdominal malignancy. In fact, a more appropriate indication is in patients with liver disease and insulin-dependent diabetes mellitus (IDDM). Here, we report on two successful cases of CLPT at our hospital. One was a patient with non-resectable advanced liver cancer. The recipient survived for 23 mo and finally died of recurrent tumor. The other was a patient with severe biliary complication after orthotopic liver transplantation and preoperative IDDM. We performed CLPT with a modified surgical technique of preserving the native pancreas. He is currently liver-disease- and insulin-free more than 27 mo post-transplant. Based on our experience in two cases of abdominal cluster transplantation, we describe the technical details of CLPT and a modification of the surgical procedure. PMID:19469010

Fluorescence spectroscopy for assessment of liver transplantation grafts concerning graft viability and patient survival

NASA Astrophysics Data System (ADS)

Vollet Filho, José D.; da Silveira, Marina R.; Castro-e-Silva, Orlando; Bagnato, Vanderlei S.; Kurachi, Cristina

2015-06-01

Evaluating transplantation grafts at harvest is essential for its success. Laser-induced fluorescence spectroscopy (LIFS) can help monitoring changes in metabolic/structural conditions of tissue during transplantation. The aim of the present study is to correlate LIFSobtained spectra of human hepatic grafts during liver transplantation with post-operative patients' mortality rate and biochemical parameters, establishing a method to exclude nonviable grafts before implantation. Orthotopic liver transplantation, piggyback technique was performed in 15 patients. LIFS was performed under 408nm excitation. Collection was performed immediately after opening donor's abdominal cavity, after cold perfusion, end of back-table period, and 5 min and 1 h after warm perfusion at recipient. Fluorescence information was compared to lactate, creatinine, bilirubin and INR levels and to survival status. LIFS was sensitive to liver changes during transplantation stages. Study-in-progress; initial results indicate correlation between fluorescence and life/death status of patients.

Aspiration and sclerotherapy: a nonsurgical treatment option for hydroceles.

PubMed

Francis, John J; Levine, Laurence A

2013-05-01

We demonstrated that hydrocele aspiration and sclerotherapy with doxycycline is an effective and safe nonsurgical treatment option for hydrocele correction. The medical records of patients who underwent hydrocele aspiration and sclerotherapy were analyzed in a retrospective cohort study for success rates as well as improvement in scrotal size and discomfort after a single hydrocele aspiration and sclerotherapy treatment. Patients who reported decreased scrotal size, improved physical symptoms and satisfaction with the procedure were considered as having success with hydrocele aspiration and sclerotherapy. A total of 29 patients (mean age 52.8 years) presenting with 32 nonseptated hydroceles underwent hydrocele aspiration and sclerotherapy with doxycycline between 2005 and 2012. Of the hydroceles 27 (84%) were successfully treated with a single aspiration and sclerotherapy procedure. Overall mean followup was 20.8 months. Three patients reported moderate pain which resolved in 2 to 3 days. Of those patients in whom hydrocele aspiration and sclerotherapy failed, 1 had hydrocele successfully resolved with a second aspiration and sclerotherapy treatment, 3 did not have success with a second procedure and underwent hydrocelectomy, and 1 wanted immediate surgical correction. Hydrocele aspiration and sclerotherapy was successful in correcting 84% of simple nonseptated hydroceles with a single treatment. This result is an increase from previously reported success rates involving a single hydrocele aspiration and sclerotherapy procedure with tetracycline (75%). The success rate of a single hydrocele aspiration and sclerotherapy procedure is similar to the reported success rates involving hydrocelectomy while avoiding the hospital expense and many other complications. We conclude that the hydrocele aspiration and sclerotherapy procedure is a reasonable, nonsurgical and underused treatment option for nonseptated simple hydroceles. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Fluoroscopically guided large balloon dilatation for treating congenital esophageal stenosis in children.

PubMed

Hu, Hong-Tao; Shin, Ji Hoon; Kim, Jin-Hyoung; Jang, Jong Keon; Park, Jung-Hoon; Kim, Tae-Hyung; Nam, Deok Ho; Song, Ho-Young

2015-07-01

We aimed to evaluate the safety and clinical effectiveness of fluoroscopically guided large balloon dilatation for treating congenital esophageal stenosis in children. Our study included seven children (mean age 4.0 years) who underwent a total of ten balloon dilatation sessions. The initial balloon diameters were 10-15 mm. The technical success, clinical success (improved food intake and reduced dysphagia within 1 month following the first balloon dilatation), dysphagia recurrence, and complications were retrospectively evaluated. Technical and clinical success rates were 100 %. During the mean 38-month follow-up period after the first balloon dilatation, 3 (43 %) patients underwent only one additional balloon dilatation 4-5 months after the first balloon dilatation for dysphagia recurrence. Two of them showed improvement without further recurrence, while the remaining one underwent partial esophagectomy. Well-contained transmural esophageal rupture (type 2) occurred in two (29 %, 2/7) patients and during two (20 %, 2/10) balloon dilatation sessions. All ruptures were successfully treated conservatively. Our study showed that fluoroscopically guided large balloon dilatation seems to be a simple and effective primary treatment technique for congenital esophageal stenosis in children. Esophageal ruptures were not uncommon although they were not fatal.

Osteo-odonto-keratoprosthesis for end-stage cornea blindness.

PubMed

Wong, H S; Then, K Y; Ramli, R

2011-10-01

We report the first case of Osteo-odonto-keratoprosthesis (OOKP) who successfully underwent surgery in Malaysia following a grade 4 (severe) chemical injury in both eyes in 2006. The patient's left eye was eviscerated and his right eye underwent penetrating keratoplasty. However, the corneal graft failed and became opaque. His right eye could only perceive light. The OOKP was offered to him hoping to recover some functional vision. He underwent a 2-stage surgery to implant the OOKP into his right eye. However, 2 months post-operation, he developed vitreous haemorrhage. A successful pars plana vitrectomy (PPV) was performed via the limited view through the lens. He attained a final visual acuity of 6/60 (N36). He was able to mobilize more independently, feed, dress himself and read large print.

Dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation in humans

PubMed Central

Weng, Xiao-chuan; Zhou, Liang; Fu, Yin-yan; Zhu, Sheng-mei; He, Hui-liang; Wu, Jian

2005-01-01

Objective: To compare the dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation (OLT) in humans. Methods: Twenty male patients undergoing liver transplantation were randomly assigned to two comparable groups of 10 patients each to receive a continuous infusion of rocuronium or atracurium under intravenous balanced anesthesia. The response of adductor pollicis to train-of-four (TOF) stimulation of unlar nerve was monitored. The infusion rates of rocuronium and atracurium were adjusted to maintain T1/Tc ratio of 2%~10%. The total dose of each drug given during each of the three phases of OLT was recorded. Results: Rocuronium requirement, which were (0.468±0.167) mg/(kg·h) during the paleohepatic phase, decreased significantly during the anhepatic phase to (0.303±0.134) mg/(kg·h) and returned to the initial values at the neohepatic period ((0.429±0.130) mg/(kg·h)); whereas atracuruim requirements remained unchanged during orthotopic liver transplantation. Conclusions: This study showed that the exclusion of the liver from the circulation results in the significantly reduced requirement of rocuronium while the requirement of atracurium was not changed, which suggests that the liver is of major importance in the clearance of rocuronium. A continuous infusion of atracurium with constant rate can provide stable neuromuscular blockade during the three stages of OLT. PMID:16130187

Radiation Dose Uncertainty and Correction for a Mouse Orthotopic and Xenograft Irradiation Model

PubMed Central

Gan, Gregory N.; Altunbas, Cem; Morton, John J.; Eagles, Justin; Backus, Jennifer; Dzingle, Wayne; Raben, David; Jimeno, Antonio

2016-01-01

Purpose In animal irradiation models, reported dose can vary significantly from the actual doses delivered. We describe an effective method for in vivo dose verification. Materials and Methods Mice bearing commercially-available cell line or patient-derived tumor cell orthotopic or flank xenografts were irradiated using a 160 kVp, 25 mA X-ray source. Entrance dose was evaluated using optically-stimulated luminescence dosimeters (OSLD) and exit dose was assessed using radiochromic film dosimetry. Results Tumor position within the irradiation field was validated using external fiducial markers. The average entrance dose in orthotopic tumors from 10 OSLDs placed on 2 different animal irradiation days was 514±37 cGy (range: 437–545). Exit dose measurements taken from 7 radiochromic films on two separate days were 341±21 cGy (a 34% attenuation). Flank tumor irradiation doses measured by OSLD were 368±9 cGy compared to exit doses of 330 cGy measured by radiochromic film. Conclusion Variations related to the irradiation model can lead to significant under or over- dosing in vivo which can affect tumor control and/or biologic endpoints that are dose dependent. We recommend that dose measurements be determined empirically based on the mouse model and irradiator used and dose compensation adjustments performed to ensure correct and appropriate doses. PMID:26689828

Orthotopic Liver Transplantation for Urea Cycle Enzyme Deficiency

PubMed Central

Todo, Satoru; Starzl, Thomas E.; Tzakis, Andreas; Benkov, Keith J.; Kalousek, Frantisek; Saheki, Takeyori; Tanikawa, Kyuichi; Fenton, Wayne A.

2010-01-01

Hyperammonemia, abnormalities in plasma amino acids and abnormalities of standard liver functions were corrected by orthotopic liver transplantation in a 14-day-old boy with carbamyl phosphate synthetase-I deficiency and in a 35-yr-old man with argininosuccinic acid synthetase deficiency. The first patient had high plasma glutamine levels and no measureable citrulline, whereas citrulline values were markedly increased in Patient 2. Enzyme analysis of the original livers showed undetectable activity of carbamyl phosphate synthetase-I in Patient 1 and arginosuccinic acid synthetase in Patient 2. Both patients were comatose before surgery. Intellectual recovery of patient 1 has been slightly retarded because of a brain abscess caused by Aspergillus infection after surgery. Both patients are well at 34 and 40 mo, respectively, after surgery. Our experience has shown that orthotopic liver transplantation corrects the life-threatening metabolic abnormalities caused by deficiencies in the urea cycle enzymes carbamyl phosphate synthetase-I and arginosuccinic acid synthetase. Seven other patients–six with ornithine transcarbamylase deficiency and another with carbamyl phosphate synthetase-I deficiency–are known to have been treated elsewhere with liver transplantation 1½ yr or longer ago. Four of these seven recipients also are well, with follow-ups of 1½ to 5 yr. Thus liver transplantation corrects the metabolic abnormalities of three of the six urea cycle enzyme deficiencies, and presumably would correct all. PMID:1544622

Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

PubMed Central

Igarashi, Kentaro; Kawaguchi, Kei; Li, Shukuan; Han, Qinghong; Tan, Yuying; Gainor, Emily; Kiyuna, Tasuku; Miyake, Kentaro; Miyake, Masuyo; Higuchi, Takashi; Oshiro, Hiromichi; Singh, Arun S.; Eckardt, Mark A.; Nelson, Scott D.; Russell, Tara A.; Dry, Sarah M.; Li, Yunfeng; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Eilber, Fritz C.; Hoffman, Robert M.

2018-01-01

Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease. PMID:29721200

Theranostic 3-Dimensional nano brain-implant for prolonged and localized treatment of recurrent glioma

NASA Astrophysics Data System (ADS)

Ramachandran, Ranjith; Junnuthula, Vijayabhaskar Reddy; Gowd, G. Siddaramana; Ashokan, Anusha; Thomas, John; Peethambaran, Reshmi; Thomas, Anoop; Unni, Ayalur Kodakara Kochugovindan; Panikar, Dilip; Nair, Shantikumar V.; Koyakutty, Manzoor

2017-03-01

Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

Successful Treatment of Corticosteroid with Antiviral Therapy for a Neonatal Liver Failure with Disseminated Herpes Simplex Virus Infection

PubMed Central

Maeba, Shinji; Hasegawa, Shunji; Shimomura, Maiko; Ichimura, Takuya; Takahashi, Kazumasa; Motoyama, Masashi; Fukunaga, Shinnosuke; Ito, Yoshinori; Ichiyama, Takashi; Ohga, Shouichi

2015-01-01

Background Herpes simplex virus (HSV) infection carries one of the poorest outcomes of neonatal liver failure (NLF). Neonates with disseminated HSV infection can develop hemophagocytic lymphohistiocytosis (HLH), and occasionally need orthotopic liver transplantation. Early interventions may be critical for the cure of NLF. Case Report We describe herewith a 6-day-old neonate with fulminant hepatic failure due to disseminated HSV-1 infection, who successfully responded to high-dose corticosteroid therapy 72 hours after the onset of disease. Preceding acyclovir, gamma globulin, and exchange blood transfusion therapies failed to control the disease. Methylprednisolone pulse therapy led to a drastic improvement of liver function and cytokine storms, and prevented the disease progression to HLH. Sustained levels of plasma and cerebrospinal fluid HSV DNA declined after prolonged acyclovir therapy. Bilateral lesions of the periventricular white matter areas, assessed by magnetic resonance imaging, disappeared at 3 months of age. The infant showed normal growth and development at 4 years of age. Conclusion Early anti-hypercytokinemia therapy using corticosteroid, and prolonged antiviral therapy might only provide the transplantation-free cure of NLF with HSV dissemination. PMID:26495160

Successful outcome of transplant of kidneys recovered from a brain-dead liver transplant recipient: case report.

PubMed

Domagała, Piotr; Kwiatkowski, Artur; Drozdowski, Jakub; Ostrowski, Krzysztof; Wszola, Michal; Diuwe, Piotr; Durlik, Magdalena; Paczek, Leszek; Chmura, Andrzej

2012-12-01

Few reports describing the use of organs donated by transplant recipients have been published. In this case report, kidneys procured from a brain-dead liver recipient were transplanted successfully. A 21-year-old man was referred for liver transplant after an overdose of acetaminophen. The patient's kidney function was initially normal, with proper urine production and normal kidney laboratory parameters. On the third day after admission, the patient's kidney laboratory parameters became elevated and hepatic encephalopathy requiring mechanical ventilation developed. An orthotopic liver transplant was performed the next day. The patient did not recover consciousness, and brain death was diagnosed on the third day after the liver transplant surgery. The maximum serum concentration of creatinine was 5.8 mg/dL (513 μmol/L) before kidney recovery, and urine production was normal. The kidneys were recovered with organ-perfusion support and were preserved by using machine perfusion. The kidneys were transplanted into 2 male recipients. Twelve months after transplant, the recipients remained in good health with satisfactory kidney function. This case demonstrates that transplanting kidneys recovered from liver transplant recipients is possible and beneficial, thus expanding the pool of potential donors.

Urea cycle disorders: a case report of a successful treatment with liver transplant and a literature review.

PubMed

Foschi, Francesco Giuseppe; Morelli, Maria Cristina; Savini, Sara; Dall'Aglio, Anna Chiara; Lanzi, Arianna; Cescon, Matteo; Ercolani, Giorgio; Cucchetti, Alessandro; Pinna, Antonio Daniele; Stefanini, Giuseppe Francesco

2015-04-07

The urea cycle is the final pathway for nitrogen metabolism. Urea cycle disorders (UCDs) include a variety of genetic defects, which lead to inefficient urea synthesis. Elevated blood ammonium level is usually dominant in the clinical pattern and the primary manifestations affect the central nervous system. Herein, we report the case of a 17-year-old girl who was diagnosed with UCD at the age of 3. Despite a controlled diet, she was hospitalized several times for acute attacks with recurrent life risk. She came to our attention for a hyperammonemic episode. We proposed an orthotopic liver transplant (OLT) as a treatment; the patient and her family were in complete agreement. On February 28, 2007, she successfully received a transplant. Following the surgery, she has remained well, and she is currently leading a normal life. Usually for UCDs diet plays the primary therapeutic role, while OLT is often considered as a last resort. Our case report and the recent literature data on the quality of life and prognosis of traditionally treated patients vs OLT patients, support OLT as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment.

Validation of a prediction model for predicting the probability of morbidity related to a trial of labour in Quebec.

PubMed

Chaillet, Nils; Bujold, Emmanuel; Dubé, Eric; Grobman, William A

2012-09-01

Pregnant women with a history of previous Caesarean section face the decision either to undergo an elective repeat Caesarean section (ERCS) or to attempt a trial of labour with the goal of achieving a vaginal birth after Caesarean (VBAC). Both choices are associated with their own risks of maternal and neonatal morbidity. We aimed to determine the external validity of a prediction model for the success of trial of labour after Caesarean section (TOLAC) that could help these women in their decision-making. We used a perinatal database including 185,437 deliveries from 32 obstetrical centres in Quebec between 2007 and 2011 and selected women with one previous Caesarean section who were eligible for a TOLAC. We compared the frequency of maternal and neonatal morbidity between women who underwent TOLAC and those who underwent an ERCS according to the probability of success of TOLAC calculated from a published model of prediction. Of 8508 eligible women, including 3113 who underwent TOLAC, both maternal and neonatal morbidities became less frequent as the predicted chance of VBAC increased (P < 0.05). Women undergoing a TOLAC were more likely to have maternal morbidity than those who underwent an ERCS when the predicted probability of VBAC was less than 60% (relative risk [RR] 2.3; 95% CI 1.4 to 4.0); conversely, maternal morbidity was not different between the two groups when the predicted probability of VBAC was at least 60% (RR 0.8; 95% CI 0.6 to 1.1). Neonatal morbidity was similar between groups when the probability of VBAC success was 70% or greater (RR 1.2; 95% CI 0.9 to 1.5). The use of a prediction model for TOLAC success could be useful in the prediction of TOLAC success and perinatal morbidity in a Canadian population. Neither maternal nor neonatal morbidity are increased with a TOLAC when the probability of VBAC success is at least 70%.

A Large Multicenter Experience With Endoscopic Suturing for Management of Gastrointestinal Defects and Stent Anchorage in 122 Patients: A Retrospective Review.

PubMed

Sharaiha, Reem Z; Kumta, Nikhil A; DeFilippis, Ersilia M; Dimaio, Christopher J; Gonzalez, Susana; Gonda, Tamas; Rogart, Jason; Siddiqui, Ali; Berg, Paul S; Samuels, Paul; Miller, Larry; Khashab, Mouen A; Saxena, Payal; Gaidhane, Monica R; Tyberg, Amy; Teixeira, Julio; Widmer, Jessica; Kedia, Prashant; Loren, David; Kahaleh, Michel; Sethi, Amrita

2016-01-01

To describe a multicenter experience using an endoscopic suturing device for management of gastrointestinal (GI) defects and stent anchorage. Endoscopic closure of GI defects including perforations, fistulas, and anastomotic leaks as well as stent anchorage has improved with technological advances. An endoscopic suturing device (OverStitch; Apollo Endosurgery Inc.) has been used. Retrospective study of consecutive patients who underwent endoscopic suturing for management of GI defects and/or stent anchorage were enrolled between March 2012 and January 2014 at multiple academic medical centers. Data regarding demographic information and outcomes including long-term success were collected. One hundred and twenty-two patients (mean age, 52.6 y; 64.2% females) underwent endoscopic suturing at 8 centers for stent anchorage (n=47; 38.5%), fistulas (n=40; 32.7%), leaks (n=15; 12.3%), and perforations (n=20; 16.4%). A total of 44.2% underwent prior therapy and 97.5% achieved technical success. Immediate clinical success was achieved in 79.5%. Long-term clinical success was noted in 78.8% with mean follow-up of 68 days. Clinical success was 91.4% in stent anchorage, 93% in perforations, 80% in fistulas, but only 27% in anastomotic leak closure. Endoscopic suturing for management of GI defects and stent anchoring is safe and efficacious. Stent migration after stent anchoring was reduced compared with published data. Long-term success without further intervention was achieved in the majority of patients. The role of endoscopic suturing for repair of anastomotic leaks remains unclear given limited success in this retrospective study.

A 27-Year Experience With Surgical Treatment of Budd-Chiari Syndrome

PubMed Central

Orloff, Marshall J.; Daily, Pat O.; Orloff, Susan L.; Girard, Barbara; Orloff, Mark S.

2000-01-01

Objective To determine the effects of surgical portal decompression in Budd-Chiari syndrome (BCS) on survival, quality of life, shunt patency, liver function, portal hemodynamics, and hepatic morphology during periods ranging from 3.5 to 27 years. Summary Background Data Experiments in the authors’ laboratory showed that surgical portal decompression reversed the deleterious effects of BCS on the liver. This study was aimed at determining whether similar benefit could be obtained in patients with BCS. Methods From 1972 to 1999, the authors conducted prospective studies of the treatment of 60 patients with BCS who were divided into three groups: the first had occlusion confined to the hepatic veins treated by direct side-to-side portacaval shunt (SSPCS); the second had occlusion involving the inferior vena cava (IVC) treated by a portal decompressive procedure that bypassed the obstructed IVC; and the third group, who had advanced cirrhosis and hepatic decompensation and were referred too late for treatment by portal decompression, required orthotopic liver transplantation. Results In the 32 patients with BCS resulting from hepatic vein occlusion alone, SSPCS had a surgical death rate of 3%, and 94% of the patients were alive 3.5 to 27 years after surgery. All 31 survivors remained free of ascites and almost all had normal liver function. No patient with a patent shunt had encephalopathy. The SSPCS remained patent in all but one patient. Liver biopsies showed no evidence of congestion or necrosis, and 48% of the biopsies were diagnosed as normal. Mesoatrial shunt was performed in eight patients with BCS caused by IVC thrombosis. All patients survived surgery, but five subsequently developed thrombosis of the synthetic graft and died. Because of the poor results, mesoatrial shunt was abandoned. Instead, a high-flow combination shunt was introduced, consisting of SSPCS combined with a cavoatrial shunt (CAS) through a Gore-Tex graft. There were no surgical or long-term deaths among 10 patients who underwent combined SSPCS and CAS, and the shunts functioned effectively during 4 to 16 years of follow-up. Ten patients with advanced cirrhosis were referred too late to benefit from surgical portal decompression, and they were approved and listed for orthotopic liver transplantation. Three patients died of liver failure while awaiting a transplant, and four patients died after the transplant. The 1- and 5-year survival rates were 40% and 30%, respectively. Conclusions SSPCS in BCS with hepatic vein occlusion alone results in reversal of liver damage, correction of hemodynamic disturbances, prolonged survival, and good quality of life when performed early in the course of BCS. Similarly good results are obtained with combined SSPCS and CAS in patients with BCS resulting from IVC occlusion. In contrast, mesoatrial shunt has been discontinued in the authors’ program because of an unacceptable incidence of graft thrombosis and death. In patients with advanced cirrhosis from long-standing, untreated BCS, orthotopic liver transplantation is the only hope of relief and results in the salvage of some patients. The key to long survival in BCS is prompt diagnosis and treatment by portal decompression. PMID:10973384

Outcome of anastomotic posterior urethroplasty with various ancillary maneuvers for post-traumatic urethral injury. Does prior urethral manipulation affect the outcome of urethroplasty?

PubMed Central

Mehmood, Shahbaz; Alsulaiman, Omer Abdulaziz; Al Taweel, Waleed Mohammad

2018-01-01

Purpose: We present our success rate and complications of delayed anastomotic urethroplasty (DAU) in patients with post-traumatic posterior urethral injury. Materials and Methods: This was a retrospective study of patients aged ≥17 years that underwent DAU for post-traumatic posterior urethral injury during 2010–2014. Stricture length was measured by ascending and descending urethrogram. Success of procedure was considered when the patient was free of stricture-ralated obstruction and needed no further intervention. Primary group includes patients who underwent first time delayed urethroplasty while secondary group included patients who had some sort of urethral manipulation in local hospital. Results were analyzed using unpaired t-test, Chi-square test, binary logistic regression, Kaplan–Meier curves, and log-rank test. Results: Of the 80 male patients, 73 (91.25%) patients underwent primary DAU while 7 (8.75%) patients had secondary DAU. Median age, stricture length, and follow-up were 27.0 ± 12.7, 1.6 ± 0.9, and 3.2 ± 0.9, respectively. Overall, success rate was 83.75% while success rate in primary group was 89.04% and secondary group was only 28.57% (P = 0.0059). Regarding ancillary maneuvers, urethral mobilization alone was done in 29 (36.25%) patients with success rate (72.41%), corporeal body separation in 36 (45%) patients with success rate (91.66%), inferior wedge pubectomy in 13 (16.25%) with success rate (84.61%), supracrural rerouting in 1 (1.25%) with success rate (100%), and abdominoperineal approach in 1 (1.25%) with success rate of 100% (P = 0.193). Patients who had prior urethral manipulation affect the outcome of definitive anastomotic urethroplasty. Conclusion: DAU has durable success rate with less morbidity. Ancillary elaborated maneuvers are frequently needed in patients with complex and elongated post-traumatic posterior urethral defect with successful outcome. PMID:29719330

Split liver transplantation: a reliable approach to expand donor pool.

PubMed

Yan, Ji-Qi; Becker, Thomas; Peng, Cheng-Hong; Li, Hong-Wei; Klempnauer, Juergen

2005-08-01

Orthotopic liver transplantation as a successful treatment of end-stage liver disease is hampered by a persistent lack of cadaveric organs. Split liver transplantation, which was first successfully performed by Medical School of Hannover in 1988, has become a mature surgical technique to expand the donor pool. Between 1993 and 1999, split liver transplantation activities have increased in Europe from 1.2% to 10.4% in all performed liver transplantations. Current data have strongly supported that the survival rate of patients after split liver transplantation is not significantly different from that of patients after whole-size orthotopic liver transplantation. The most important step of donor graft selection is surgeon's observation judged by the experience of individual transplant center. The paper aims to provide the guideline of donor selection, hepatic graft splitting, and recipient management as well. Medical School of Hannover has accumulated plentiful experience of split liver transplantation for more than 10 cases ever since 1998. Besides that, we also reviewed a variety of literatures from other famous European and American centers specialized in this field for many years. According to our experience combined with the view points of others, the donor should meet the following criteria as well: (1) age less than 50 years; (2) hemodynamics stable; (3) ICU less than 5 days; (4) Na less than 170 mmol/L or better if less than 150 mmol/L. In 1996 and 1997, the Hamburg group and the UCLA group separately introduced a breakthrough technique performing split liver transplantation in situ. Evidently, the in situ technique has been limited by prolonged time of donor organ procurement, coordination with other organ procurement teams, and even extra burden on donor hospital. Some groups, therefore, have restored the ex situ or bench splitting technique, and fortunately the transplant outcomes of the ex situ technique are equivalent to those of the in situ one. Recently some new techniques have been introduced to split the liver for two adult patients, including the split-cava technique. It is clear that the most important factor for determining the prognosis of the patient is the time of receiving liver transplantation, not the type of liver transplantation. We still need to pay close attention to the graft to recipient weight ratio (GRWR) and the UNOS classification or MELD score before the patient is subjected to split liver transplantation.

Successful outpatient graded administration of trimethoprim-sulfamethoxazole in patients without HIV and with a history of sulfonamide adverse drug reaction.

PubMed

Pyle, Regan C; Butterfield, Joseph H; Volcheck, Gerald W; Podjasek, Jenna C; Rank, Matthew A; Li, James T C; Harish, Amitha; Poe, Kimberly L; Park, Miguel A

2014-01-01

The outcomes of trimethoprim-sulfamethoxazole (TMP-SMX) desensitization have been widely reported in the HIV literature but less so in the non-HIV literature. To evaluate the safety and efficacy of graded administration of TMP-SMX in patients without HIV and with a history of TMP-SMX adverse drug reaction (ADR). A retrospective chart review, 2004-2012, of all the patients without HIV seen in the Division of Allergic Diseases and with a history of TMP-SMX ADR who underwent outpatient graded administration of TMP-SMX was conducted. The medical record was reviewed for age, sex, details of the initial ADR to TMP-SMX, an indication for TMP-SMX administration, and outcome. Patients also were contacted by telephone, and medical records were reviewed to determine long-term outcomes. Seventy-two patients (46 women [64%]; mean [SD] age, 57.7 ± 13.89 years]) were included. The most common patient-reported reactions to TMP-SMX were rash 39 (54%), and hives 9 (13%). TMP-SMX administration was needed for the following indications: prophylaxis (62 [86%]) and treatment of infection (10 [14%]). Forty-three of the patients (60%) underwent a 1-day TMP-SMX administration protocol. Thirty-five of the 43 (81%) underwent a 6-step (90 minutes to 6 hours) protocol and 7 of the 43 (16%) underwent a novel 14-step TMP-SMX protocol. Twenty-nine (40%) underwent a >1-day TMP-SMX administration protocol. Our overall success rate was 90% (mean duration of 11 months). Ninety-eight percent of the patients successfully completed a 1-day graded administration protocol, and 76% successfully completed a >1-day protocol. TMP-SMX was stopped in 8 patients because of the ADR. We report the largest case series of successful outpatient graded administration of TMP-SMX with both 1-day and >1-day protocols, which have shown to be safe and well tolerated in patients without HIV and with a history of sulfonamide ADR. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model.

PubMed

Malviya, Gaurav; Nayak, Tapan; Gerdes, Christian; Dierckx, Rudi A J O; Signore, Alberto; de Vries, Erik F J

2016-04-04

A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice, radiolabeled NK cells were retained in the lung tumor lesions up to 72 h p.i. without tumor regression. In tumor-bearing mice that were only irradiated but did not receive radiolabeled murine NK cells, a high tumor burden was observed at 72 h p.i., which indicates that irradiation in combination with murine NK cell allocation, but not irradiation alone, induced a remarkable antitumor effect in the orthotopic A549 lung tumor bearing mouse model. In conclusion, we describe a method to evaluate murine NK cell trafficking and biodistribution, which can be used to determine potential effects of immune-mediated therapeutic agents on NK cell biodistribution.

Outcomes of endonasal endoscopic dacryocystorhinostomy after maxillectomy in patients with paranasal sinus and skull base tumors.

PubMed

Abu-Ghanem, Sara; Ben-Cnaan, Ran; Leibovitch, Igal; Horowitz, Gilad; Fishman, Gadi; Fliss, Dan M; Abergel, Avraham

2014-06-01

Maxillectomy followed by radiotherapy and/or chemotherapy can result in lacrimal blockage and the need for subsequent dacryocystorhinostomy (DCR). Endonasal endoscopic DCR, as opposed to external DCR, allows better accuracy and leaves no scar. To date no report was published regarding the results of endoscopic DCR in these patients. The current study presents a retrospective review of all patients with paranasal and skull base tumors who developed nasolacrimal duct blockage after ablative maxillectomy with or without radiotherapy and/or chemotherapy and underwent endonasal endoscopic DCR between January 2006 and October 2012 in a tertiary reference medical center. According to our results, ten patients underwent 11 subsequent endonasal endoscopic DCR. There were 6 men and 4 women with a median age of 55 years (range, 19-81 years); four suffered from benign tumors and six had malignant tumors. All underwent maxillectomy. Six received high-dose radiotherapy. Time interval between primary ablative surgery and endonasal endoscopic DCR was 18 months (range, 7-118 months). Silicone stents were removed after median period of 11 weeks (range, 1-57 weeks). Nine out of ten patients experienced symptomatic improvement following one endonasal endoscopic DCR. One patient had recurrent epiphora and underwent a successful endonasal endoscopic revision DCR. In conclusion, endonasal endoscopic DCR in patients with paranasal and skull base tumors, who previously underwent maxillectomy, is generally successful and not associated with a high rate of complications or failure. Moreover, our findings may suggest that silicone stents can be removed shortly after the operation with high success rate.

Fast track vaginal surgery.

PubMed

Ottesen, Marianne; Sørensen, Mette; Rasmussen, Yvonne; Smidt-Jensen, Steen; Kehlet, Henrik; Ottesen, Bent

2002-02-01

Our aim was to describe the need for postoperative hospitalization after vaginal surgery for utero-vaginal prolapse with well-defined charts for postoperative care. A prospective, descriptive study. Consecutive women admitted for first-time vaginal surgery for utero-vaginal prolapse at a public university hospital in Copenhagen, Denmark, underwent surgery and postoperative care in a fast track setting from September 15, 1999 to June 15 2000. A multimodal rehabilitation model with emphasis on information, standardized general anesthesia, reduced surgical distress, optimized pain-relief, early oral nutrition and ambulation, minimal use of indwelling catheter and vaginal packing. Postoperative hospital stay, complications, re-admission, success rate, patients' satisfaction and acceptability. Forty-one women with a median age of 69 years (range, 44-88 years) were included. All underwent anterior and/or posterior vaginal repair. Nineteen (46.3%) underwent vaginal hysterectomy, and eight (19.5%) underwent the Manchester procedure. Postoperative hospital stay was median 24 hr. Only three (7.3%) were discharged later than 48 hr. No re-admissions occurred. The most frequent complications were urinary retention exceeding 450 ml, and urinary tract infection (12.2%, and 9.8%, respectively). Short-term success rate was 97.6%. Patients' satisfaction rates were 85.4-95.1%. The median score of acceptability was 10 on a 0-10 points scale. The need for postoperative hospitalization was median 24 hr after vaginal surgery in a fast track setting, independently of the complexity of the procedure performed. Short-term success rate, satisfaction rates, and acceptability were all excellent. Follow up has been established to evaluate long-term success rates and recurrence.

Safety and efficacy of self-expandable metal stents for obstructive proximal and distal large bowel cancer.

PubMed

Mitra, V; Hu, M; Majumdar, D; Krishnan, V; Chaudhury, B; Hancock, J; Dwarakanath, D

2017-03-01

Self-expandable metal stents are often used to treat obstructive large bowel cancers. This study assessed the safety and efficacy of colonic stent insertion carried out in a district general hospital. Methods A retrospective review was carried out between 1 January 2007 and 28 February 2014 to identify patients who underwent stent insertion for malignant colorectal obstruction. Results Seventy-five patients (median age 75.2 years, 70.6% male) with primary colorectal cancer underwent stent insertion - 53 underwent semi-elective self-expanded metal stent insertion (for subacute bowel obstruction) and 22 had emergency stent inserted (for acute bowel obstruction). The majority (88%) had self-expanded metal stents inserted for palliation. Technical and clinical success rates were 98.7% and 91.2%, respectively. One patient had stent-related perforation; there was no procedure-related mortality. Conclusion This study shows that self-expanded metal stent insertion in malignant colorectal obstruction is safe and effective and can be successfully delivered in a district general hospital with high technical and clinical success rates.

Long term outcomes of cardiac transplant for immunoglobulin light chain amyloidosis: The Mayo Clinic experience

PubMed Central

Grogan, Martha; Gertz, Morie; McCurdy, Arleigh; Roeker, Lindsey; Kyle, Robert; Kushwaha, Sudhir; Daly, Richard; Dearani, Joseph; Rodeheffer, Richard; Frantz, Robert; Lacy, Martha; Hayman, Suzanne; McGregor, Christopher; Edwards, Brooks; Dispenzieri, Angela

2016-01-01

AIM: To determine the outcome of orthotopic heart transplantation (OHT) in immunoglobulin light chain (AL) amyloidosis. METHODS: The medical records of patients with AL who underwent orthotopic heart transplantation at the Mayo Clinic in Rochester Minnesota from 1992 to 2011 were reviewed. Patients met at least one of the following at: New York Heart Association class IV heart failure, ventricular thickness > 15 mm, ejection fraction < 40%. Selection guidelines for heart transplant included age < 60 years, absence of multiple myeloma and significant extra-cardiac organ involvement. Baseline characteristics including age, gender, organ involvement, and New York Heart Association functional class were recorded. Laboratory data, waiting time until heart transplant, and type of treatment of the underlying plasma cell disorder were recorded. Survival from the time of OHT was calculated using Kaplan-Meier survival curves. Survival of patients undergoing OHT for AL was compared to that of non-amyloid patients undergoing OHT during the same time period. RESULTS: Twenty-three patients (median age 53 years) with AL received OHT. There were no deaths in the immediate perioperative period. Twenty patients have died post OHT. For the entire cohort, the median overall survival was 3.5 years (95%CI: 1.2, 8.2 years). The 1-year survival post OHT was 77%, the 2-year survival 65%, and the 5-year survival 43%. The 5-year survival for non-amyloid patients undergoing OHT during the same era was 85%. Progressive amyloidosis contributed to death in twelve patients. Of those without evidence of progressive amyloidosis, the cause of death included complications of autologous hematopoietic stem cell transplantation for 3 patients, post-transplant lymphoproliferative disorder for 2 patients; and for the remaining one death was related to each of the following causes: acute rejection; cardiac vasculopathy; metastatic melanoma; myelodysplastic syndrome; and unknown. Eight patients had rejection at a median of 1.8 mo post OHT (range 0.4 to 4.9 mo); only one patient died of rejection. Median survival of seven patients who achieved a complete hematologic response to either chemotherapy or autologous hematopoietic stem cell transplantation was 10.8 years. CONCLUSION: Our data demonstrate that long term survival after heart transplant is feasible in AL patients with limited extra-cardiac involvement who achieve complete hematologic response. PMID:27358783

Predictive Value of Serum Creatinine, Blood Urea Nitrogen, Uric Acid, and β2-Microglobulin in the Evaluation of Acute Kidney Injury after Orthotopic Liver Transplantation.

PubMed

Lu, Hai-Yang; Ning, Xin-Yu; Chen, Ying-Qi; Han, Shu-Jun; Chi, Ping; Zhu, Sai-Nan; Yue, Yun

2018-05-05

As a major complication after orthotopic liver transplantation (OLT), the occurrence of acute kidney injury (AKI) is frequently defined by serum creatinine (Cr); however, the accuracy of commonly used blood urea nitrogen (BUN), uric acid (UA), and β 2 -microglobulin (β 2 -MG) remains to be explored. This retrospective study compared the accuracy of these parameters for post-OLT AKI evaluation. Patients who underwent OLT in three centers between July 2003 and December 2013 were enrolled. The postoperative AKI group was diagnosed by the Kidney Disease Improving Global Outcomes (KDIGO) criteria and classified by stage. Measurement data were analyzed using the t-test or Wilcoxon rank-sum test; enumerated data were analyzed using the Chi-square test or Fisher's exact test. Diagnostic reliability and predictive accuracy were evaluated using receiver operating characteristic (ROC) curve analysis. This study excluded 976 cases and analyzed 697 patients (578 men and 119 women); the post-OLT AKI incidence was 0.409. Compared with the no-AKI group, the AKI group showed very significant differences in Model for End-stage Liver Disease score (14.74 ± 9.91 vs. 11.07 ± 9.54, Z = 5.404; P < 0.001), hepatic encephalopathy (45 [15.8%] vs. 30 [7.3%], χ 2 = 12.699; P < 0.001), hemofiltration (28 [9.8%] vs. 0 [0.0%], χ 2 = 42.171; P < 0.001), and 28-day mortality (23 [8.1%] vs. 9 [2.2%], χ 2 = 13.323; P <0.001). Moreover, mean values of Cr, BUN, UA, and β 2 -MG in the AKI group differed significantly at postoperative days 1, 3, and 7 (all P < 0.001). ROC curve area was 0.847 of Cr for the detection of AKI Stage 1 (sensitivity 80.1%, specificity 75.7%, cutoff value 88.23 μmol/L), 0.916 for Stage 2 (sensitivity 87.6%, specificity 82.6%, cutoff value 99.9 μmol/L), and 0.972 for Stage 3 (sensitivity 94.1%, specificity 88.2%, cutoff value 122.90 μmol/L). The sensitivity and specificity of serum Cr might be a high-value indicator for the diagnosis and grading of post-OLT AKI.

Ureteral stenting can be a negative predictor for successful outcome following shock wave lithotripsy in patients with ureteral stones.

PubMed

Kang, Dong Hyuk; Cho, Kang Su; Ham, Won Sik; Chung, Doo Yong; Kwon, Jong Kyou; Choi, Young Deuk; Lee, Joo Yong

2016-11-01

To evaluate ureteral stenting as a negative predictive factor influencing ureteral stone clearance and to estimate the probability of one-session success in shock wave lithotripsy (SWL) patients with a ureteral stone. We retrospectively reviewed the medical records of 1,651 patients who underwent their first SWL. Among these patients, 680 had a ureteral stone measuring 4-20 mm and were thus eligible for our study. The 57 patients who underwent ureteral stenting during SWL were identified. Maximal stone length (MSL), mean stone density (MSD), skin-to-stone distance (SSD), and stone heterogeneity index (SHI) were determined by pre-SWL noncontrast computed tomography. After propensity score matching, 399 patients were extracted from the total patient cohort. There were no significant differences between stenting and stentless groups after matching, except for a higher one-session success rate in the stentless group (78.6% vs. 49.1%, p=0.026). In multivariate analysis, shorter MSL, lower MSD, higher SHI, and absence of a stent were positive predictors for one-session success in patients who underwent SWL. Using cutoff values of MSL and MSD obtained from receiver operator curve analysis, in patients with a lower MSD (≤784 HU), the success rate was lower in those with a stent (61.1%) than in those without (83.5%) (p=0.001). However, in patients with a higher MSL (>10 mm), the success rate was lower in those with a stent (23.6%) than in those without (52.2%) (p=0.002). Ureteral stenting during SWL was a negative predictor of one-session success in patients with a ureteral stone.

Benefits and limitations of multimodality imaging in the diagnosis of a primary cardiac lymphoma.

PubMed

Nijjar, Prabhjot Singh; Masri, Sofia Carolina; Tamene, Ashenafi; Kassahun, Helina; Liao, Kenneth; Valeti, Uma

2014-12-01

Primary cardiac tumors are far rarer than tumors metastatic to the heart. Angiosarcoma is the primary cardiac neoplasm most frequently detected; lymphomas constitute only 1% of primary cardiac tumors. We present the case of a 55-year-old woman with a recently diagnosed intracardiac mass who was referred to our institution for consideration of urgent orthotopic heart transplantation. Initial images suggested an angiosarcoma; however, a biopsy specimen of the mass was diagnostic for diffuse large B-cell lymphoma. The patient underwent chemotherapy rather than surgery, and she was asymptomatic 34 months later. We use our patient's case to discuss the benefits and limitations of multiple imaging methods in the evaluation of cardiac masses. Certain features revealed by computed tomography, cardiac magnetic resonance, and positron emission tomography can suggest a diagnosis of angiosarcoma rather than lymphoma. Cardiac magnetic resonance and positron emission tomography enable reliable distinction between benign and malignant tumors; however, the characteristics of different malignant tumors can overlap. Despite the great usefulness of multiple imaging methods for timely diagnosis, defining the extent of spread and the hemodynamic impact, and monitoring responses to treatment, we think that biopsy analysis is still warranted in order to obtain a correct histologic diagnosis in cases of suspected malignant cardiac tumors.

Alkaline phosphatase: the next independent predictor of the poor 90-day outcome in alcoholic hepatitis.

PubMed

Kasztelan-Szczerbinska, Beata; Slomka, Maria; Celinski, Krzysztof; Szczerbinski, Mariusz

2013-01-01

Determination of risk factors relevant to 90-day prognosis in AH. Comparison of the conventional prognostic models such as Maddrey's modified discriminant function (mDF) and Child-Pugh-Turcotte (CPT) score with newer ones: the Glasgow Alcoholic Hepatitis Score (GAHS); Age, Bilirubin, INR, Creatinine (ABIC) score, Model for End-Stage Liver Disease (MELD), and MELD-Na in the death prediction. The clinical and laboratory variables obtained at admission were assessed. The mDF, CPT, GAHS, ABIC, MELD, and MELD-Na scores' different areas under the curve (AUCs) and the best threshold values were compared. Logistic regression was used to assess predictors of the 90-day outcome. One hundred sixteen pts fulfilled the inclusion criteria. Twenty (17.4%) pts died and one underwent orthotopic liver transplantation (OLT) within 90 days of follow-up. No statistically significant differences in the models' performances were found. Multivariate logistic regression identified CPT score, alkaline phosphatase (AP) level higher than 1.5 times the upper limit of normal (ULN), and corticosteroids (CS) nonresponse as independent predictors of mortality. The CPT score, AP > 1.5 ULN, and the CS nonresponse had an independent impact on the 90-day survival in AH. Accuracy of all studied scoring systems was comparable.

Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.

PubMed

Kohmoto, J; Nakao, A; Stolz, D B; Kaizu, T; Tsung, A; Ikeda, A; Shimizu, H; Takahashi, T; Tomiyama, K; Sugimoto, R; Choi, A M K; Billiar, T R; Murase, N; McCurry, K R

2007-10-01

Carbon monoxide (CO) provides protection against oxidative stress via anti-inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naïve lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use.

The effect of donor treatment with hydrogen on lung allograft function in rats.

PubMed

Kawamura, Tomohiro; Huang, Chien-Sheng; Peng, Ximei; Masutani, Kosuke; Shigemura, Norihisa; Billiar, Timothy R; Okumura, Meinoshin; Toyoda, Yoshiya; Nakao, Atsunori

2011-08-01

Because inhaled hydrogen provides potent anti-inflammatory and antiapoptotic effects against acute lung injury, we hypothesized that treatment of organ donors with inhaled hydrogen during mechanical ventilation would decrease graft injury after lung transplantation. Orthotopic left lung transplants were performed using a fully allogeneic Lewis to Brown Norway rat model. The donors were exposed to mechanical ventilation with 98% oxygen plus 2% nitrogen or 2% hydrogen for 3 h prior to harvest, and the lung grafts underwent 4 h of cold storage in Perfadex (Vitrolife, Göteborg, Sweden). The graft function, histomorphologic changes, and inflammatory reactions were assessed. The combination of mechanical ventilation and prolonged cold ischemia resulted in marked deterioration of gas exchange when the donors were ventilated with 2% nitrogen/98% oxygen, which was accompanied by upregulation of proinflammatory cytokines and proapoptotic molecules. These lung injuries were attenuated significantly by ventilation with 2% hydrogen. Inhaled hydrogen induced heme oxygenase-1, an antioxidant enzyme, in the lung grafts prior to implantation, which might contribute to protective effects afforded by hydrogen. Preloaded hydrogen gas during ventilation prior to organ procurement protected lung grafts effectively from ischemia/reperfusion-induced injury in a rat lung transplantation model. Copyright © 2011 Mosby, Inc. All rights reserved.

Initial Poor Function and Primary Nonfunction in Deceased-Donor Orthotopic Liver Transplantation Maintaining Short Cold Ischemic Time.

PubMed

Das, Somak; Swain, Sudeepta Kumar; Addala, Pavan Kumar; Balasubramaniam, Ramakrishnan; Gopakumar, C V; Zirpe, Dinesh; Renganathan, Kirubakaran; Kollu, Harsha; Patel, Darshan; Vibhute, Bipin B; Rao, Prashantha S; Krishnan, Elankumaran; Gopasetty, Mahesh; Khakhar, Anand K; Vaidya, Anil; Ramamurthy, Anand

2016-12-01

Nations with emerging deceased-donor liver transplantation programs, such as India, face problems associated with poor donor maintenance. Cold ischemic time (CIT) is typically maintained short by matching donor organ recovery and recipient hepatectomy to achieve maximum favorable outcome. We analyzed different extended criteria donor factors including donor acidosis, which may act as a surrogate marker of poor donor maintenance, to quantify the risk of primary nonfunction (PNF) or initial poor function (IPF). A single-center retrospective outcome analysis of prospectively collected data of patients undergoing deceased-donor liver transplantation over 2 years to determine the impact of different extended criteria donor factors on IPF and PNF. From March 2013 to February 2015, a total of 84 patients underwent deceased-donor liver transplantation. None developed PNF. Thirteen (15.5%) patients developed IPF. Graft macrosteatosis and donor acidosis were only related to IPF ( P = .002 and P = .032, respectively). Cold ischemic time was maintained short (81 cases ≤8 hours, maximum 11 hours) in all cases. Poor donor maintenance as evidenced by donor acidosis and graft macrosteatosis had significant impact in developing IPF when CIT is kept short. Similar study with larger sample size is required to establish extended criteria cutoff values.

Pericardial constriction after cardiac transplantation.

PubMed

Bansal, Ramesh; Perez, Leandro; Razzouk, Anees; Wang, Nan; Bailey, Leonard

2010-03-01

In this study we present a series of 5 cases that developed constrictive pericarditis after orthotopic heart transplantation. All 5 patients had pericardial effusion of non-infectious etiology in the early post-transplant period. They subsequently presented with heart failure unresponsive to standard medical management. The diagnosis was made by comprehensive echo-Doppler studies. Findings were confirmed at surgical inspection and complete pericardiectomy led to improvement in hemodynamics in 4 patients. One patient had relief from constriction but died of non-cardiac complications. One patient with constriction has been re-listed for transplantation due to intermittent heart block and associated cardiac allograft vasculopathy. Early diagnosis of pericardial constriction after orthotopic heart transplantation requires a high index of clinical suspicion and optimal use of Doppler echocardiography. Early diagnosis and timely surgical pericardiectomy may correct this condition entirely and result in satisfactory long-term results.

IL2RG, identified as overexpressed by RNA-seq profiling of pancreatic intraepithelial neoplasia, mediates pancreatic cancer growth

PubMed Central

Ayars, Michael; O’Sullivan, Eileen; Macgregor-Das, Anne; Shindo, Koji; Kim, Haeryoung; Borges, Michael; Yu, Jun; Hruban, Ralph H.; Goggins, Michael

2017-01-01

Pancreatic ductal adenocarcinoma evolves from precursor lesions, the most common of which is pancreatic intraepithelial neoplasia (PanIN). We performed RNA-sequencing analysis of laser capture microdissected PanINs and normal pancreatic duct cells to identify differentially expressed genes between PanINs and normal pancreatic duct, and between low-grade and high-grade PanINs. One of the most highly overexpressed transcripts identified in PanIN is interleukin-2 receptor subunit gamma (IL2RG) encoding the common gamma chain, IL2Rγ. CRISPR-mediated knockout of IL2RG in orthotopically implanted pancreatic cancer cells resulted in attenuated tumor growth in mice and reduced JAK3 expression in orthotopic tumors. These results indicate that IL2Rγ/JAK3 signaling contributes to pancreatic cancer cell growth in vivo. PMID:29137350

Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3

PubMed Central

Subramaniam, Aruljothi; Shanmugam, Muthu K; Ong, Tina H; Li, Feng; Perumal, Ekambaram; Chen, Luxi; Vali, Shireen; Abbasi, Taher; Kapoor, Shweta; Ahn, Kwang Seok; Kumar, Alan Prem; Hui, Kam M; Sethi, Gautam

2013-01-01

BACKGROUND AND PURPOSE Aberrant activation of STAT3 is frequently encountered and promotes proliferation, survival, metastasis and angiogenesis in hepatocellular carcinoma (HCC). Here, we have investigated whether emodin mediates its effect through interference with the STAT3 activation pathway in HCC. EXPERIMENTAL APPROACH The effect of emodin on STAT3 activation, associated protein kinases and apoptosis was investigated using various HCC cell lines. Additionally, we also used a predictive tumour technology to analyse the effects of emodin. The in vivo effects of emodin were assessed in an orthotopic mouse model of HCC. KEY RESULTS Emodin suppressed STAT3 activation in a dose- and time-dependent manner in HCC cells, mediated by the modulation of activation of upstream kinases c-Src, JAK1 and JAK2. Vanadate treatment reversed emodin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase and emodin induced the expression of the tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, silencing of the SHP-1 gene by siRNA abolished the ability of emodin to inhibit STAT3 activation. Finally, when administered i.p., emodin inhibited the growth of human HCC orthotopic tumours in male athymic nu/nu mice and STAT3 activation in tumour tissues. CONCLUSIONS AND IMPLICATIONS Emodin mediated its effects predominantly through inhibition of the STAT3 signalling cascade and thus has a particular potential for the treatment of cancers expressing constitutively activated STAT3. PMID:23848338

3-Bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth

PubMed Central

WANG, TING-AN; ZHANG, XIAO-DONG; GUO, XING-YU; XIAN, SHU-LIN; LU, YUN-FEI

2016-01-01

Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT. PMID:26708213

Nanoparticle-enabled, image-guided treatment planning of target specific RNAi therapeutics in an orthotopic prostate cancer model.

PubMed

Lin, Qiaoya; Jin, Cheng S; Huang, Huang; Ding, Lili; Zhang, Zhihong; Chen, Juan; Zheng, Gang

2014-08-13

The abilities to deliver siRNA to its intended action site and assess the delivery efficiency are challenges for current RNAi therapy, where effective siRNA delivery will join force with patient genetic profiling to achieve optimal treatment outcome. Imaging could become a critical enabler to maximize RNAi efficacy in the context of tracking siRNA delivery, rational dosimetry and treatment planning. Several imaging modalities have been used to visualize nanoparticle-based siRNA delivery but rarely did they guide treatment planning. We report a multimodal theranostic lipid-nanoparticle, HPPS(NIR)-chol-siRNA, which has a near-infrared (NIR) fluorescent core, enveloped by phospholipid monolayer, intercalated with siRNA payloads, and constrained by apoA-I mimetic peptides to give ultra-small particle size (<30 nm). Using fluorescence imaging, we demonstrated its cytosolic delivery capability for both NIR-core and dye-labeled siRNAs and its structural integrity in mice through intravenous administration, validating the usefulness of NIR-core as imaging surrogate for non-labeled therapeutic siRNAs. Next, we validated the targeting specificity of HPPS(NIR)-chol-siRNA to orthotopic tumor using sequential four-steps (in vivo, in situ, ex vivo and frozen-tissue) fluorescence imaging. The image co-registration of computed tomography and fluorescence molecular tomography enabled non-invasive assessment and treatment planning of siRNA delivery into the orthotopic tumor, achieving efficacious RNAi therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

PubMed

Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

2015-07-01

Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

PubMed

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

PubMed Central

Jandial, Rahul; Neman, Josh; Tamae, Daniel; Kowolik, Claudia M.; Wuenschell, Gerald E.; Ciminera, Alexandra K.; De Jesus, Luis R.; Ouyang, Ching; Chen, Mike Y.

2018-01-01

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)2) increased levels of the DNA-AGE N2-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. PMID:29385725

Curative potential of GM-CSF-secreting tumor cell vaccines on established orthotopic liver tumors: mechanisms for the superior antitumor activity of live tumor cell vaccines.

PubMed

Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa

2004-01-01

In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel

Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer.

PubMed

Hiroshima, Yukihiko; Maawy, Ali A; Katz, Matthew H G; Fleming, Jason B; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2015-03-01

Patient-derived orthotopic xenograft (PDOX) nude-mouse models replicate the behavior of clinical cancer, including metastasis. The objective of the study was to determine the efficacy of zoledronic acid (ZA) on metastasis of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of pancreatic cancer. In the present study, we examined the efficacy of ZA on pancreatic cancer growth and metastasis in a PDOX nude-mouse model. ZA monotherapy did not significantly suppress primary tumor growth. However, the primary tumor weight of gemcitabine (GEM) and combination GEM + ZA-treated mice was significantly decreased compared to the control group (GEM: P = 0.003; GEM + ZA: P = 0.002). The primary tumor weight of GEM + ZA-treated mice was significantly decreased compared to GEM-treated mice (P = 0.016). The metastasis weight decreased in ZA- or GEM-treated mice compared to the control group (ZA: P = 0.009; GEM: P = 0.007. No metastasis was detected in combination GEM + ZA-treated mice compared to the control group (GEM + ZA; P = 0.005). The results of the present study indicate that ZA can selectively target metastasis in a pancreatic cancer PDOX model and that the combination of ZA and GEM should be evaluated clinically in the near future for this highly treatment-resistant disease. © 2014 Wiley Periodicals, Inc.

Presence of transient hydronephrosis immediately after surgery has a limited influence on renal function 1 year after ileal neobladder construction.

PubMed

Narita, Takuma; Hatakeyama, Shingo; Koie, Takuya; Hosogoe, Shogo; Matsumoto, Teppei; Soma, Osamu; Yamamoto, Hayato; Yoneyama, Tohru; Tobisawa, Yuki; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Ohyama, Chikara

2017-08-31

Urinary tract obstruction and postoperative hydronephrosis are risk factor for renal function deterioration after orthotopic ileal neobladder construction. However, reports of relationship between transient hydronephrosis and renal function are limited. We assess the influence of postoperative transient hydronephrosis on renal function in patients with orthotopic ileal neobladder construction. Between January 2006 and June 2013, we performed radical cystectomy in 164 patients, and 101 received orthotopic ileal neobladder construction. This study included data available from 64 patients with 128 renal units who were enrolled retrospectively. The hydronephrosis grade of each renal unit scored 0-4. The patients were divided into 4 groups according to the grade of hydronephrosis: control, low, intermediate, and high. The grade of postoperative hydronephrosis was compared with renal function 1 month and 1 year after surgery. There were no significant differences in renal function before surgery between groups. One month after surgery, the presence of hydronephrosis was significantly associated with decreased renal function. However, 1 year after urinary diversion hydronephrosis grades were improved significantly, and renal function was comparable between groups. Postoperative hydronephrosis at 1 month had no significant influence on renal function 1 year after ileal neobladder construction. Limitations include retrospective design, short follow-up periods, and a sample composition. The presence of transient hydronephrosis immediately after surgery may have limited influence on renal function 1 year after ileal neobladder construction.

3-bromopyruvate and sodium citrate target glycolysis, suppress survivin, and induce mitochondrial-mediated apoptosis in gastric cancer cells and inhibit gastric orthotopic transplantation tumor growth.

PubMed

Wang, Ting-An; Zhang, Xiao-Dong; Guo, Xing-Yu; Xian, Shu-Lin; Lu, Yun-Fei

2016-03-01

Glycolysis is the primary method utilized by cancer cells to produce the energy (adenosine triphosphate, ATP) required for cell proliferation. Therefore, inhibition of glycolysis may inhibit tumor growth. We previously found that both 3-bromopyruvate (3-BrPA) and sodium citrate (SCT) can inhibit glycolysis in vitro; however, the underlying inhibitory mechanisms remain unclear. In the present study, we used a human gastric cancer cell line (SGC-7901) and an orthotopic transplantation tumor model in nude mice to explore the specific mechanisms of 3-BrPA and SCT. We found that both 3-BrPA and SCT effectively suppressed cancer cell proliferation, arrested the cell cycle, induced apoptosis, and decreased the production of lactate and ATP. 3-BrPA significantly reduced the glycolytic enzyme hexokinase activity, while SCT selectively inhibited phosphofructokinase-1 activity. Furthermore, 3-BrPA and SCT upregulated the expression of pro-apoptotic proteins (Bax, cytochrome c, and cleaved caspase-3) and downregulated the expression of anti-apoptotic proteins (Bcl-2 and survivin). Finally, our animal model of gastric cancer indicated that intraperitoneal injection of 3-BrPA and SCT suppressed orthotopic transplantation tumor growth and induced tumor apoptosis. Taken together, these results suggest that 3-BrPA and SCT selectively suppress glycolytic enzymes, decrease ATP production, induce mitochondrial-mediated apoptosis, downregulate survivin, and inhibit tumor growth. Moreover, an intraperitoneal injection is an effective form of administration of 3-BrPA and SCT.

[Effects of Rhizoma kaempferiae volatile oil on tumor growth and cell cycle of MKN-45 human gastric cancer cells orthotopically transplanted in nude mice].

PubMed

Xiao, Yan; Wei, Pin-Kang; Li, Jun; Shi, Jun; Yu, Zhi-Hong; Lin, Hui-Ming

2006-07-01

To evaluate the effects of Rhizoma kaempferiae volatile oil on tumor growth and cell cycle of MKN-45 human gastric cancer cells orthotopically transplanted in nude mice. One hundred and five nude mice orthotopically transplanted with MKN-45 human gastric cancer cells were randomly divided into seven groups: untreated group, normal saline-treated group, dissolvant-treated group, cyclophosphamide (CTX)-treated group and high-, medium-, and low-dose Rhizoma kaempferiae volatile oil-treated groups. Corresponding interventions were implemented in each group except the untreated group. The antitumor effects in vivo were evaluated. Cell cycle distribution and apoptosis of MKN-45 human gastric cancer cells were determined by using flow cytometry (FCM). The ultrastructure of MKN-45 gastric cancer cells was observed by a transmission electron microscope. In the high-, medium-, and low-dose Rhizoma kaempferiae volatile oil-treated groups, the growth inhibition rates of gastric cancer were 57.2%, 28.0% and 5.0% respectively, and the gastric cancer cells were arrested at G(0)/G(1) phase. This antitumor effect was dose-dependent. The apoptotic cells occurred more frequently in the high-dose Rhizoma kaempferiae volatile oil-treated group and the CTX-treated group than those in the medium- and low-dose Rhizoma kaempferiae volatile oil-treated groups. The Rhizoma kaempferiae volatile oil is an effective composition for growth inhibition of gastric cancer, and its mechanism may be related to regulating the cell cycle and inducing apoptosis.

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model

PubMed Central

Higuchi, Tamami; Yokobori, Takehiko; Naito, Tomoharu; Kakinuma, Chihaya; Hagiwara, Shinji; Nishiyama, Masahiko; Asao, Takayuki

2018-01-01

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer. PMID:29435042

The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing's sarcoma with a FUS-ERG fusion and CDKN2A deletion: Direction for third-line patient therapy.

PubMed

Miyake, Kentaro; Murakami, Takashi; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Miyake, Masuyo; Li, Yunfeng; Nelson, Scott D; Dry, Sarah M; Bouvet, Michael; Elliott, Irmina A; Russell, Tara A; Singh, Arun S; Eckardt, Mark A; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2017-11-28

The aim of the present study was to determine the usefulness of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of a doxorubicin-resistant metastatic Ewing's sarcoma, with a unique combination of a FUS-ERG fusion and CDKN2A deletion, to identify effective drugs for third-line chemotherapy of the patient. Our previous study showed that cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors were effective on the Ewing's sarcoma PDOX, but not doxorubicin, similar to the patient's resistance to doxorubicin. The results of the previous PDOX study were successfully used for second-line therapy of the patiend. In the present study, the PDOX mice established with the Ewing's sarcoma in the right chest wall were randomized into 5 groups when the tumor volume reached 60 mm 3 : untreated control; gemcitabine combined with docetaxel (intraperitoneal [i.p.] injection, weekly, for 2 weeks); irinotecan combined with temozolomide (irinotecan: i.p. injection; temozolomide: oral administration, daily, for 2 weeks); pazopanib (oral administration, daily, for 2 weeks); yondelis (intravenous injection, weekly, for 2 weeks). All mice were sacrificed on day 15. Body weight and tumor volume were assessed 2 times per week. Tumor weight was measured after sacrifice. Irinotecan combined with temozolomide was the most effective regimen compared to the untreated control group (p=0.022). Gemcitabine combined with docetaxel was also effective (p=0.026). Pazopanib and yondelis did not have significant efficacy compared to the untreated control (p=0.130, p=0.818). These results could be obtained within two months after the physician's request and were used for third-line therapy of the patient.

Intracranial AAV-IFN-β gene therapy eliminates invasive xenograft glioblastoma and improves survival in orthotopic syngeneic murine model.

PubMed

GuhaSarkar, Dwijit; Neiswender, James; Su, Qin; Gao, Guangping; Sena-Esteves, Miguel

2017-02-01

The highly invasive property of glioblastoma (GBM) cells and genetic heterogeneity are largely responsible for tumor recurrence after the current standard-of-care treatment and thus a direct cause of death. Previously, we have shown that intracranial interferon-beta (IFN-β) gene therapy by locally administered adeno-associated viral vectors (AAV) successfully treats noninvasive orthotopic glioblastoma models. Here, we extend these findings by testing this approach in invasive human GBM xenograft and syngeneic mouse models. First, we show that a single intracranial injection of AAV encoding human IFN-β eliminates invasive human GBM8 tumors and promotes long-term survival. Next, we screened five AAV-IFN-β vectors with different promoters to drive safe expression of mouse IFN-β in the brain in the context of syngeneic GL261 tumors. Two AAV-IFN-β vectors were excluded due to safety concerns, but therapeutic studies with the other three vectors showed extensive tumor cell death, activation of microglia surrounding the tumors, and a 56% increase in median survival of the animals treated with AAV/P2-Int-mIFN-β vector. We also assessed the therapeutic effect of combining AAV-IFN-β therapy with temozolomide (TMZ). As TMZ affects DNA replication, an event that is crucial for second-strand DNA synthesis of single-stranded AAV vectors before active transcription, we tested two TMZ treatment regimens. Treatment with TMZ prior to AAV-IFN-β abrogated any benefit from the latter, while the reverse order of treatment doubled the median survival compared to controls. These studies demonstrate the therapeutic potential of intracranial AAV-IFN-β therapy in a highly migratory GBM model as well as in a syngeneic mouse model and that combination with TMZ is likely to enhance its antitumor potency. © 2016 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Evaluation of innate and adaptive immunity contributing to the antitumor effects of PD1 blockade in an orthotopic murine model of pancreatic cancer

PubMed Central

D'Alincourt Salazar, Marcela; Manuel, Edwin R.; Tsai, Weimin; D'Apuzzo, Massimo; Goldstein, Leanne; Blazar, Bruce R.; Diamond, Don J.

2016-01-01

ABSTRACT Despite the clinical success of anti-PD1 antibody (α-PD1) therapy, the immune mechanisms contributing to the antineoplastic response remain unclear. Here, we describe novel aspects of the immune response involved in α-PD1-induced antitumor effects using an orthotopic KrasG12D/p53R172H/Pdx1-Cre (KPC) model of pancreatic ductal adenocarcinoma (PDA). We found that positive therapeutic outcome involved both the innate and adaptive arms of the immune system. Adoptive transfer of total splenocytes after short-term (3 d) but not long-term (28 d) PD1 blockade significantly extended survival of non-treated tumor-bearing recipient mice. This protective effect appeared to be mostly mediated by T cells, as adoptive transfer of purified natural killer (NK) cells and/or granulocyte receptor 1 (Gr1)+ cells or splenocytes depleted of Gr1+ cells and NK cells did not exhibit transferrable antitumor activity following short-term PD1 blockade. Nevertheless, splenic and tumor-derived CD11b+Gr1+ cells and NK cells showed significant persistence of α-PD1 bound to these cells in the treated primary recipient mice. We observed that short-term inhibition of PD1 signaling modulated the profiles of multifunctional cytokines in the tumor immune-infiltrate, including downregulation of vascular endothelial growth factor A (VEGF-A). Altogether, the data suggest that systemic blockade of PD1 results in rapid modulation of antitumor immunity that differs in the tumor microenvironment (TME) when compared to the spleen. These results demonstrate a key role for early immune-mediated events in controlling tumor progression in response to α-PD1 treatment and warrant further investigation into the mechanisms governing responses to the therapy at the innate-adaptive immune interface. PMID:27471630

Synergistic Drug Combinations with a CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.

PubMed

Pikman, Yana; Alexe, Gabriela; Roti, Giovanni; Conway, Amy Saur; Furman, Andrew; Lee, Emily S; Place, Andrew E; Kim, Sunkyu; Saran, Chitra; Modiste, Rebecca; Weinstock, David M; Harris, Marian; Kung, Andrew L; Silverman, Lewis B; Stegmaier, Kimberly

2017-02-15

Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity. Results: We first determined that both NOTCH1 -mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012-24. ©2016 AACR See related commentary by Carroll et al., p. 873 . ©2016 American Association for Cancer Research.

Effect of p27 gene combined with Pientzehuang ([characters: see text]) on tumor growth in osteosarcoma-bearing nude mice.

PubMed

Ren, Shou-song; Yuan, Fang; Liu, Ying-hong; Zhou, Le-tian; Li, Jun

2015-11-01

To observe the effect of p27 gene recombinant adenovirus combined with Chinese medicine Pientzehuang ([characters: see text]) on the growth of xenografted human osteosarcoma in nude mice. Tissue transplantation was used to construct the orthotopic model of human osteosarcoma Saos-2 cell in nude mice. Thirty tumor-bearing nude mice were randomly divided into 5 groups with 6 mice in each group: blank control group (model of osteosarcoma), empty vector group (recombinant adeno-associated virus-multiple cloning site), Pientzehuang group, p27 gene group and combined treatment group (p27 gene combined with Pientzehuang). The effect of combined treatment on human osteosarcoma was analyzed through the tumor formation, tumor volume and inhibition rate of tumor growth. The expression of p27 was measured by immunohistochemical staining and Western blot. The orthotopic model of osteosarcoma in nude mice was successfully constructed. The general appearance of tumor-bearing nude mice in Pientzehuang and p27 gene groups was markedly improved compared with the blank control group; and in the combined treatment group it was significantly improved compared with the Pientzehuang and p27 gene groups. The tumor growth in the Pientzehuang and p27 gene groups was significantly inhibited compared with the blank control group P<0.05); while in the combined treatment group it was markedly inhibited compared with the Pientzehuang and p27 gene groups (P<0.05). The rates of tumor growth inhibition were 34.1%, 56.5% and 63.8% in the Pientzehuang, p27 gene and combined treatment groups, respectively. Meanwhile, the protein expression of p27 gene in the p27 gene group was significantly increased compared with the blank control group (P<0.05); and it was significantly increased in the combined treatment group compared with the p27 gene and Pientzehuang groups (P<0.05). p27 gene introduced by adenovirus combined with Pientzehuang can inhibit the growth of human osteosarcoma cell Saos-2 in nude mice.

Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer

PubMed Central

Schroeder, Barbara; Park, Cheol Hong; Chandra Mohan, KVP; Khurana, Ashwani; Corominas-Faja, Bruna; Cuyàs, Elisabet; Alarcón, Tomás; Kleer, Celina; Menendez, Javier A.; Lupu, Ruth

2016-01-01

The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies. PMID:27223424

The success rate of TED upper eyelid retraction reoperations.

PubMed

Golan, Shani; Rootman, Dan B; Goldberg, Robert A

2016-12-01

Although reoperation rates for upper lid retraction surgery for thyroid eye disease (TED) typically range between 8% and 23%, there is little literature describing the outcomes of these second operations. In this retrospective observational cohort study, all patients that underwent surgery for upper eyelid retraction over a 14-year period at a single institution were included. Cases were included if a second eyelid retraction surgery was performed during the study period. Success of surgery was defined as a marginal reflex distance (MRD1) of 2.5 to 4.5 mm in each eye and less than 1 mm difference in MRD1 between the eyes. Overcorrection and undercorrection were defined as above and below these bounds, respectively. 72 eyes in 49 patients were included in the study. The mean age was 56.6 (±11.5) years. By definition, all patients had at least 1 lid lengthening surgery for upper eyelid retraction, and at least 1 subsequent surgery. For this second surgery, 61 eyes (85%) underwent retraction surgery and 11 eyes (15%) underwent ptosis surgery. After this second operation, 31% were undercorrected and 33% were overcorrected. A third surgery was performed in 19 eyes (25%), 12 had surgery for residual retraction and 7 for ptosis. After the third operation 10% of eyes were under corrected and 11% were over corrected. Four patients underwent a fourth surgery: one for retraction and three for ptosis. Success was noted in 35% after the second surgery and 44% after the third. Surgical success in eyelid retraction surgery increases from a second to a third consecutive surgery, and residual asymmetry was roughly equally distributed between over- and undercorrection.

Transcatheter arterial embolization for traumatic mesenteric bleeding: a 15-year, single-center experience

PubMed Central

Shin, Jong Soo; Shin, Ji Hoon; Ko, Heung-Kyu; Kim, Jong Woo; Yoon, Hyun-Ki

2016-01-01

PURPOSE We aimed to assess the safety and effectiveness of transcatheter arterial embolization (TAE) for mesenteric bleeding following trauma. METHODS From 2001 to 2015, 12 patients were referred to our interventional unit for mesenteric bleeding following trauma, based on clinical decisions and computed tomography (CT) images. After excluding one patient with no bleeding focus and one patient who underwent emergency surgery, a total of 10 patients (male:female ratio, 9:1; mean age, 52.1 years) who underwent super selective TAE of visceral arteries were included in this study. Technical and clinical success, complications, and 30-day mortality rate were analyzed. RESULTS In 10 patients who underwent TAE, the types of trauma were motor vehicle collision (n=6), fall (n=2), assault (n=1), and penetrating injury (n=1), and the bleeding arteries were in the pancreaticoduodenal arterial arcade (n=4), jejunal artery (n=3), colic artery (n=2), and sigmoid artery (n=1). N-butyl-2-cyanoacrylate (NBCA) (n=2), microcoils (n=2), and combinations of NBCA, microcoils, or gelatin sponge particles (n=6) were used as embolic agents. Technical success was achieved in all 10 patients, with immediate cessation of bleeding. Clinical success rate was 90% (9/10), and all patients were discharged with no further treatment required for mesenteric bleeding. However, one patient showed rebleeding 10 days later and underwent repeated TAE with successful result. There were no TAE-related ischemic complications such as bowel infarction. The 30-day mortality rate was 0%. CONCLUSION Our clinical experience suggests that TAE used to control mesenteric bleeding following trauma is safe and effective as a minimally invasive alternative to surgery. PMID:27306658

Hysteroscopic tubal electrocoagulation versus laparoscopic tubal ligation for patients with hydrosalpinges undergoing in vitro fertilization.

PubMed

El-Mazny, Akmal; Abou-Salem, Nermeen; Hammam, Mohamed; Saber, Walid

2015-09-01

To investigate the use and success rate of hysteroscopic tubal electrocoagulation for the treatment of hydrosalpinx-related infertility among patients undergoing in vitro fertilization (IVF) who have laparoscopic contraindications. A prospective study was conducted among patients who had unilateral or bilateral hydrosalpinges identified on hysterosalpingography and vaginal ultrasonography, and who were undergoing IVF at a center in Cairo, Egypt, between January 1, 2013, and October 30, 2014. All patients who had contraindications for laparoscopy were scheduled for hysteroscopic tubal electrocoagulation (group 1); the other patients underwent laparoscopic tubal ligation (group 2). For all patients, hysterosalpingography was performed 3 months after their procedure to evaluate proximal tubal occlusion. Among 85 enrolled patients, 22 underwent hysteroscopic tubal electrocoagulation and 63 underwent laparoscopic tubal ligation. The procedure was successful in terms of tubal occlusion for 25 (93%) of 27 hydrosalpinges in group 1, and 78 (96%) of 81 hydrosalpinges in group 2 (P=0.597). No intraoperative or postoperative complications were reported. Hysteroscopic tubal electrocoagulation was found to be a successful treatment for hydrosalpinges before IVF when laparoscopy is contraindicated. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Feasibility, efficacy, and predictive factors for the technical success of endoscopic nasogallbladder drainage: a prospective study.

PubMed

Yane, Kei; Maguchi, Hiroyuki; Katanuma, Akio; Takahashi, Kuniyuki; Osanai, Manabu; Kin, Toshifumi; Takaki, Ryo; Matsumoto, Kazuyuki; Gon, Katsushige; Matsumori, Tomoaki; Tomonari, Akiko; Nojima, Masanori

2015-03-01

Several studies have shown the useful-ness of endoscopic nasogallbladder drainage (ENGBD) in patients with acute cholecystitis. However, the procedure is difficult, and factors that affect technical success have not yet been clarified. We conducted a prospective study to eval-uate the technical feasibility, efficacy, and predictive factors for the technical success of ENGBD in patients with acute cholecystitis. All patients with moderate or severe acute cholecystitis who were enrolled underwent ENGBD between April 2009 and April 2011. Patients with surgically altered anatomy or pancreatobiliary malignancies were ex-cluded. The primary outcomes included technical success, clinical success, and complications. Factors that could affect the technical success were also examined. Of the 27 patients who underwent ENGBD during the study period, technical success was achieved in 21 (78%) and clinical improvement was achieved in 20 (95%). Early complications were encountered in four patients (15%). Gallbladder wall thickness (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.08 to 2.47) and age (OR, 1.16; 95% CI, 1.00 to 1.35) were effective predictors of technical failure. ENGBD was effective in resolving acute cholecystitis; however, this modality was technically challenging and had a limited suc-cess rate. Because of technical difficulties, ENGBD should be reserved for limited indications. (Gut Liver, 2015;9239-246).

Is routine voiding cystourethrogram necessary following double hit for primary vesicoureteral reflux?

PubMed

Arlen, Angela M; Scherz, Hal C; Filimon, Eleonora; Leong, Traci; Kirsch, Andrew J

2015-02-01

Current AUA guidelines recommend voiding cystourethrogram (VCUG) following endoscopic treatment of vesicoureteral reflux (VUR). We evaluated the clinical and radiographic outcomes of children undergoing Double HIT (hydrodistention implantation technique) for primary VUR to determine success rates and the necessity of postoperative VCUG. Children with a history of febrile urinary tract infection (fUTI) undergoing Double HIT for primary VUR between 2009 and 2012 were identified. Patients were prospectively classified as high or low clinical and radiographic risk. Children were categorized as high clinical risk if they had ≥ 3 fUTIs or documented bladder bowel dysfunction (BBD). High radiographic risk included those <2 years of age or with grade 4-5 VUR. Initially, all children underwent postoperative VCUG ("routine" group), while only those with an indication (high radiographic risk or clinical failure) did so during the latter portion of the study ("indicated" group). Clinical success was defined as no postoperative fUTI and radiographic success as negative postoperative VCUG. Average clinical follow-up was 34.7 ± 17.2 months. Two hundred and twenty-two children (198 girls, 24 boys) underwent Double HIT at a mean age of 4.1 ± 2.7 years. Mean maximum VUR grade was 3 ± 0.8. Sixty-eight children (30.6%) had documented BBD. Fourteen children (6.3%) experienced postoperative fUTI, for a clinical success rate of 93.7%. One hundred and fourteen patients (51.4%) underwent postoperative VCUG; 76 were "routine" and 38 were "indicated" [Figure]. Of children classified as low clinical/radiographic risk, 96.6% did not have a postoperative fUTI, compared to 91.1% for high risk patients (P = 0.771). Odds of clinical success for routine VCUG group were 9.9 times higher than for the indicated VCUG group (95% CI, 2-50). Odds of radiographic success for the routine cohort were 13 times higher than for the indicated group (95% CI, 4.2-40). Nine children (4.1%) underwent additional procedures. We found no difference in clinical success among the different risk groups; the number of children with postoperative fUTI was relatively few so there was not statistical power to discern any differences between patients who experienced clinical success versus clinical failure. However, children with an "indicated" VCUG (i.e. those less than 2 years of age, grade 4-5 VUR or those with a fUTI) were 13 times more likely to experience a radiographic failure. This cohort of 38 patients had a 50% radiographic cure rate and a 78.9% clinical cure rate, compared to the overall long-term clinical success rate of 93.7%. Our data demonstrates that we can predict failures with relatively high sensitivity, and it may therefore be prudent to selectively obtain postoperative VCUG rather than recommend it for all children undergoing dextranomer hyaluronic acid co-polymer (Dx/HA) injection. Our study has several limitations that warrant consideration. Not all children underwent a postoperative VCUG, so the true radiographic success rate is unknown. Incidence of fUTI may also be artificially low, as some radiographic failures proceeded directly to another injection or reimplantation. While we were able to demonstrate that children undergoing an "indicated" VCUG were more likely to experience radiographic failure, a larger patient cohort is necessary to determine whether age or VUR grade is more predictive of failure. Finally all patients underwent endoscopic Dx/HA injection, therefore the incidence "spontaneous resolution" is unknown. Long-term clinical success following Double HIT for the endoscopic correction of primary VUR is high, and the majority of children avoid additional procedures. Unless indicated by high-grade, young age, clinical failure, or family/surgeon preference, consideration should be given to making postoperative VCUG an option rather than a recommendation in children undergoing endoscopic treatment of primary VUR using the Double HIT method. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Non-operative management of isolated liver trauma.

PubMed

Li, Min; Yu, Wen-Kui; Wang, Xin-Bo; Ji, Wu; Li, Jie-Shou; Li, Ning

2014-10-01

Liver trauma is the most common abdominal emergency with high morbidity and mortality. Now, non-operative management (NOM) is a selective method for liver trauma. The aim of this study was to determine the success rate, mortality and morbidity of NOM for isolated liver trauma. Medical records of 81 patients with isolated liver trauma in our unit were analyzed retrospectively. The success rate, mortality and morbidity of NOM were evaluated. In this series, 9 patients with grade IV-V liver injuries underwent emergent operation due to hemodynamic instability; 72 patients, 6 with grade V, 18 grade IV, 29 grade III, 15 grade II and 4 grade I, with hemodynamic stability received NOM. The overall success rate of NOM was 97.2% (70/72). The success rates of NOM in the patients with grade I-III, IV and V liver trauma were 100%, 94.4% and 83.3%. The complication rates were 10.0% and 45.5% in the patients who underwent NOM and surgical treatment, respectively. No patient with grade I-II liver trauma had complications. All patients who underwent NOM survived. NOM is the first option for the treatment of liver trauma if the patient is hemodynamically stable. The grade of liver injury and the volume of hemoperitoneum are not suitable criteria for selecting NOM. Hepatic angioembolization associated with the correction of hypothermia, coagulopathy and acidosis is important in the conservative treatment for liver trauma.

Long-term outcome of urethroplasty after failed urethrotomy versus primary repair.

PubMed

Barbagli, G; Palminteri, E; Lazzeri, M; Guazzoni, G; Turini, D

2001-06-01

A urethral stricture recurring after repeat urethrotomy challenges even a skilled urologist. To address the question of whether to repeat urethrotomy or perform open reconstructive surgery, we retrospectively review a series of 93 patients comparing those who underwent primary repair versus those who had undergone urethrotomy and underwent secondary treatment. From 1975 to 1998, 93 males between age 13 and 78 years (mean 39) underwent surgical treatment for bulbar urethral stricture. In 46 (49%) of the patients urethroplasty was performed as primary repair, and in 47 (51%) after previously failed urethrotomy. The strictures were localized in the bulbous urethra without involvement of penile or membranous tracts. The etiology was ischemic in 37 patients, traumatic in 23, unknown in 17 and inflammatory in 16. To simplify evaluation of the results, the clinical outcome was considered either a success or a failure at the time any postoperative procedure was needed, including dilation. In our 93 patients primary urethroplasty had a final success rate of 85%, and after failed urethrotomy 87%. Previously failed urethrotomy did not influence the long-term outcome of urethroplasty. The long-term results of different urethroplasty techniques had a final success rate ranging from 77% to 96%. We conclude that failed urethrotomy does not condition the long-term result of surgical repair. With extended followup, the success rate of urethroplasty decreases with time but it is in fact still higher than that of urethrotomy.

Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats

PubMed Central

Sjöqvist, Sebastian; Jungebluth, Philipp; Ling Lim, Mei; Haag, Johannes C.; Gustafsson, Ylva; Lemon, Greg; Baiguera, Silvia; Angel Burguillos, Miguel; Del Gaudio, Costantino; Rodríguez, Antonio Beltrán; Sotnichenko, Alexander; Kublickiene, Karolina; Ullman, Henrik; Kielstein, Heike; Damberg, Peter; Bianco, Alessandra; Heuchel, Rainer; Zhao, Ying; Ribatti, Domenico; Ibarra, Cristián; Joseph, Bertrand; Taylor, Doris A.; Macchiarini, Paolo

2014-01-01

A tissue-engineered oesophageal scaffold could be very useful for the treatment of pediatric and adult patients with benign or malignant diseases such as carcinomas, trauma or congenital malformations. Here we decellularize rat oesophagi inside a perfusion bioreactor to create biocompatible biological rat scaffolds that mimic native architecture, resist mechanical stress and induce angiogenesis. Seeded allogeneic mesenchymal stromal cells spontaneously differentiate (proven by gene-, protein and functional evaluations) into epithelial- and muscle-like cells. The reseeded scaffolds are used to orthotopically replace the entire cervical oesophagus in immunocompetent rats. All animals survive the 14-day study period, with patent and functional grafts, and gain significantly more weight than sham-operated animals. Explanted grafts show regeneration of all the major cell and tissue components of the oesophagus including functional epithelium, muscle fibres, nerves and vasculature. We consider the presented tissue-engineered oesophageal scaffolds a significant step towards the clinical application of bioengineered oesophagi. PMID:24736316

[Replantation at lower leg level].

PubMed

Daigeler, A; Fansa, H; Westphal, T; Schneider, W

2003-11-01

Replantation in reconstructive surgery is an established procedure due to microsurgical techniques. It can be routinely performed in unilateral lower leg amputation. In some cases of bilateral amputation, in which orthotopic replantation is not possible due to the complex trauma, heterotopic replantation is a therapeutic option. This avoids prosthetic fitting. We report five cases of orthotopic and two of heterotopic lower limb replantations. Functional outcome concerning sensibility, mobility, pain, and aesthetic result were assessed clinically and using a questionnaire. Functional outcome and patient satisfaction were good. The psychological situation of the patients as well as mobility and stability of the replanted limbs were satisfying. Heterotopically replanted patients found the replanted legs superior to the prostheses. We conclude that, in lower leg amputation, attempts should be made to replant the extremity. In bilateral lower leg amputations, at least one limb should be reconstructed, even if "only" a heterotopic replantation can be performed.

Decreased heterotopic osteogenesis in vitamin-D-deficient, but normocalcemic guinea pigs

NASA Technical Reports Server (NTRS)

Dziedzic-Goclawska, A.; Toverud, S. U.; Kaminski, A.; Boass, A.; Yamauchi, M.

1992-01-01

The effect of vitamin D deficiency unhampered by hypocalcemia on de novo bone formation was studied in guinea pigs. Heterotopic induction of osteogenesis was evaluated 4 weeks after intramuscular transplantation of allogenic urinary bladder transitional epithelium from vitamin-D-repleted (+D) donors into +D and -D recipients. In -D recipients the frequency of osteogenesis and the amount of induced bone were significantly diminished; induced bone was less mature, scantly cellular woven bone poorly repopulated with bone marrow. No effect of vitamin D deficiency on orthotopic bone growth and on mineralization of orthotopic and heterotopically induced bone was observed. It is proposed that in addition to inducing factors (BMPs, growth factors) which may be responsible for transformation of mesenchymal cells to osteoprogenitor cells, normal concentrations of 1,25-(OH)2D3 may be required for proliferation and further differentiation of these cells into osteoblasts and for expression of genes engaged in extracellular matrix formation and maturation.

Primary breast cancer of the vulva: a case report.

PubMed

Diniz da Costa, Ana Teresa Minhoto; Coelho, Ana Maria; Lourenço, Alexandre Valentim; Bernardino, Margarida; Ribeirinho, Ana Luisa; Jorge, Carlos Calhaz

2012-04-01

The occurrence of primary breast cancer of the vulva is extremely rare (24 cases described in the English-language literature). We report a case of a primary breast carcinoma of the vulva. An 82-year-old woman presented with a nodule of the left labia minor, which was excised. The histologic examination revealed the presence of adenocarcinoma of mammary origin, positive for common breast markers and for estrogen and progesterone receptors. The study for orthotopic breast carcinoma was negative, as well as the study for metastatic disease. The diagnosis of primary breast carcinoma was established. Our patient was then submitted to pelvic and inguinal radiotherapy as well as an aromatase inhibitor (letrozole), and she remained completely asymptomatic. Because of the rarity of this condition, guidelines for therapy are unavailable. The management suggested in the literature is that of primary orthotopic breast neoplasm of a similar stage.

Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

PubMed Central

Yano, Shuya; Hiroshima, Yukihiko; Maawy, Ali; Kishimoto, Hiroyuki; Suetsugu, Atsushi; Miwa, Shinji; Toneri, Makoto; Yamamoto, Mako; Katz, Matthew H.G.; Fleming, Jason B.; Urata, Yasuo; Tazawa, Hiroshi; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

2015-01-01

Precise fluorescence-guided surgery (FGS) for pancreatic cancer has the potential to greatly improve the outcome in this recalcitrant disease. In order to achieve this goal, we have used genetic reporters to color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP) containing adenovirus OBP401 was used to label the cancer cells of the pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX model enabled FGS to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence, which bright-light surgery (BLS) or single color could not. FGS, with color-coded cancer and stroma cells has important potential for improving the outcome of recalcitrant cancer. PMID:26088297

Percutaneous transhepatic biliary metal stent for malignant hilar obstruction: results and predictive factors for efficacy in 159 patients from a single center.

PubMed

Li, Mingwu; Bai, Ming; Qi, Xingshun; Li, Kai; Yin, Zhanxin; Wang, Jianhong; Wu, Wenbing; Zhen, Luanluan; He, Chuangye; Fan, Daiming; Zhang, Zhuoli; Han, Guohong

2015-06-01

To investigate and compare the efficacy and safety of percutaneous transhepatic biliary stenting (PTBS) using a one- or two-stage procedure and determine the predictive factors for the efficacious treatment of malignant hilar obstruction (MHO). 159 consecutive patients with MHO who underwent PTBS were enrolled between January 2010 and June 2013. Patients were classified into one- or two-stage groups. Independent predictors of therapeutic success were evaluated using a logistic regression model. 108 patients were treated with one-stage PTBS and 51 patients were treated with two-stage PTBS. The stents were technically successful in all patients. Successful drainage was achieved in 114 patients (71.4 %). A total of 42 early major complications were observed. Re-interventions were attempted in 23 patients during follow-up. The cumulative primary patency rates at 3, 6, and 12 months were 88, 71, and 48 %, respectively. Stent placement using a one- or two-stage procedure did not significantly affect therapeutic success, early major complications, median stent patency, or survival. A stent placed across the duodenal papilla was an independent predictor of therapeutic success (odds ratio = 0.262, 95 % confidence interval [0.107-0.642]). Patients with stents across papilla had a lower rate of cholangitis compared with patients who had a stent above papilla (7.1 vs. 20.3 %, respectively, p = 0.03). The majority of patients with MHO who underwent one-stage PTBS showed similar efficacy and safety outcomes compared with those who underwent two-stage PTBS. Stent placement across the duodenal papilla was associated with a higher therapeutic success rate.

Percutaneous Transhepatic Biliary Metal Stent for Malignant Hilar Obstruction: Results and Predictive Factors for Efficacy in 159 Patients from a Single Center

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Mingwu, E-mail: lmw-jack@china.com.cn; Bai, Ming, E-mail: mingbai1983@gmail.com; Qi, Xingshun, E-mail: qixingshun19840717@126.com

AimTo investigate and compare the efficacy and safety of percutaneous transhepatic biliary stenting (PTBS) using a one- or two-stage procedure and determine the predictive factors for the efficacious treatment of malignant hilar obstruction (MHO).Methods159 consecutive patients with MHO who underwent PTBS were enrolled between January 2010 and June 2013. Patients were classified into one- or two-stage groups. Independent predictors of therapeutic success were evaluated using a logistic regression model.Results108 patients were treated with one-stage PTBS and 51 patients were treated with two-stage PTBS. The stents were technically successful in all patients. Successful drainage was achieved in 114 patients (71.4 %). Amore » total of 42 early major complications were observed. Re-interventions were attempted in 23 patients during follow-up. The cumulative primary patency rates at 3, 6, and 12 months were 88, 71, and 48 %, respectively. Stent placement using a one- or two-stage procedure did not significantly affect therapeutic success, early major complications, median stent patency, or survival. A stent placed across the duodenal papilla was an independent predictor of therapeutic success (odds ratio = 0.262, 95 % confidence interval [0.107–0.642]). Patients with stents across papilla had a lower rate of cholangitis compared with patients who had a stent above papilla (7.1 vs. 20.3 %, respectively, p = 0.03).ConclusionsThe majority of patients with MHO who underwent one-stage PTBS showed similar efficacy and safety outcomes compared with those who underwent two-stage PTBS. Stent placement across the duodenal papilla was associated with a higher therapeutic success rate.« less

Tricuspid valve regurgitation after heart transplantation.

PubMed

Kwon, Murray H; Shemin, Richard J

2017-05-01

Tricuspid valve regurgitation (TVR) in the orthotopic heart transplant (OHT) recipient is quite common and has varied clinical sequelae. In its severest forms, it can lead to right-sided failure symptoms indistinguishable from that seen in native heart TVR disease. While certain implantation techniques are widely recognized to reduce the risk of TVR in the cardiac allograft, concomitant tricuspid annuloplasty, while having advocates, is not currently accepted as a routinely established adjunct. Decisions to surgically correct TVR in the OHT recipient must be made carefully, as certain clinical scenarios have high risk of failure. Like in the native heart, anatomic etiologies typically have the greatest chances for success compared to functional etiologies. While repair options have been utilized, there is emerging data to support replacement as the more durable option. While mechanical prostheses are impractical in the heart transplant recipient, biologic valves offer the advantage of continued access to the right ventricle for biopsies in addition to acceptable durability in the low pressure system of the right side.

Liver xenotransplantation.

PubMed

Marino, I R; Tzakis, A G; Fung, J J; Todo, S; Doyle, H R; Manez, R; Starzl, T E

1993-10-01

During the past 30 years orthotopic liver transplantation has become a highly successful form of surgical treatments. The significant advances achieved in this field have led to an increased demand for organs and created a wide gap between organ availability and organ supply. A wider availability of organs for transplantation would allow an expansions rather than a contraction of the indications for transplantation, and, at the same time a relaxation of the patient selection criteria. All these facts clearly justify the renewed interest observed in the last decade in xenotransplantation. The original concept of xenografting, meaning the transplantation of cells, tissues, or organs between different species, is so ancient that it is easily recognizable in Greek and Roman mythology. The centaur Chiron, the teacher of Esculapius, and the Chimera are legendary examples of discordant xenogeneic creatures. However, it is only during this century that scientists have been able to bring this idea into the clinical arena. The early efforts were prompted by the shortage of humans organs at a time when there were few alternatives for treating end-stage organ failure.

Efficacy of oral vancomycin in recurrent primary sclerosing cholangitis following liver transplantation.

PubMed

Hey, Penelope; Lokan, Julie; Johnson, Paul; Gow, Paul

2017-09-25

Primary sclerosing cholangitis (PSC) is a liver disease that leads to progressive destruction and stricturing of the biliary tree. Unfortunately, apart from orthotopic liver transplantation (OLT), there are no universally accepted therapies to treat this disease. Even following transplantation, recurrence of PSC is seen in approximately one quarter of patients and leads to high rates of graft failure. Oral vancomycin, through possible immunomodulatory and anti-inflammatory mechanisms, has been shown in small-scale studies to be successful in improving liver function tests in patients with pretransplant PSC. We report the first case of an adult patient diagnosed with recurrent PSC 4 years after OLT who was treated with oral vancomycin leading to complete normalisation of his liver biochemistry. This case adds to the growing literature of a potential therapeutic role for this antibiotic in PSC and highlights interesting questions regarding mechanisms of disease. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Adult patent ductus arteriosus: successful surgery with mitral valvuloplasty.

PubMed

Hobo, Kyoko; Hanayama, Naoji; Umezu, Kentaro; Shimada, Naohiro; Toyama, Akihiko; Takazawa, Arihumi

2009-06-01

The development of left ventricular dysfunction is a serious complication of longstanding patent ductus arteriosus. An 80-year-old woman who underwent patent ductus arteriosus ligation 13 years previously developed congestive heart failure and mitral regurgitation. She underwent surgical repair with transpulmonary ductus closure and mitral valve annuloplasty under cardiopulmonary bypass. She made a full recovery with improved left ventricular function.

Successful implementation of property cleanup under the Ohio and the Texas voluntary programs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roffman, A.

1999-07-01

Cleanups of two properties, one located in Ohio and the other in Texas were successfully implemented. The facilities were printing plants that manufactured printed material and forms for commercial and industrial use. Primary products and chemicals involved in the manufacturing of the forms included ink, petroleum products and cleaning solvents. The Ohio property underwent a successful cleanup under the Ohio EPA Voluntary Action Program (VAP). It met the Ohio EPA residential land use cleanup standards for soil and shallow groundwater. A No Further Action letter has been submitted to the state and it resulted in the issuance of a Covenantmore » Not to Sue. The Texas facility underwent a successful cleanup under the Texas Natural Resource Conservation Commission (TNRCC) Voluntary Cleanup Program (VCP). It resulted in the issuance of a Certificate of Completion (COC) for residential land use for soil, and a conditional COC for industrial land use for the shallow groundwater.« less

Intravesical Toll-like receptor 7 agonist R-837: Optimization of its formulation in an orthotopic mouse model of bladder cancer

PubMed Central

Hayashi, Tomoko; Crain, Brian; Corr, Maripat; Chan, Michael; Cottam, Howard B; Maj, Roberto; Barberis, Alcide; Leoni, Lorenzo; Carson, Dennis A

2013-01-01

Objective To study the immune response caused by the intravesical administration of the immunomodulator R-837 in various formulations and to estimate its therapeutic potential for bladder cancer. Methods Female C57BL/6 mice were intravesically treated with different formulations of R-837, a Toll-like receptor 7 agonist used for treating genital warts and skin malignancy. The tested formulation mixtures contained different ratios of lactic acid, a thermosensitive poloxamer polymer (Lutrol F127) and 2-(hydroxypropyl)-β-cyclodextrin (HPβCD). Induction of tumor necrosis factor α (TNFα) and keratinocyte-derived chemokine (KC) was analyzed by Luminex microbeads assay. The therapeutic potential of intravesical administration of R-837 was assessed in an orthotopic, syngeneic mouse model of bladder cancer using MB49 cells. Results Intravesical administration of R-837 in lactic acid alone induced systemic and bladder TNFα and KC in a dose-dependent manner. Formulations including poloxamer decreased systemic absorption of R-837 and significantly reduced systemic and local induction of KC. Addition of HPβCD in the poloxamer formulation particularly reversed levels of systemic and local levels of TNFα and KC. Histological examination showed that poloxamer-HPβCD formulation allowed infiltration of mononuclear cells into urothelium and lamina propria. In studies using orthotopic mouse bladder cancer, the tumor loads in R-837-treated mice were significantly lower than those in vehicle-treated or non-treated mice. Conclusion The optimized poloxamer-HPβCD formulation of R-837 shows therapeutic potential for bladder cancer while avoiding adverse side-effects. PMID:20337728

A novel vascular-targeting peptide for gastric cancer delivers low-dose TNFα to normalize the blood vessels and improve the anti-cancer efficiency of 5-fluorouracil.

PubMed

Lu, Lan; Li, Zhi Jie; Li, Long Fei; Shen, Jing; Zhang, Lin; Li, Ming Xing; Xiao, Zhan Gang; Wang, Jian Hao; Cho, Chi Hin

2017-11-01

Various vascular-targeted agents fused with tumor necrosis factor α (TNFα) have been shown to improve drug absorption into tumor tissues and enhance tumor vascular function. TCP-1 is a peptide selected through in vivo phage library biopanning against a mouse orthotopic colorectal cancer model and is a promising agent for drug delivery. This study further investigated the targeting ability of TCP-1 phage and peptide to blood vessels in an orthotopic gastric cancer model in mice and assessed the synergistic anti-cancer effect of 5-fluorouracil (5-FU) with subnanogram TNFα targeted delivered by TCP-1 peptide. In vivo phage targeting assay and in vivo colocalization analysis were carried out to test the targeting ability of TCP-1 phage/peptide. A targeted therapy for improvement of the therapeutic efficacy of 5-FU and vascular function was performed through administration of TCP-1/TNFα fusion protein in this model. TCP-1 phage exhibited strong homing ability to the orthotopic gastric cancer after phage injection. Immunohistochemical staining suggested that and TCP-1 phage/TCP-1 peptide could colocalize with tumor vascular endothelial cells. TCP-1/TNFα combined with 5-FU was found to synergistically inhibit tumor growth, induce apoptosis and reduce cell proliferation without evident toxicity. Simultaneously, subnanogram TCP-1/TNFα treatment normalized tumor blood vessels. Targeted delivery of low-dose TNFα by TCP-1 peptide can potentially modulate the vascular function of gastric cancer and increase the drug delivery of chemotherapeutic drugs. Copyright © 2017. Published by Elsevier Inc.

Vascular Disruption in Combination with mTOR Inhibition in Renal Cell Carcinoma

PubMed Central

Ellis, Leigh; Shah, Preeti; Hammers, Hans; Lehet, Kristin; Sotomayor, Paula; Azabdaftari, Gissou; Seshadri, Mukund; Pili, Roberto

2013-01-01

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted. PMID:22084164

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

PubMed Central

Santio, Niina M.; Eerola, Sini K.; Paatero, Ilkka; Yli-Kauhaluoma, Jari; Anizon, Fabrice; Moreau, Pascale; Tuomela, Johanna; Härkönen, Pirkko; Koskinen, Päivi J.

2015-01-01

Background and methods Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. Results We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. Conclusions Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies. PMID:26075720

Biological characterization of preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model: A multi-modality approach

PubMed Central

Garimella, Rama; Eskew, Jeff; Bhamidi, Priyanka; Vielhauer, George; Hong, Yan; Anderson, H. Clarke; Tawfik, Ossama; Rowe, Peter

2013-01-01

Osteosarcoma (OS) is a bone malignancy that affects children and adolescents. It is a highly aggressive tumor and typically metastasizes to lungs. Despite aggressive chemotherapy and surgical treatments, the current 5 year survival rate is 60–70%. Clinically relevant models are needed to understand OS pathobiology, metastatic progression from bones to lungs, and ultimately, to develop more efficacious treatment strategies and improve survival rates in OS patients with metastasis. The main goal of this study was to develop and characterize an in vivo OS model that will allow non-invasive tracking of tumor progression in real time, and aid in studying OS pathobiology, and screening of potential therapeutic agents against OS. In this study, we have used a multi-modality approach using bioluminescent imaging, electron microscopy, micro-computed tomography, and histopathology to develop and characterize a preclinical Bioluminescent Osteosarcoma Orthotopic Mouse (BOOM) model, using 143B human OS cell line. The results of this study clearly demonstrate that the BOOM model represents the clinical disease as evidenced by a spectrum of changes associated with tumor establishment, progression and metastasis, and detection of known OS biomarkers in the primary and metastatic tumor tissue. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of renal metastasis in OS orthotopic model using 143B cells; (c) evidence of Runx2 expression in the metastatic lung tissue; and (d) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the BOOM model. PMID:25688332

Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse model of invasive glioblastoma.

PubMed

Crommentuijn, Matheus H W; Maguire, Casey A; Niers, Johanna M; Vandertop, W Peter; Badr, Christian E; Würdinger, Thomas; Tannous, Bakhos A

2016-04-01

Glioblastoma (GBM) is the most common malignant brain tumor in adults. We designed an adeno-associated virus (AAV) vector for intracranial delivery of secreted, soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) to GBM tumors in mice and combined it with the TRAIL-sensitizing cardiac glycoside, lanatoside C (lan C). We applied this combined therapy to two different GBM models using human U87 glioma cells and primary patient-derived GBM neural spheres in culture and in orthotopic GBM xenograft models in mice. In U87 cells, conditioned medium from AAV2-sTRAIL expressing cells combined with lan C induced 80% cell death. Similarly, lan C sensitized primary GBM spheres to sTRAIL causing over 90% cell death. In mice bearing intracranial U87 tumors treated with AAVrh.8-sTRAIL, administration of lan C caused a decrease in tumor-associated Fluc signal, while tumor size increased within days of stopping the treatment. Another round of lan C treatment re-sensitized GBM tumor to sTRAIL-induced cell death. AAVrh.8-sTRAIL treatment alone and combined with lanatoside C resulted in a significant decrease in tumor growth and longer survival of mice bearing orthotopic invasive GBM brain tumors. In summary, AAV-sTRAIL combined with lanatoside C induced cell death in U87 glioma cells and patient-derived GBM neural spheres in culture and in vivo leading to an increased in overall mice survival. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Ischaemia-reperfusion injury in orthotopic mouse lung transplants – a scanning electron microscopy study

PubMed Central

Draenert, Alice; Marquardt, Klaus; Inci, Ilhan; Soltermann, Alex; Weder, Walter; Jungraithmayr, Wolfgang

2011-01-01

Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin–eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. PMID:21272104

Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets

PubMed Central

Kunnumakkara, Ajaikumar B.; Sung, Bokyung; Ravindran, Jayaraj; Diagaradjane, Parmeswaran; Deorukhkar, Amit; Dey, Sanjit; Koca, Cemile; Tong, Zhimin; Gelovani, Juri G.; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.

2011-01-01

Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis. PMID:21935918

Non-invasive imaging of prostate cancer progression in nude mice using iRFP gene reporter

NASA Astrophysics Data System (ADS)

Zhu, Banghe; Wu, Grace; Robinson, Holly; Wilganowski, Nathaniel; Sevick-Muraca, Eva M.

2013-03-01

Prostate cancer (PCa) is the second most common cancer in US men. Metastasis is the final step of tumor progression and remains the primary cause of PCa death. Hence preclinical, orthotopic models of PCa metastasis are necessary to develop new therapeutics against metastatic disease. Yet unlike irrelevant subcutaneous tumor models, the deployment of orthotopic models of cancer metastasis in drug research and development is limited by the inability to longitudinally monitor cancer progression/regression in response to administration of experimental pharmaceuticals. Recently, a nearinfrared fluorescent protein (iRFP) was created for deeper imaging [1]. Imaging prostate tumor growth and lymph node metastasis in nude mice therefore becomes possible using this new fluorescent gene reporter. In this study, we first developed an intensified CCD (ICCD)-based iRFP fluorescence imaging device. Then human PCa PC3 cell lines expressing iRFP gene reporter were orthotopically implanted in male Nu/Nu mice at 8-10 weeks old. After 6-10 weeks, in vivo, in situ and ex vivo fluorescence imaging was performed. In vivo iRFP fluorescence imaging showed that the detected fluorescence concentrated at the prostate and became stronger over time, indicating the growth of implanted PCa. Fluorescence was non-invasively detected at locations of prostate-draining lymph nodes as early as 5 weeks post implantation, indicating the metastasis to lymph nodes. In situ and ex vivo fluorescence imaging demonstrated that the detected signals from PCa and lymph nodes were correlated with cancer positive status of tissues as assessed through standard pathology.

[Inhibitory effect of Xiaotan Sanjie Recipe on the microsatellite instability of orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice].

PubMed

Ye, Min; Sun, Da-Zhi; Wei, Pin-kang

2014-05-01

To study the inhibitory effect of Xiaotan Sanjie Recipe (XSR) on the microsatellite instability of orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice. The 3rd passage subcutaneous transplantation tumor was taken as the origin of the model by using MKN-45 human gastric cancer cell lines. MKN-45 human gastric cancer nude mouse model was established using OB glue adhesive method. Then 30 nude mice were divided into the model group, the XSR group, and the chemotherapy group. Mice in the XSR group were intragastrically given XSR at the daily dose of 0.4 mL. Mice in the chemotherapy group were intragastrically given Fluorouracil at the daily dose of 0.4 mL. No intervention was given to mice in the model group. After 6 weeks of medication, the tumor weight was measured, and the tumor inhibition rate calculated. The size, the peak height, and the peak area of 5 microsatellite instability sites were detected. The tumor inhibition rate was 40. 84% in the XSR group. The tumor weight was significantly lower in the XSR group than in the model group (P < 0.01), showing no statistical difference when compared with the chemotherapy group (P >0.05). The incidence of high microsatellite instability (MSI-H) in the model group was 70%, and the incidence of low microsatellite instability (MSI-L) was 30%. Microsatellite stable site tended be stable after 6 weeks of XSR treatment. XSR showed inhibition on microsatellite instable orthotopic transplantation tumor in MKN-45 human gastric cancer nude mice.

Orthotopic Transplantation of Cryopreserved Mouse Ovaries and Gonadotrophin Releasing Hormone Analogues in the Restoration of Function following Chemotherapy-Induced Ovarian Damage

PubMed Central

Li, Qing; Szatmary, Peter; Liu, Yanyang; Ding, Zhenyu; Zhou, Jin; Sun, Yi; Luo, Feng

2015-01-01

Therapy advances are constantly improving survival rates of cancer patients, however the toxic effects of chemotherapy drugs can seriously affect patients’ quality of life. In women, fertility and premature ovarian endocrine dysfunction are of particular concern. It is urgently we find methods to preserve or reconstruct ovarian function for these women. This study compares GnRHa treatment with ovarian tissue cryopreservation and orthotopic transplantation in a chemotherapy-induced ovarian damage murine model. 56 inbred Lewis rats were divided into 4 treatment groups: Saline control (group I); cyclophosphamide only (group II); cyclophosphamide plus GnRHa (group III); cyclophosphamide and grafting of thawed cryopreserved ovaries (group IV). Body weight, estrous cycle recovery time, ovarian weight, morphology and follicle count, as well as breeding and fertility were compared among groups. Only group IV was able to restore to normal body weight by the end of the observation period and resumed normal estrous cycles in a shorter time compared to other treatment groups. There was a decrease in primordial follicles in all treatment groups, but group III had the greatest reduction. Although, there was no difference in pregnancy, only one animal littered normal pups in group II, none littered in group III and four littered in group IV. Thus, cryopreservation and orthotopic transplantation of ovarian tissue can restore the fertility of rats subjected to chemotherapy in a manner that is superior to GnRHa treatment. We also observed increased rates of hepatic, splenic and pulmonary haemorrhage in group III, suggesting there may be synergistic toxicity of GnRHa and cyclophosphamide. PMID:25811681

NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye

PubMed Central

Zhang, Caiqin; Zhao, Yong; Zhao, Ningning; Tan, Dengxu; Zhang, He; Chen, Xue; Zhang, Hai; An, Jiaze

2018-01-01

Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 109/cm2 tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide 68Ga (68Ga-MHI-148) for PET tracing. We applied the dual-modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and 68Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of 68Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm × 0.3 cm) and rabbits (1.2 cm × 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC. PMID:29706843

Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer.

PubMed

Jackson, Amanda L; Sun, Wenchuan; Kilgore, Joshua; Guo, Hui; Fang, Ziwei; Yin, Yajie; Jones, Hannah M; Gilliam, Timothy P; Zhou, Chunxiao; Bae-Jump, Victoria L

2017-11-21

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease.

Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer

PubMed Central

Jackson, Amanda L.; Sun, Wenchuan; Kilgore, Joshua; Guo, Hui; Fang, Ziwei; Yin, Yajie; Jones, Hannah M.; Gilliam, Timothy P.; Zhou, Chunxiao; Bae-Jump, Victoria L.

2017-01-01

Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti-tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease. PMID:29245964

EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma

PubMed Central

Lee, Jeong-Won; Stone, Rebecca L.; Lee, Sun Joo; Nam, Eun Ji; Roh, Ju-Won; Nick, Alpa M.; Han, Hee-Dong; Shahzad, Mian M.K.; Kim, Hye-Sun; Mangala, Lingegowda S.; Jennings, Nicholas B.; Mao, Shenlan; Gooya, John; Jackson, Dowdy; Coleman, Robert L.; Sood, Anil K.

2013-01-01

Purpose EphA2 overexpression is frequently observed in endometrial cancers, and is predictive of poor clinical outcome. Here, we utilize an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor, monomethylauristatin F (MMAF). Experimental design EphA2 expression was examined in endometrial cancer cell lines by Western Blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models. Results EphA2 was expressed in the Hec-1A and Ishikawa cells, but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2 positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays demonstrated that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86 to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared to controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The anti-tumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells. Conclusions The preclinical data for endometrial cancer treatment using MEDI-547 demonstrate substantial anti-tumor activity. PMID:20388851

Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation.

PubMed

Kuo, Elbert; Bharat, Ankit; Goers, Trudie; Chapman, Will; Yan, Le; Street, Tyler; Lu, Wei; Walter, Michael; Patterson, Alexander; Mohanakumar, Thalachallour

2006-09-01

The long-term survival after human lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Clinically, community-acquired respiratory viral infections have been correlated with an increased incidence of BOS. The goal of this study was to investigate the role of respiratory viral infections in chronic lung allograft rejection using the murine orthotopic tracheal transplantation model. Eighty orthotopic tracheal transplants were performed using BALB/c and C57BL/6 mice. Recipient mice were infected intranasally with Sendai virus (SdV), a murine parainfluenza type I virus. Experiments altering the infectious dose, infection time, harvest time, allogeneic response, and viral response were performed. Tracheal allograft rejection was monitored using percent fibrosis and lamina propria to cartilage ratio measurements. Interferon-gamma ELISPOT analysis against irradiated donor (BALB/c) splenocytes was used as immunologic indicator of alloreactivity after transplantation. Sendai virus infection revealed a dose-dependent transient suppression of alloreactivity with a decrease in tracheal allograft fibrosis and frequency of alloreactive T cells at 30 days. This immunosuppression was reversed by day 60, leading to increased tracheal allograft fibrosis with a concomitant increase in the frequency of interferon-gamma producing alloreactive T cells. Pretransplant sensitization with donor antigens prevented the initial suppression of alloreactivity due to SdV infection. Furthermore, pretransplant immunization against SdV infection resulted in rapid clearing of the infection and reduced the immunopathology of rejection. Respiratory viral infections can cause enhanced tracheal allograft rejection despite the initial phase of transient immunosuppression. Early treatment or vaccination against the respiratory infections may represent a viable intervention to reduce the risk of chronic rejection.

Antimetastatic Efficacy of the Combination of Caffeine and Valproic Acid on an Orthotopic Human Osteosarcoma Cell Line Model in Nude Mice.

PubMed

Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Murakami, Takashi; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Hoffman, Robert M

2017-03-01

We have previously reported that caffeine can enhance chemotherapy efficacy of bone and soft tissue sarcoma via cell-cycle perturbation. Valproic acid has histone deacetylase (HDAC) inhibitory activity. We have also reported the anti-tumor efficacy of combination treatment with caffeine and valproic acid against osteosarcoma primary tumors in a cell-line orthotopic mouse model. In this study, we performed combination treatment of caffeine and valproic acid on osteosarcoma cell lines in vitro and in spontaneous and experimental lung metastasis mouse models of osteosarcoma. Survival of 143B-RFP human osteosarcoma cells after exposure to caffeine and valproic acid for 72 hours was determined using the WST-8 assay. IC 50 values and combination indices were calculated. Mouse models of primary osteosarcoma and spontaneous lung metastasis were obtained by orthotopic intra-tibial injection of 143B-RFP cells. Valproic acid, caffeine, and combination of both drugs were administered from day 7, five times a week, for four weeks. Six weeks after orthotopic injection, lung samples were excised and observed with a fluorescence imaging system. A mouse model of experimental lung metastasis was obtained by tail vein injection of 143B-RFP cells. The mice were treated with these agents from day 0, five times a week for four weeks. Both caffeine and valproic acid caused concentration-dependent cell kill in vitro. Synergistic efficacy of the combination treatment was observed. In the spontaneous lung-metastasis model, the number of lung metastasis was 9.0±2.6 in the untreated group (G1); 10.8±2.9 in the caffeine group (G2); 10.0±3.1 in the valproic-acid group (G3); and 3.0±1.1 in the combination group (G4); (p=6.78E-5 control vs. combination; p=0.006 valproic acid vs. combination; p=0.003 caffeine vs. combination). In the experimental lung-metastasis model, the combination group significantly reduced lung metastases and improved overall survival (p=0.0005). Efficacy of the combination of caffeine and valproic acid was observed in vitro and in spontaneous and experimental lung-metastasis mouse models of osteosarcoma. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Ethanolic Extract of Traditional Chinese Medicine (TCM) Gamboge Inhibits Colon Cancer via the Wnt/Beta-Catenin Signaling Pathway in an Orthotopic Mouse Model.

PubMed

Wang, Wei; Li, Youran; Chen, Yiqi; Chen, Hongjin; Zhu, Ping; Xu, Minmin; Wang, Hao; Wu, Minna; Yang, Zhijian; Hoffman, Robert M; Gu, Yunfei

2018-04-01

The aim of the present study was to investigate the efficacy of an ethanolic extract of gamboge (EEG), a traditional Chinese medicine (TCM), both in vitro on colon cancer cells and in vivo in an orthotopic mouse model of human colon cancer. The in vitro cytotoxicity of EEG on colon cancer cells was determined with the CCK8 proliferation assay and the Annexin V-PE/7-AAD apoptosis assay. Efficacy of EEG in vivo was evaluated in an orthotopic mouse model of human colon cancer implated with the green fluorescent protein-expressing human colon cancer cell line SW480-GFP. The tumor-bearing mice were treated with vehicle (0.2 ml/dose normal saline, po, daily), irinotecan (50 mg/kg/dose, ip, twice a week), 5-FU (15 mg/kg/dose, ip, every other day) as positive controls or EEG at doses of 12.5, 25 and 50 mg/kg/dose, po, daily. Real-time fluorescence imaging was performed to determine tumor inhibition in each treated group compared to the untreated controls. The protein expression of β-catenin, MMP-7, cyclin D1 and E-cadherin in the tumors was analyzed by immunohistochemistry. EEG significantly induced proliferation inhibition and apoptosis of SW480 colon cancer cells in vitro in a dose-dependent manner. Tumor growth in the colon-cancer orthotopic model was significantly inhibited by irinotecan, 5-FU and all three doses of EEG. The efficacy of EEG was comparable to irinotecan and 5-FU. Irinotecan, 5-FU and 50 mg/kg EEG significantly decreased the protein expression of β-catenin and MMP-7. Cyclin D1 expression was decreased and E-cadherin expression was increased by irinotecan, 5-FU and all three doses of EEG. The present study demonstrates anti-tumor efficacy of EEG on colon cancer both in vitro and in vivo through inducing proliferation inhibition and apoptosis of SW480 colon cancer cells and inhibiting tumor growth, respectively. EEG exerts anti-tumor activity at least partly via down-regulation of the Wnt/β-catenin signaling pathway. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic-Cancer Orthotopic Mouse Model.

PubMed

Murakami, Takashi; Hiroshima, Yukihiko; Zhang, Yong; Zhao, Ming; Kiyuna, Tasuku; Hwang, Ho Kyoung; Miyake, Kentaro; Homma, Yuki; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Ichikawa, Yasushi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2018-01-01

The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8 + tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8 + TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 × 10 7 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 ± 2.8) than the untreated control (G1) (39.9 ± 30.7, P < 0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P < 0.01). Immunohistochemical staining with anti-mouse CD8 + antibody was performed in order to detect TILs determined by calculating the average number of CD8 + cells in three high power fields (200×) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, P < 0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8 + T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Song, Changhoon; Hong, Beom-Ju; Bok, Seoyeon

Purpose: To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Methods and Materials: Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15 Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [{sup 18}F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day −1), at 6 hours (day 0), and 2 (daymore » 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Results: Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87 ± 0.483 at day −1, 1.67 ± 0.116 at day 0, 2.92 ± 0.334 at day 2, and 2.13 ± 0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. Conclusions: We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15 Gy and had returned to the pretreatment levels 2 days after irradiation and had decreased slightly by day 6. Our results indicate that single high-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.« less

Predicting the discharge status after liver transplantation at a single center: a new approach for a new era.

PubMed

Kelly, Dympna M; Bennett, Renee; Brown, Nancy; McCoy, Judy; Boerner, Derek; Yu, Changhong; Eghtesad, Bijan; Barsoum, Wael; Fung, John J; Kattan, Michael W

2012-07-01

The aim of this study was to develop a tool for preoperatively predicting the need of a patient to attend an extended care facility after orthotopic liver transplantation (OLT). A multidisciplinary group, which included 2 transplant surgeons, 2 transplant nurses, 1 nurse manager, 2 physical therapists, 1 case manager, 1 home health care professional, 1 rehabilitation physician, and 1 statistician, met to identify preoperative factors relevant to discharge planning. The parameters that were examined as potential predictors of the discharge status were as follows: age, sex, language, Karnofsky score, OLT alone (versus a combined procedure), creatinine, bilirubin, international normalized ratio (INR), albumin, body mass index (BMI), Child-Turcotte-Pugh score, chemical Model for End-Stage Liver Disease score, renal dialysis, location before transplantation, comorbidities (encephalopathy, ascites, hydrothorax, and hepatopulmonary syndrome), diabetes mellitus (DM), cardiac ejection fraction and right ventricular systolic pressure, sex and availability of the primary caregiver, donor risk index, and donor characteristics. Between January 2004 and April 2010, 730 of 777 patients (94%) underwent only liver transplantation, and 47 patients (6%) underwent combined procedures. Five hundred nineteen patients (67%) were discharged home, 215 (28%) were discharged to a facility, and 43 (6%) died early after OLT. A multivariate logistic regression analysis identified the following parameters as significantly influencing the discharge status: a low Karnofsky score, an older age, female sex, an INR of 2.0, a creatinine level of 2.0 mg/dL, DM, a high bilirubin level, a low albumin level, a low or high BMI, and renal dialysis before OLT. The nomogram was prospectively validated with a population of 126 OLT recipients with a concordance index of 0.813. In conclusion, a new approach to improving the efficiency of hospital care is essential. We believe that this tool will aid in reducing lengths of stay and improving the experience of patients by facilitating early discharge planning. Copyright © 2012 American Association for the Study of Liver Diseases.

Glaucoma Drainage Device Erosion Following Ptosis Surgery.

PubMed

Bae, Steven S; Campbell, Robert J

2017-09-01

To highlight the potential risk of glaucoma drainage device erosion following ptosis surgery. Case report. A 71-year-old man underwent uncomplicated superotemporal Ahmed glaucoma valve implantation in the left eye in 2008. Approximately 8 years later, the patient underwent bilateral ptosis repair, which successfully raised the upper eyelid position. Three months postoperatively, the patient's glaucoma drainage implant tube eroded through the corneal graft tissue and overlying conjunctiva to become exposed. A graft revision surgery was successfully performed with no further complications. Caution and conservative lid elevation may be warranted when performing ptosis repair in patients with a glaucoma drainage implant, and patients with a glaucoma implant undergoing ptosis surgery should be followed closely for signs of tube erosion.

Management of inadvertent needle penetration resulting in subretinal triamcinolone acetonide and retinal detachment.

PubMed

Tran, Kimberly D; Crane, Ashley M; Flynn, Harry W

2018-06-01

To report management of inadvertent needle penetration during subtenons triamcinolone acetonide administration resulting in retinal detachment. A 71-year-old female with history of diabetes, hypothyroidism, and mild myopia underwent subtenons triamcinolone acetonide (TA) injection in the right eye for nodular scleritis. There was unexpected patient movement concurrent with the injection resulting in needle penetration, subretinal and intravitreal injection of TA, superotemporal retinal break, and macula-involving retinal detachment. The patient underwent partial subretinal TA removal, successful retinal detachment repair, and recovered 20/25 visual acuity. In spite of prominent subretinal TA and retinal detachment, successful repair of retinal detachment and recovery of good visual acuity is possible.

COMBINED REPLACEMENT OF THE AORTIC VALVE AND ASCENDING AORTA IN JEHOVAH'S WITNESSES: REPORT OF TWO CASES

PubMed Central

Beddermann, Christoph; Norman, John C.; Cooley, Denton A.

1979-01-01

Two Jehovah's Witnesses with large ascending thoracic aortic aneurysms and aortic insufficiency secondary to annuloaortic ectasia underwent successful combined replacement of the aortic valve and the ascending aorta. One patient received a composite graft containing an aortic valve prosthesis, which necessitated supravalvular coronary ostia reimplantation; the other patient underwent separate aortic valve and left supracoronary ascending aneurysm replacement, with reimplantation of the right coronary ostium into the graft. No blood or blood derivatives were administered. Both patients had uneventful recoveries and continue to do well. To our knowledge, they represent the first reported cases of successful combined replacement of the aortic valve and ascending aorta in Jehovah's Witnesses. Images PMID:15216324

Surgical management of 2 different presentations of ear canal atresia in dogs

PubMed Central

Béraud, Romain

2012-01-01

A 6-year-old French spaniel and a 14-month-old German shepherd dog were diagnosed with ear canal atresia. Based on presentation, computed tomography, and auditory function evaluation, the first dog underwent excision of the horizontal ear canal and bulla curettage, and the second underwent re-anastomosis of the vertical canal to the external meatus. Both dogs had successful outcomes. PMID:23024390

Alternative Treatment for Bleeding Peristomal Varices: Percutaneous Parastomal Embolization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pabon-Ramos, Waleska M., E-mail: waly.pr@duke.edu; Niemeyer, Matthew M.; Dasika, Narasimham L., E-mail: narasimh@med.umich.edu

2013-10-15

Purpose: To describe how peristomal varices can be successfully embolized via a percutaneous parastomal approach. Methods: The medical records of patients who underwent this procedure between December 1, 2000, and May 31, 2008, were retrospectively reviewed. Procedural details were recorded. Median fluoroscopy time and bleeding-free interval were calculated. Results: Seven patients underwent eight parastomal embolizations. The technical success rate was 88 % (one failure). All embolizations were performed with coils combined with a sclerosant, another embolizing agent, or both. Of the seven successful parastomal embolizations, there were three cases of recurrent bleeding; the median time to rebleeding was 45 daysmore » (range 26-313 days). The remaining four patients did not develop recurrent bleeding during the follow-up period; their median bleeding-free interval was 131 days (range 40-659 days). Conclusion: This case review demonstrated that percutaneous parastomal embolization is a feasible technique to treat bleeding peristomal varices.« less

Repeated Acquisitions and Extinctions in Classical Conditioning of the Rabbit Nictitating Membrane Response

ERIC Educational Resources Information Center

Kehoe, E. James

2006-01-01

The rabbit nictitating membrane (NM) response underwent successive stages of acquisition and extinction training in both delay (Experiment 1) and trace (Experiment 2) classical conditioning. In both cases, successive acquisitions became progressively faster, although the largest, most reliable acceleration occurred between the first and second…

Percutaneous Balloon Dilatation for the Treatment of Early and Late Ureteral Strictures After Renal Transplantation: Long-Term Follow-Up

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bachar, Gil N.; Mor, E.; Bartal, G.

2004-08-15

We report our experience with percutaneous balloon dilatation (PBD) for the treatment of ureteral strictures in patients with renal allografts. Of the 422 consecutive patients after renal transplantation in our center 10 patients had ureteral strictures. An additional 11 patients were referred from other centers. The 21 patients included 15 men and 6 women aged 16 to 67 years. Strictures were confirmed by sonography and scintigraphy in all cases. Patients underwent 2 to 4 PBDs at 7-10-day intervals. Clinical success was defined as resolution of the stenosis and hydronephrosis on sequential ultrasound and normalization of creatinine levels. Patients were dividedmore » into two groups: those who underwent transplantation more than 3 months previously and those who underwent transplantation less than 3 months previously. PBD was successful in 13 of the 21 patients (62%). There was no statistically significant difference in success rate between the patients with early (n 12) and those with late (n = 9) obstruction: 58.4% and 66%, respectively. No major complications were documented. PBD is a safe and simple tool for treating ureteral strictures and procedure-related morbidity is low. It can serve as an initial treatment in patients with early or late ureteral strictures after renal transplantation.« less

Intrinsic Limitations to Unilateral Parathyroid Exploration

PubMed Central

Moore, Francis D.; Mannting, Finn; Tanasijevic, Milenko

1999-01-01

Objective To evaluate a method of limited parathyroid exploration for primary hyperparathyroidism. Summary Background Data Although preoperative localization of parathyroid adenomas has become sensitive enough for clinical practice, it has not achieved success as the basis for limited parathyroid exploration, because multiglandular disease is routinely underdiagnosed. The rapid intraoperative parathyroid hormone assay is sensitive for multiglandular disease, because hormone levels will not fall within 10 minutes of adenoma removal if additional abnormal tissue is present. A combination technique in which the exploration is limited according to the localization studies and the success is confirmed with the parathyroid hormone assay has promise for producing a high rate of curative limited parathyroid explorations. Methods Forty-eight consecutive patients with primary hyperparathyroidism and indications for surgery underwent preoperative localization. After tests, 45 patients underwent unilateral parathyroid exploration and confirmation of the success of unilateral exploration during surgery using the rapid parathyroid hormone assay. The intraoperative management of these patients and their follow-up to 3 months was recorded. Results Thirty-two of the 48 patients (67%) had successful unilateral exploration as gauged by a marked drop in parathyroid hormone levels during the procedure and by 3-month clinical follow-up. Of the 16 patients who ultimately underwent bilateral exploration, 7 had parathyroid hormone levels that did not fall after adenoma removal. Of these seven, five were found to have a second adenoma and two had slow metabolism of hormone with no additional abnormal tissue found. In 5 of the 16 patients, bilateral exploration was performed for erroneous localization. Four additional patients underwent bilateral exploration for improved exposure or negative results on localization tests. Conclusions These results show that unilateral parathyroid exploration is limited by the intrinsic 15% rate of multiglandular primary hyperparathyroidism, combined with the imperfections of preoperative localizing techniques. Although an 85% rate of unilateral exploration can theoretically be obtained for unselected cases, the other vagaries of the technique make a 70% rate a more reasonable expectation. PMID:10493485

Successful Treatment of Residual Curvature in Peyronie Disease in Men Previously Treated With Intralesional Collagenase Clostridium Histolyticum.

PubMed

DeLay, Kenneth; Diao, Linley; Nguyen, Hoang Minh Tue; Zurawin, Jonathan; Libby, Russell; Yafi, Faysal; Hellstrom, Wayne J G

2017-12-01

To determine the success and feasibility of surgically correcting residual curvature after intralesional collagenase clostridium histolyticum (CCH) for the treatment of Peyronie disease (PD). We performed a retrospective analysis of patients who had intralesional CCH treatment for PD and who subsequently underwent penile plication (PP), plaque incision and grafting (PIG), or inflatable penile prosthesis (IPP) placement. Ten men who underwent PP, PIG, or IPP for the treatment of residual curvature after intralesional CCH were identified. Six patients underwent PP; 1 patient underwent PIG; and 3 patients underwent IPP with ancillary straightening maneuvers. The mean time from the last CCH injection to surgical correction was 150.9 days, or 5 months. The mean pre-CCH curvature was 67 degrees and the mean post-CCH curvature was 51 degrees. Eight of 10 patients had no residual curvature after surgical treatment. The mean postprocedure curvature was 4.5 degrees. The mean operative time was 72.1 minutes. The mean estimated blood loss was 20 mL. Increased fibrosis with increased surgical difficulty was noted in 3 (all <6 months post CCH treatment) of 10 patients. No postoperative complications were noted. The surgical treatment of PD after intralesional CCH is safe and effective. If surgery is considered, this should be performed at least 6 months after the last CCH injection, given the potential for an increased inflammatory reaction in this area. Copyright © 2017 Elsevier Inc. All rights reserved.

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Biliary complications after orthotopic liver transplantation from donors after cardiac death: broad spectrum of disease.

PubMed

Abou Abbass, A; Abouljoud, M; Yoshida, A; Kim, D Y; Slater, R; Hundley, J; Kazimi, M; Moonka, D

2010-11-01

Donation-after-death liver transplantation (DCD-LT) carries higher complication rates compared with donation-after-brain death liver transplantation (DBD-LT). In this report we describe our experience with biliary complications in DCD-LT with emphasis on anatomical patterns and outcomes. We performed retrospective review of patients' medical records from August 2004 to December 2008, during which time total of 26 DCD-LTs were performed. Mean follow-up was 29 months (range 3 to 51 months). Biliary complications occurred in 12 patients (46%), of whom 9 were related to DCD (35%). Four patients had more than 1 biliary complication, and 4 had concomitant arterial problems (stricture/thrombosis). Treatment of complications included: ERCP (n = 5, 3 resolved), conversion to roux (n = 5, 2 resolved), revision of roux (n = 1), percutaneous transhepatic cholangiography (n = 1), artery revision (n = 3). Three patients with casts had operative extraction of casts depicting a mummified biliary tree; histology showed casts and fibrosis and anastomotic suture material. Six patients underwent retransplantation (23%). Among retransplanted patients, 2 deaths occurred (7.7%). Our experience with DCD-LT reveals a high prevalence of biliary complications with a new and wide spectrum of clinicopathologic findings. Better strategies for prevention of these unique biliary complications are needed to better justify the added risks and costs for performance of DCD-LT. Copyright © 2010 Elsevier Inc. All rights reserved.

Cost of achieving equivalent outcomes in sicker patients after liver transplant.

PubMed

Dhar, Vikrom K; Wima, Koffi; Kim, Young; Hoehn, Richard S; Jung, Andrew D; Ertel, Audrey E; Diwan, Tayyab S; Paterno, Flavio; Shah, Shimul A

2018-03-01

We aimed to characterize variability in cost after straightforward orthotopic liver transplant (OLT). Using the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified patients who underwent OLT between 2011 and 2014. Patients meeting criteria for straightforward OLT, defined as length of stay < 14 days with discharge to home, were selected (n = 5763) and grouped into tertiles (low, medium, high) according to cost of perioperative stay. Patients undergoing straightforward OLT were of similar demographics regardless of cost. High cost patients were more likely to require preoperative hemodialysis, had higher severity of illness, and higher model for end-stage liver disease (MELD) (p < 0.01). High cost patients required greater utilization of resources including lab tests, blood transfusions, and opioids (p < 0.01). Despite having higher burden of disease and requiring increased resource utilization, high cost OLT patients with a straightforward perioperative course were shown to have identical 2-year graft and overall survival compared to lower cost patients (p = 0.82 and p = 0.63), respectively. Providing adequate perioperative care for OLT patients with higher severity of illness and disease burden requires increased cost and resource utilization; however, doing so provides these patients with long term survival equivalent to more routine patients. Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs.

PubMed

Ekser, Burcin; Klein, Edwin; He, Jing; Stolz, Donna B; Echeverri, Gabriel J; Long, Cassandra; Lin, Chih Che; Ezzelarab, Mohamed; Hara, Hidetaka; Veroux, Massimiliano; Ayares, David; Cooper, David K C; Gridelli, Bruno

2012-01-01

Orthotopic liver transplantation was carried out in baboons using wild-type (WT, n = 1) or genetically-engineered pigs (α1,3-galactosyltransferase gene-knockout, GTKO), n = 1; GTKO pigs transgenic for human CD46, n = 7) and a clinically-acceptable immunosuppressive regimen. Biopsies were obtained from the WT pig liver pre-Tx and at 30 min, 1, 2, 3, 4 and 5 h post-transplantation. Biopsies of genetically-engineered livers were obtained pre-Tx, 2 h after reperfusion and at necropsy (4-7 days after transplantation). Tissues were examined by light, confocal, and electron microscopy. All major native organs were also examined. The WT pig liver underwent hyperacute rejection. After genetically-engineered pig liver transplantation, hyperacute rejection did not occur. Survival was limited to 4-7 days due to repeated spontaneous bleeding in the liver and native organs (as a result of profound thrombocytopenia) which necessitated euthanasia. At 2 h, graft histology was largely normal. At necropsy, genetically-engineered pig livers showed hemorrhagic necrosis, platelet aggregation, platelet-fibrin thrombi, monocyte/macrophage margination mainly in liver sinusoids, and vascular endothelial cell hypertrophy, confirmed by confocal and electron microscopy. Immunohistochemistry showed minimal deposition of IgM, and almost absence of IgG, C3, C4d, C5b-9, and of a cellular infiltrate, suggesting that neither antibody- nor cell-mediated rejection played a major role.

Direct lymphangiography as treatment option of lymphatic leakage: indications, outcomes and role in patient's management.

PubMed

Gruber-Rouh, Tatjana; Naguib, Nagy N N; Lehnert, Thomas; Harth, Marc; Thalhammer, Axel; Beeres, Martin; Tsaur, Igor; Hammersting, Renate; Wichmann, Julian L; Vogl, Thomas J; Jacobi, Volkmar

2014-12-01

To evaluate the effectiveness of lymphography as a minimally invasive treatment option of lymphatic leakage in terms of local control and to investigate which parameters influence the success rate. This retrospective study protocol was approved by the ethic committee. Patient history, imaging data, therapeutic options and follow-up were recorded and retrospectively analyzed. Between June 1998 and February 2013, 71 patients (m:w = 42:29, mean age, 52.4; range 42–75 years) with lymphatic leakage in form of lymphatic fistulas (n = 37), lymphocele (n = 11), chylothorax (n = 13) and chylous ascites (n = 10)underwent lymphography. Sixty-four patients (90.1%) underwent successful lymphography while lymphography failed in 7 cases. Therapeutic success was evaluated and correlated to the volume of lymphatic leakage and to the volume of the applied iodized oil. Signs of leakage or contrast extravasation were directly detected in 64 patients. Of 64 patients, 45 patients (70.3%) were treated and cured after lymphography. Based on the lymphography findings, 19 patients (29.7%) underwent surgical intervention with a completely occlusion of lymphatic leakage. The lymphatic leak could be completely occluded in 96.8% of patients when the lymphatic drainage volume was less than 200 mL/day (n = 33). Even when lymphatic drainage was higher than 200 mL/day (n = 31),therapeutic lymphography was still successful in 58.1% of the patients. Lymphography is an effective, minimally invasive method in the detection and treatment of lymphatic leakage. The volume of lymphatic drainage per day is a significant predictor of the therapeutic success rate. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

History and evolution of dorsal onlay urethroplasty for bulbar urethral stricture repair using skin or buccal mucosal grafts.

PubMed

Barbagli, G; Lazzeri, M

2007-01-01

OBJECTIVES. To illustrate the history and the evolution over time of bulbar dorsal onlay urethroplasty, comparing outcomes when using buccal mucosa or skin grafts. MATERIALS AND METHODS. Ninety-four patients underwent bulbar urethral reconstruction using two dorsal onlay techniques, namely augmented anastomotic urethroplasty and dorsal onlay graft urethroplasty. Preoperative evaluation included clinical history, physical examination, urine culture, residual urine measurement, uroflowmetry and urethrography. Thirty-four patients underwent augmented anastomotic urethroplasty using penile skin (10 cases) or buccal mucosa (24 cases) grafts. Sixty patients underwent dorsal onlay graft urethroplasty using penile skin (38 cases) or buccal mucosa (22 cases) grafts. Forty-eight out of 94 patients received skin grafts and 46 buccal mucosal grafts. RESULTS. Sixty-four (68%) out of 94 cases were successful, whereas 30 (32%) failed. The 34 augmented anastomotic urethroplasties provided successful outcomes in 24 cases (70.6%), but poor outcomes in 10 (29.4%) cases. The 60 dorsal onlay graft urethroplasty proved to be successful in 42 cases (70%), failing in 18 (30%) cases. Twenty-eight (58.3%) out of 48 penile skin grafts were successful and 20 (41.7%) failed. Thirty-six (78.3%) out of 46 buccal mucosa grafts were successful and 10 (21.7%) failed. The 30 failed cases were then treated with internal urethrotomy in 14 cases (46.7%), perineal urethrostomy in 8 cases (26.7%), two-stage repair in 4 cases (13.3%), and one-stage repair in 4 cases (13.3%). CONCLUSIONS. The dorsal onlay technique used for bulbar urethral stricture repair has changed over time. In our experience, the buccal mucosa seems to be the best substitute graft material for bulbar urethroplasty using dorsal approach.

Health-related quality of life and outcomes after surgical treatment of complications from vaginally placed mesh.

PubMed

Hokenstad, Erik D; El-Nashar, Sherif A; Blandon, Roberta E; Occhino, John A; Trabuco, Emanuel C; Gebhart, John B; Klingele, Christopher J

2015-01-01

We aimed to report on health-related quality of life after surgical excision of vaginally placed mesh for treatment of pelvic organ prolapse and to identify predictors of successful surgical management. We identified patients who underwent surgery for treatment of complications from vaginally placed mesh from January 1, 2003, through December 31, 2011, and conducted a follow-up survey. Logistic regression models were used to identify predictors of successful treatment. We identified 114 patients who underwent surgery for mesh-related complications and 68 underwent mesh excision. Of the 68 patients, 44 (64.7%) completed the survey. Of the 44 responders, 41 returned their consent form and were included in the analysis. Only 22 (54%) patients reported a successful outcome after mesh excision. Of 29 (71%) sexually active patients, 23 had dyspareunia before mesh excision and only 3 patients reported resolution of dyspareunia after excision. We reported a multivariable model for predicting successful surgical outcome with an area under the curve for the receiver operator characteristic of 0.781. In this model, complete excision of mesh, new overactive bladder symptoms after mesh placement, and a body mass index higher than 30 kg/m were associated with successful patient-reported outcomes; adjusted odds ratios (95% confidence intervals) were 5.46 (1.10-41.59), 7.76 (1.18-89.55), and 8.41 (1.35-92.41), respectively. Only half of the patients who had surgery for vaginally placed mesh complications reported improvement after surgery, with modest improvement in dyspareunia. Patients who had complete mesh excision, new overactive bladder symptoms, and obesity were more likely to report improvement.

Clinical impacts of inhibition of renin-angiotensin system in patients with acute ST-segment elevation myocardial infarction who underwent successful late percutaneous coronary intervention.

PubMed

Park, Hyukjin; Kim, Hyun Kuk; Jeong, Myung Ho; Cho, Jae Yeong; Lee, Ki Hong; Sim, Doo Sun; Yoon, Nam Sik; Yoon, Hyun Ju; Hong, Young Joon; Kim, Kye Hun; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jim

2017-01-01

Successful percutaneous coronary intervention (PCI) of the occluded infarct-related artery (IRA) in latecomers may improve long-term survival mainly by reducing left ventricular remodeling. It is not clear whether inhibition of renin-angiotensin system (RAS) brings additional better clinical outcomes in this specific population subset. Between January 2008 and June 2013, 669 latecomer patients with acute ST-segment elevation myocardial infarction (STEMI) (66.2±12.1 years, 71.0% males) in Korea Acute Myocardial Infarction Registry (KAMIR) who underwent a successful PCI were enrolled. The study population underwent a successful PCI for a totally occluded IRA. They were divided into two groups according to whether they were prescribed RAS inhibitors at the time of discharge: group I (RAS inhibition, n=556), and group II (no RAS inhibition, n=113). During the one-year follow-up, major adverse cardiac events (MACE), which consist of cardiac death and myocardial infarction, occurred in 71 patients (10.6%). There were significantly reduced incidences of MACE in the group I (hazard ratio=0.34, 95% confidence interval 0.199-0.588, p=0.001). In subgroup analyses, RAS inhibition was beneficial in patients with male gender, history of hypertension or diabetes mellitus, and even in patients with left ventricular ejection fraction (LVEF) ≥40%. In the baseline and follow-up echocardiographic data, benefit in changes of LVEF and left ventricular end-systolic volume was noted in group I. In latecomers with STEMI, RAS inhibition improved long-term clinical outcomes after a successful PCI, even in patients with low risk who had relatively preserved LVEF. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Predictors of successful external cephalic version in an Australian maternity hospital.

PubMed

Mowat, Alex; Gardener, Glenn

2014-02-01

There are minimal data involving predictors of success of external cephalic version (ECV) in an Australian healthcare setting. To determine the predictors of successful ECV as well as the success rate of ECV and the mode of, and presentation at, delivery for women undergoing ECV for breech presentation from 36-weeks gestation. A prospective review was carried out on all women who had undergone ECV from 36-weeks gestation at the Mater Mothers Hospital over an 8-year period from 2001 to 2008. Data were collected prospectively and were collated in conjunction with database review, chart review and telephonic patient interviews. A total of 355 women underwent ECV for breech presentation. The overall success rate was 66% (57% for nulliparous, 76% for multiparous). A woman who underwent ECV had a 46% chance of a vaginal birth. If the ECV was successful, she had a 70% chance of vaginal birth. From bivariate analysis, parity, amniotic fluid index (AFI) and estimated fetal weight (EFW) were determined to be possible predictors of success of ECV and were included in the logistic regression modelling. In the regression analysis, multiparity increased the odds of successful ECV by 2.18. For every one unit increase in AFI, the odds of successful ECV increased by 1.18. Multiparity and amniotic fluid volume as assessed by AFI were the significant predictors of immediate success of ECV. Conversely, lower AFI and nulliparity are factors that are likely to reduce the likelihood of successful ECV. © 2013 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Aorta-atria-septum combined incision for aortic valve re-replacement

PubMed Central

Xu, Yiwei; Ye, Xiaofeng; Li, Zhaolong

2018-01-01

This case report illustrates a patient who underwent supra-annular mechanical aortic valve replacement then suffered from prosthesis dysfunction, increasing pressure gradient with aortic valve. She was successfully underwent aortic valve re-replacement, sub-annular pannus removing and aortic annulus enlargement procedures through combined cardiac incision passing through aortic root, right atrium (RA), and upper atrial septum. This incision provides optimal visual operative field and simplifies dissection. PMID:29850170

Outcome of urethral strictures treated by endoscopic urethrotomy and urethroplasty

PubMed Central

Tinaut-Ranera, Javier; Arrabal-Polo, Miguel Ángel; Merino-Salas, Sergio; Nogueras-Ocaña, Mercedes; López-León, Víctor Manuel; Palao-Yago, Francisco; Arrabal-Martín, Miguel; Lahoz-García, Clara; Alaminos, Miguel; Zuluaga-Gomez, Armando

2014-01-01

Introduction: We analyze the outcomes of patients with urethral stricture who underwent surgical treatment within the past 5 years. Methods: This is a retrospective study of male patients who underwent surgery for urethral stricture at our service from January 2008 to June 2012. We analyzed the comorbidities, type, length and location of the stricture and the surgical treatment outcome after endoscopic urethrotomy, urethroplasty or both. Results: In total, 45 patients with a mean age of 53.7 ± 16.7 years underwent surgical treatment for urethral stricture. Six months after surgery, 46.7% of the patients had a maximum urinary flow greater than 15 mL/s, whereas 87.3% of the patients exhibited no stricture by urethrography after the treatment. The success rate in the patients undergoing urethrotomy was 47.8% versus 86.4% in those undergoing urethroplasty (p = 0.01). Twenty percent of the patients in whom the initial urethrotomy had failed subsequently underwent urethroplasty, thereby increasing the treatment success. Conclusion: In most cases, the treatment of choice for urethral stricture should be urethroplasty. Previous treatment with urethrotomy does not appear to produce adverse effects that affect the outcome of a urethroplasty if urethrotomy failed, so urethrotomy may be indicated in patients with short strictures or in patients at high surgical risk. PMID:24454595

Outcome of urethral strictures treated by endoscopic urethrotomy and urethroplasty.

PubMed

Tinaut-Ranera, Javier; Arrabal-Polo, Miguel Ángel; Merino-Salas, Sergio; Nogueras-Ocaña, Mercedes; López-León, Víctor Manuel; Palao-Yago, Francisco; Arrabal-Martín, Miguel; Lahoz-García, Clara; Alaminos, Miguel; Zuluaga-Gomez, Armando

2014-01-01

We analyze the outcomes of patients with urethral stricture who underwent surgical treatment within the past 5 years. This is a retrospective study of male patients who underwent surgery for urethral stricture at our service from January 2008 to June 2012. We analyzed the comorbidities, type, length and location of the stricture and the surgical treatment outcome after endoscopic urethrotomy, urethroplasty or both. In total, 45 patients with a mean age of 53.7 ± 16.7 years underwent surgical treatment for urethral stricture. Six months after surgery, 46.7% of the patients had a maximum urinary flow greater than 15 mL/s, whereas 87.3% of the patients exhibited no stricture by urethrography after the treatment. The success rate in the patients undergoing urethrotomy was 47.8% versus 86.4% in those undergoing urethroplasty (p = 0.01). Twenty percent of the patients in whom the initial urethrotomy had failed subsequently underwent urethroplasty, thereby increasing the treatment success. In most cases, the treatment of choice for urethral stricture should be urethroplasty. Previous treatment with urethrotomy does not appear to produce adverse effects that affect the outcome of a urethroplasty if urethrotomy failed, so urethrotomy may be indicated in patients with short strictures or in patients at high surgical risk.

Improved therapeutic outcomes of thermal ablation on rat orthotopic liver allograft sarcoma models by radioiodinated hypericin induced necrosis targeted radiotherapy

PubMed Central

Gao, Long; Zhang, Jian; Ma, Tengchuang; Yao, Nan; Gao, Meng; Shan, Xin; Ni, Yicheng; Shao, Haibo; Xu, Ke

2016-01-01

Residual tumor resulting in tumor recurrence after various anticancer therapies is an unmet challenge in current clinical oncology. This study aimed to investigate the hypothesis that radioiodinated hypericin (131I-Hyp) may inhibit residual tumor recurrence after microwave ablation (MWA) on rat orthotopic liver allograft sarcoma models. Thirty Sprague-Dawley (SD) rats with hepatic tumors were divided into three groups: Group A received laparotomy MWA and sequential intravenous injection (i.v.) of 131I labelled hypericin (131I-Hyp) in a time interval of 24 h; Group B received only laparotomy MWA; Group C was a blank control. Tumor inhibitory effects were monitored with in vivo magnetic resonance imaging (MRI) and these findings were compared to histopathology data before (baseline, day 0) and 1, 4, and 8 days after MWA. In addition, biodistribution of 131I-Hyp was assessed with in vivo single-photon emission computed tomography-computed tomography (SPECT-CT) imaging, in vitro autoradiography, fluorescent microscopy, and gamma counting. A fast clearance of 131I-Hyp and increasing deposit in necrotic tumors appeared over time, with a significantly higher radioactivity than other organs (0.9169 ± 1.1138 % ID/g, P < 0.01) on day 9. Tumor growth was significantly slowed down in group A compared to group B and C according to MRI images and corresponding tumor doubling time (12.13 ± 1.99, 4.09 ± 0.97, 3.36 ± 0.72 days respectively). The crescent tagerability of 131I-Hyp to necrosis was visualized consistently by autoradiography and fluorescence microscopy. In conclusion, 131I-Hyp induced necrosis targeted radiotherapy improved therapeutic outcomes of MWA on rat orthotopic liver allograft sarcoma models. PMID:27285983

Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.

PubMed

Ota, Shinichi; Geschwind, Jean-Francois H; Buijs, Manon; Wijlemans, Joost W; Kwak, Byung Kook; Ganapathy-Kanniappan, Shanmugasundaram

2013-06-01

Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.

Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model

PubMed Central

Manzanares, Miguel Á.; Campbell, Deanna J.W.; Maldonado, Gabrielle T.

2017-01-01

Periostin and mesothelin have each been suggested to be predictors of poor survival for patients with intrahepatic cholangiocarcinoma, although the clinical prognostic value of both of these biomarkers remains uncertain. The aim of the current study was to investigate these biomarkers for their potential to act as tumor progression factors when assessed in orthotopic tumor and three‐dimensional culture models of rat cholangiocarcinoma progression. Using our orthotopic model, we demonstrated a strong positive correlation between tumor and serum periostin and mesothelin and increasing liver tumor mass and associated peritoneal metastases that also reflected differences in cholangiocarcinoma cell aggressiveness and malignant grade. Periostin immunostaining was most prominent in the desmoplastic stroma of larger sized more aggressive liver tumors and peritoneal metastases. In comparison, mesothelin was more highly expressed in the cholangiocarcinoma cells; the slower growing more highly differentiated liver tumors exhibited a luminal cancer cell surface immunostaining for this biomarker, and the rapidly growing less differentiated liver and metastatic tumor masses largely showed cytoplasmic mesothelin immunoreactivity. Two molecular weight forms of mesothelin were identified, one at ∼40 kDa and the other, a more heavily glycosylated form, at ∼50 kDa. Increased expression of the 40‐kDa mesothelin over that of the 50 kDa form predicted increased malignant progression in both the orthotopic liver tumors and in cholangiocarcinoma cells of different malignant potential in three‐dimensional culture. Moreover, coculturing of cancer‐associated myofibroblasts with cholangiocarcinoma cells promoted overexpression of the 40‐kDa mesothelin, which correlated with enhanced malignant progression in vitro. Conclusion: Periostin and mesothelin are useful predictors of tumor progression in our rat desmoplastic cholangiocarcinoma models. This supports their relevance to human intrahepatic cholangiocarcinoma. (Hepatology Communications 2018;2:155–172) PMID:29404524

Efficacy of glycogen synthase kinase-3β targeting against osteosarcoma via activation of β-catenin

PubMed Central

Yamamoto, Norio; Nishida, Hideji; Hayashi, Katsuhiro; Kimura, Hiroaki; Takeuchi, Akihiko; Miwa, Shinji; Igarashi, Kentaro; Kato, Takashi; Aoki, Yu; Higuchi, Takashi; Hirose, Mayumi; Hoffman, Robert M; Minamoto, Toshinari; Tsuchiya, Hiroyuki

2016-01-01

Development of innovative more effective therapy is required for refractory osteosarcoma patients. We previously established that glycogen synthase kinase-3β (GSK- 3β) is a therapeutic target in various cancer types. In the present study, we explored the therapeutic efficacy of GSK-3β inhibition against osteosarcoma and the underlying molecular mechanisms in an orthotopic mouse model. Expression and phosphorylation of GSK-3β in osteosarcoma and normal osteoblast cell lines was examined, together with efficacy of GSK-3β inhibition on cell survival, proliferation and apoptosis and on the growth of orthotopically-transplanted human osteosarcoma in nude mice. We also investigated changes in expression, phosphorylation and co-transcriptional activity of β-catenin in osteosarcoma cells following GSK-3β inhibition. Expression of the active form of GSK- 3β (tyrosine 216-phosphorylated) was higher in osteosarcoma than osteoblast cells. Inhibition of GSK-3β activity by pharmacological inhibitors or of its expression by RNA interference suppressed proliferation of osteosarcoma cells and induced apoptosis. Treatment with GSK-3β-specific inhibitors attenuated the growth of orthotopic osteosaroma in mice. Inhibition of GSK-3β reduced phosphorylation at GSK- 3β-phospho-acceptor sites in β-catenin and increased β-catenin expression, nuclear localization and co-transcriptional activity. These results suggest the efficacy of GSK-3β inhibitors is associated with activation of β-catenin, a putative tumor suppressor in bone and soft tissue sarcoma and an important component of osteogenesis. Our study thereby demonstrates a critical role for GSK-3β in sustaining survival and proliferation of osteosarcoma cells, and identifies this kinase as a potential therapeutic target against osteosarcoma. PMID:27780915

Myeloid Cell COX-2 deletion reduces mammary tumor growth through enhanced cytotoxic T-lymphocyte function

PubMed Central

Chen, Edward P.; Markosyan, Nune; Connolly, Emma; Lawson, John A.; Li, Xuanwen; Grant, Gregory R.; Grosser, Tilo; FitzGerald, Garret A.; Smyth, Emer M.

2014-01-01

Cyclooxygenase-2 (COX-2) expression is associated with poor prognosis across a range of human cancers, including breast cancer. The contribution of tumor cell-derived COX-2 to tumorigenesis has been examined in numerous studies; however, the role of stromal-derived COX-2 is ill-defined. Here, we examined how COX-2 in myeloid cells, an immune cell subset that includes macrophages, influences mammary tumor progression. In mice engineered to selectively lack myeloid cell COX-2 [myeloid-COX-2 knockout (KO) mice], spontaneous neu oncogene-induced tumor onset was delayed, tumor burden reduced, and tumor growth slowed compared with wild-type (WT). Similarly, growth of neu-transformed mammary tumor cells as orthotopic tumors in immune competent syngeneic myeloid-COX-2 KO host mice was reduced compared with WT. By flow cytometric analysis, orthotopic myeloid-COX-2 KO tumors had lower tumor-associated macrophage (TAM) infiltration consistent with impaired colony stimulating factor-1-dependent chemotaxis by COX-2 deficient macrophages in vitro. Further, in both spontaneous and orthotopic tumors, COX-2-deficient TAM displayed lower immunosuppressive M2 markers and this was coincident with less suppression of CD8+ cytotoxic T lymphocytes (CTLs) in myeloid-COX-2 KO tumors. These studies suggest that reduced tumor growth in myeloid-COX-2 KO mice resulted from disruption of M2-like TAM function, thereby enhancing T-cell survival and immune surveillance. Antibody-mediated depletion of CD8+, but not CD4+ cells, restored tumor growth in myeloid-COX-2 KO to WT levels, indicating that CD8+ CTLs are dominant antitumor effectors in myeloid-COX-2 KO mice. Our studies suggest that inhibition of myeloid cell COX-2 can potentiate CTL-mediated tumor cytotoxicity and may provide a novel therapeutic approach in breast cancer therapy. PMID:24590894

The Antineoplastic Activity of Photothermal Ablative Therapy with Targeted Gold Nanorods in an Orthotopic Urinary Bladder Cancer Model.

PubMed

Yang, Xiaoping; Su, Lih-Jen; La Rosa, Francisco G; Smith, Elizabeth Erin; Schlaepfer, Isabel R; Cho, Suehyun K; Kavanagh, Brian; Park, Wounjhang; Flaig, Thomas W

2017-07-27

Gold nanoparticles treated with near infrared (NIR) light can be heated preferentially, allowing for thermal ablation of targeted cells. The use of novel intravesical nanoparticle-directed therapy in conjunction with laser irradiation via a fiber optic cystoscope, represents a potential ablative treatment approach in patients with superficial bladder cancer. To examine the thermal ablative effect of epidermal growth factor receptor (EGFR)-directed gold nanorods irradiated with NIR light in an orthotopic urinary bladder cancer model. Gold nanorods linked to an anti-EGFR antibody (Conjugated gold NanoRods - CNR) were instilled into the bladder cavity of an orthotopic murine xenograft model with T24 bladder cancer cells expressing luciferase. NIR light was externally administered via an 808 nm diode laser. This treatment was repeated weekly for 4 weeks. The anti-cancer effect was monitored by an in vivo imaging system in a non-invasive manner, which was the primary outcome of our study. The optimal approach for an individual treatment was 2.1 W/cm 2 laser power for 30 seconds. Using this in vivo model, NIR light combined with CNR demonstrated a statistically significant reduction in tumor-associated bioluminescent activity ( n  = 16) compared to mice treated with laser alone ( n  = 14) at the end of the study ( p  = 0.035). Furthermore, the CNR+NIR light treatment significantly abrogated bioluminescence signals over a 6-week observation period, compared to pre-treatment levels ( p  = 0.045). Photothermal tumor ablation with EGFR-directed gold nanorods and NIR light proved effective and well tolerated in a murine in vivo model of urinary bladder cancer.

Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer

PubMed Central

Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

2016-01-01

Background Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. Methods CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections Results The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Conclusion Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery. PMID:27584018

Use of Panitumumab-IRDye800 to Image Microscopic Head and Neck Cancer in an Orthotopic Surgical Model

PubMed Central

Heath, C. Hope; Deep, Nicholas L.; Sweeny, Larissa; Zinn, Kurt R; Rosenthal, Eben L.

2013-01-01

Background Fluorescence imaging hardware (SPY) has recently been developed for intraoperative assessment of blood flow via detection of probes emitting in the near-infrared (NIR) spectrum. This study sought to determine if this imaging system was capable of detecting micrometastatic head and neck squamous cell carcinoma (HNSCC) in preclinical models. Methods A NIR fluorescent probe (IRDye800CW) was covalently linked to a monoclonal antibody targeting EGFR (panitumumab) or non-specific IgG. HNSCC flank (SCC-1) and orthotopic (FADU and OSC19) xenografts were imaged 48-96hrs following systemic injection of labeled panitumumab or IgG. The primary tumor and regional lymph nodes were dissected using fluorescence guidance with the SPY system and grossly assessed with a charge-coupled NIR system (Pearl). Histologic slides were also imaged with a NIR charged-coupled device (Odyssey) and fluorescence intensity was correlated with pathologic confirmation of disease. Results Orthotopic tongue tumors were clearly delineated from normal tissue with tumor-to-background ratios of 2.9(Pearl) and 2.3(SPY). Disease detection was significantly improved with panitumumab-IRDye compared to IgG-IRDye800 (P<0.05). Tissue biopsies (average size=3.7mm) positive for fluorescence were confirmed for pathologic disease by histology and immunohistochemistry (n=25/25). Biopsies of non-fluorescent tissue were proven to be negative for malignancy (n=28/28). The SPY was able to detect regional lymph node metastasis (<1.0mm) and microscopic areas of disease. Standard histological assessment in both frozen and paraffin-embedded histologic specimens was augmented using the Odyssey. Conclusions Panitumumab-IRDye800 may have clinical utility in detection and removal of microscopic HNSCC using existing intraoperative optical imaging hardware and may augment analysis of frozen and permanent pathology. PMID:22669455

Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer.

PubMed

Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-Pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

2016-01-01

Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections. The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery.

Repeated assessment of orthotopic glioma pO2 by multi-site EPR oximetry: A technique with the potential to guide therapeutic optimization by repeated measurements of oxygen

PubMed Central

Khan, Nadeem; Mupparaju, Sriram; Hou, Huagang; Williams, Benjamin B.; Swartz, Harold

2011-01-01

Tumor hypoxia plays a vital role in therapeutic resistance. Consequently, measurements of tumor pO2 could be used to optimize the outcome of oxygen-dependent therapies, such as, chemoradiation. However, the potential optimizations are restricted by the lack of methods to repeatedly and quantitatively assess tumor pO2 during therapies, particularly in gliomas. We describe the procedures for repeated measurements of orthotopic glioma pO2 by multi-site electron paramagnetic resonance (EPR) oximetry. This oximetry approach provides simultaneous measurements of pO2 at more than one site in the glioma and contralateral cerebral tissue. The pO2 of intracerebral 9L, C6, F98 and U251 tumors, as well as contralateral brain, were measured repeatedly for five consecutive days. The 9L glioma was well oxygenated with pO2 of 27 - 36 mm Hg, while C6, F98 and U251 glioma were hypoxic with pO2 of 7 - 12 mm Hg. The potential of multi-site EPR oximetry to assess temporal changes in tissue pO2 was investigated in rats breathing 100% O2. A significant increase in F98 tumor and contralateral brain pO2 was observed on day 1 and day 2, however, glioma oxygenation declined on subsequent days. In conclusion, EPR oximetry provides the capability to repeatedly assess temporal changes in orthotopic glioma pO2. This information could be used to test and optimize the methods being developed to modulate tumor hypoxia. Furthermore, EPR oximetry could be potentially used to enhance the outcome of chemoradiation by scheduling treatments at times of increase in glioma pO2. PMID:22079559

Influence of in vivo growth on human glioma cell line gene expression: Convergent profiles under orthotopic conditions

PubMed Central

Camphausen, Kevin; Purow, Benjamin; Sproull, Mary; Scott, Tamalee; Ozawa, Tomoko; Deen, Dennis F.; Tofilon, Philip J.

2005-01-01

Defining the molecules that regulate tumor cell survival is an essential prerequisite for the development of targeted approaches to cancer treatment. Whereas many studies aimed at identifying such targets use human tumor cells grown in vitro or as s.c. xenografts, it is unclear whether such experimental models replicate the phenotype of the in situ tumor cell. To begin addressing this issue, we have used microarray analysis to define the gene expression profile of two human glioma cell lines (U251 and U87) when grown in vitro and in vivo as s.c. or as intracerebral (i.c.) xenografts. For each cell line, the gene expression profile generated from tissue culture was significantly different from that generated from the s.c. tumor, which was significantly different from those grown i.c. The disparity between the i.c gene expression profiles and those generated from s.c. xenografts suggests that whereas an in vivo growth environment modulates gene expression, orthotopic growth conditions induce a different set of modifications. In this study the U251 and U87 gene expression profiles generated under the three growth conditions were also compared. As expected, the profiles of the two glioma cell lines were significantly different when grown as monolayer cultures. However, the glioma cell lines had similar gene expression profiles when grown i.c. These results suggest that tumor cell gene expression, and thus phenotype, as defined in vitro is affected not only by in vivo growth but also by orthotopic growth, which may have implications regarding the identification of relevant targets for cancer therapy. PMID:15928080

SYMPATHETIC INNERVATION, NOREPINEPHRINE CONTENT, AND NOREPINEPHRINE TURNOVER IN ORTHOTOPIC AND SPONTANEOUS MODELS OF BREAST CANCER

PubMed Central

Dawes, Ryan P.; Madden, Kelley S.

2016-01-01

Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression. PMID:26718447

Preconditioning methods influence tumor property in an orthotopic bladder urothelial carcinoma rat model

PubMed Central

MIYAZAKI, KOZO; MORIMOTO, YUJI; NISHIYAMA, NOBUHIRO; SATOH, HIROYUKI; TANAKA, MASAMITSU; SHINOMIYA, NARIYOSHI; ITO, KEIICHI

2014-01-01

Urothelial carcinoma (UC) is an extremely common type of cancer that occurs in the bladder. It has a particularly high rate of recurrence. Therefore, preclinical studies using animal models are essential to determine effective forms of treatment. In the present study, in order to establish an orthotopic bladder UC animal model with clinical relevance, the effects of preconditioning methods on properties of the developed tumor were evaluated. The bladder cavity was pretreated with phosphate-buffered saline (PBS), acid-base, trypsin (TRY) or poly (L-lysine) (PLL) and then rat UC cells (AY-27) (4×106 cells) were inoculated. The results demonstrated that, two weeks later, the tumorigenic rate (88%) and tumor count (2.3 per rat) were not significantly different among the preconditioning methods, whereas tumor volume and invasion depth into bladder tissue were significantly different. Average tumor volumes were >50 mm3 in the PBS and acid-base-treated groups and <10 mm3 in the TRY- and PLL-treated groups. The percentage of invasive tumors (T2 or more advanced stage) was ∼75% of total tumors in the PBS- and acid-base-treated groups, whereas the percentages were reduced in the TRY- and PLL-treated groups (58 and 32%, respectively). Non-invasive tumors (Ta or T1) accounted for 54% of tumors in the PLL-treated group, which was 2-5-fold higher than the percentages in the remaining groups. Properties of the developed tumor in the rat orthotopic UC model were different depending on preconditioning methods. Therefore, different animal models suitable for a discrete preclinical examination may be established by using the appropriate preconditioning condition. PMID:24649309

Ischaemia-reperfusion injury in orthotopic mouse lung transplants - a scanning electron microscopy study.

PubMed

Draenert, Alice; Marquardt, Klaus; Inci, Ilhan; Soltermann, Alex; Weder, Walter; Jungraithmayr, Wolfgang

2011-02-01

Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin-eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. © 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.

Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thorek, Daniel L.J., E-mail: dthorek1@jhmi.edu; Kramer, Robin M.; Chen, Qing

2015-10-01

Purpose: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Micemore » could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. Results: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.« less

SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy.

PubMed

Wang, Feng; Xia, Xiaojun; Yang, Chunying; Shen, Jianliang; Mai, Junhua; Kim, Han-Cheon; Kirui, Dickson; Kang, Ya'an; Fleming, Jason B; Koay, Eugene J; Mitra, Sankar; Ferrari, Mauro; Shen, Haifa

2018-03-30

Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy. We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by Flow Cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-L-cysteine) in SMAD4 -depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4 -depleted Panc-1 cells. SMAD4 -depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild type SMAD4 in SMAD4 -mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model ( P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples. Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy. Copyright ©2018, American Association for Cancer Research.

Repeated assessment of orthotopic glioma pO(2) by multi-site EPR oximetry: a technique with the potential to guide therapeutic optimization by repeated measurements of oxygen.

PubMed

Khan, Nadeem; Mupparaju, Sriram; Hou, Huagang; Williams, Benjamin B; Swartz, Harold

2012-02-15

Tumor hypoxia plays a vital role in therapeutic resistance. Consequently, measurements of tumor pO(2) could be used to optimize the outcome of oxygen-dependent therapies, such as, chemoradiation. However, the potential optimizations are restricted by the lack of methods to repeatedly and quantitatively assess tumor pO(2) during therapies, particularly in gliomas. We describe the procedures for repeated measurements of orthotopic glioma pO(2) by multi-site electron paramagnetic resonance (EPR) oximetry. This oximetry approach provides simultaneous measurements of pO(2) at more than one site in the glioma and contralateral cerebral tissue. The pO(2) of intracerebral 9L, C6, F98 and U251 tumors, as well as contralateral brain, were measured repeatedly for five consecutive days. The 9L glioma was well oxygenated with pO(2) of 27-36 mm Hg, while C6, F98 and U251 glioma were hypoxic with pO(2) of 7-12mm Hg. The potential of multi-site EPR oximetry to assess temporal changes in tissue pO(2) was investigated in rats breathing 100% O(2). A significant increase in F98 tumor and contralateral brain pO(2) was observed on day 1 and day 2, however, glioma oxygenation declined on subsequent days. In conclusion, EPR oximetry provides the capability to repeatedly assess temporal changes in orthotopic glioma pO(2). This information could be used to test and optimize the methods being developed to modulate tumor hypoxia. Furthermore, EPR oximetry could be potentially used to enhance the outcome of chemoradiation by scheduling treatments at times of increase in glioma pO(2). Copyright © 2011 Elsevier B.V. All rights reserved.

Pathological autopsy of a patient that underwent a successful ablation of an electrical storm from the left ventricular summit.

PubMed

Hori, Yuichi; Nakahara, Shiro; Mine, Sohtaro; Anjo, Naofumi; Fujii, Akiko; Ueda, Yoshihiko; Taguchi, Isao

2016-12-01

A 65-year-old man with non-ischemic cardiomyopathy, underwent an autopsy 2 months after the successful ablation of a sustained left ventricular (LV) summit ventricular tachycardia (VT). The patient died due to interstitial pneumonia from amiodarone use. The earliest activation sites of the VT were documented from both inside the anterior interventricular vein (AIV) and epicardial surface. The diameter of the AIV was 3-4 mm, and the radiofrequency (RF) lesion inside the AIV was a slight lesion due to high impedance with a high temperature. The lesion from the epicardial surface was also superficial and insufficient due to neighboring coronary arteries and the existence of epicardial fat. A successful application was performed from the LV endocardium, and diffuse myocardial fibrosis was observed in the mid-myocardium including inside the RF lesions. The actual relationship between the myocardial fibrosis and LV summit VT remains unclear, but this case showed the difficulty of achieving a successful ablation from the epicardial side, when the focus exists in the mid-myocardium around the LV summit.

Magnetic navigation facilitates percutaneous coronary intervention for complex lesions.

PubMed

Sandhu, Gurpreet S; Sanon, Saurabh; Holmes, David R; Gulati, Rajiv; Brilakis, Emmanouil S; Lennon, Ryan J; Rihal, Charanjit S

2014-10-01

We sought to determine the utility of a magnetic navigation system (MNS) in treating a variety of coronary artery lesions including those that could not be revascularized with standard percutaneous coronary intervention (PCI). MNS may add value in the treatment of tortuous arteries and bifurcation lesions; however its widespread adoption has lagged because of cost and a lack of clear advantage over conventional PCI. We performed a retrospective analysis to determine whether MNS improved procedural success for highly complex lesions. One hundred and forty-eight patients underwent treatment with MNS at Mayo Clinic, Rochester. Clinical data, angiographic and procedural characteristics, lesion crossing success and outcomes were reviewed. Overall 133 patients underwent successful revascularization with 87% (143) of 164 lesions crossed using MNS alone. Another six lesions required a combination of MNS and conventional devices resulting in overall success of 91% (149/164). Eighteen complex lesions had previously failed PCI and 12 (67%) were successfully treated with MNS. Success after failed PCI was higher (88%) when a frequent user operated MNS, but occasional users also noted incremental success (30%). Twenty-five chronic total occlusions were included amongst these 164 lesions, with observed antegrade MNS lesion crossing rates of 78% for regular and 14% for occasional users. MNS is a useful adjunct to performance of PCI. This specialized technology has a clear learning curve and can facilitate treatment of highly complex lesions. © 2013 Wiley Periodicals, Inc.

A Preliminary Report on Combined Penoscrotal and Perineal Approach for Placement of Penile Prosthesis with Corporal Fibrosis

PubMed Central

Brusky, John P.; Tran, Viet Q.; Rieder, Jocelyn M.; Aboseif, Sherif R.

2008-01-01

Purpose. This paper aims at describing the combined penoscrotal and perineal approach for placement of penile prosthesis in cases of severe corporal fibrosis and scarring. Materials and methods. Three patients with extensive corporal fibrosis underwent penile prosthesis placement via combined penoscrotal and perineal approach from 1997 to 2006. Follow-up ranged from 15 to 129 months. Results. All patients underwent successful implantation of semirigid penile prosthesis. There were no short- or long-term complications. Conclusions. Results on combined penoscrotal and perineal approach to penile prosthetic surgery in this preliminary series of patients suggest that it is a safe technique and increases the chance of successful outcome in the surgical management of severe corporal fibrosis. PMID:19043562

Survival of rats bearing advanced intracerebral F 98 tumors after glutathione depletion and microbeam radiation therapy: conclusions from a pilot project.

PubMed

Schültke, E; Bräuer-Krisch, E; Blattmann, H; Requardt, H; Laissue, J A; Hildebrandt, G

2018-05-10

Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain. In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma.

PubMed

Whittle, Sarah B; Patel, Kalyani; Zhang, Linna; Woodfield, Sarah E; Du, Michael; Smith, Valeria; Zage, Peter E

2016-12-01

Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib would be effective against neuroblastoma in preclinical models. Methods We evaluated the effects of ponatinib on survival and migration of human neuroblastoma cells in vitro. Using orthotopic xenograft mouse models of human neuroblastoma, we analyzed tumors treated with ponatinib for growth, gross and histologic appearance, and vascularity. Results Ponatinib treatment of neuroblastoma cells resulted in decreased cell viability and migration in vitro. In mice with orthotopic xenograft neuroblastoma tumors, treatment with ponatinib resulted in decreased growth and vascularity. Conclusions Ponatinib reduces neuroblastoma cell viability in vitro and reduces tumor growth and vascularity in vivo. The antitumor effects of ponatinib suggest its potential as a novel therapeutic agent for neuroblastoma, and further preclinical testing is warranted.

Formation of solid tumors by a single multinucleated cancer cel

PubMed Central

Weihua, Zhang; Lin, Qingtang; Ramoth, Asa J.; Fan, Dominic; Fidler, Isaiah J.

2011-01-01

BACKGROUND Large multinucleated cells (MNC) commonly exist in tumorigenic cancer cell lines widely used in research, but their contributions to tumorigenesis are unknown. METHODS In this study, we characterized MNCs in the murine fibrosarcoma cell line UV-2237 in vitro and in vivo at a single cell level. RESULTS We observed that MNCs originated from a rare subpopulation of mononuclear cells; MNCs were positive for a senescent marker, β-galacosidase (SA-β-Gal); MNCs were responsible for the majority of clonogenic activity when cultured in hard agar; MNCs were more resistant to chemotherapeutic agents than were mononuclear cells; MNCs could undergo asymmetric division (producing mononuclear cells) and self-renewal in vitro and in vivo; and, most importantly a single MNC produced orthotopic subcutaneous tumors (composed mainly of mononuclear cells) that gave rise to spontaneous lung metastases in nude mice. CONCLUSIONS MNCs can be growth-arrested under stress, are highly resistant to chemotherapy, and can generate clonal orthotopic metastatic tumors PMID:21365635

[Hepatic cell transplantation: a new therapy in liver diseases].

PubMed

Pareja, Eugenia; Cortés, Miriam; Martínez, Amparo; Vila, Juan José; López, Rafael; Montalvá, Eva; Calzado, Angeles; Mir, José

2010-07-01

Liver transplantation has been remarkably effective in the treatment in patients with end-stage liver disease. However, disparity between solid-organ supply and increased demand is the greatest limitation, resulting in longer waiting times and increase in mortality of transplant recipients. This situation creates the need to seek alternatives to orthotopic liver transplantation.Hepatocyte transplantation or liver cell transplantation has been proposed as the best method to support patients. The procedure consists of transplanting individual cells to a recipient organ in sufficient quantity to survive and restore the function. The capacity of hepatic regeneration is the biological basis of hepatocyte transplantation. This therapeutic option is an experimental procedure in some patients with inborn errors of metabolism, fulminant hepatic failure and acute and chronic liver failure, as a bridge to orthotopic liver transplantation. In the Hospital La Fe of Valencia, we performed the first hepatocyte transplantation in Spain creating a new research work on transplant program. Copyright 2009 AEC. Published by Elsevier Espana. All rights reserved.

The customization of APACHE II for patients receiving orthotopic liver transplants

PubMed Central

Moreno, Rui

2002-01-01

General outcome prediction models developed for use with large, multicenter databases of critically ill patients may not correctly estimate mortality if applied to a particular group of patients that was under-represented in the original database. The development of new diagnostic weights has been proposed as a method of adapting the general model – the Acute Physiology and Chronic Health Evaluation (APACHE) II in this case – to a new group of patients. Such customization must be empirically tested, because the original model cannot contain an appropriate set of predictive variables for the particular group. In this issue of Critical Care, Arabi and co-workers present the results of the validation of a modified model of the APACHE II system for patients receiving orthotopic liver transplants. The use of a highly heterogeneous database for which not all important variables were taken into account and of a sample too small to use the Hosmer–Lemeshow goodness-of-fit test appropriately makes their conclusions uncertain. PMID:12133174

Recent advances in the field of ovarian tissue cryopreservation and opportunities for research.

PubMed

Ladanyi, Camille; Mor, Amir; Christianson, Mindy S; Dhillon, Namisha; Segars, James H

2017-06-01

The purpose of this study was to summarize the latest advances and successes in the field of ovarian tissue cryopreservation while identifying gaps in current knowledge that suggest opportunities for future research. A systematic review was performed according to PRISMA guidelines for all relevant full-text articles in PubMed published in English that reviewed or studied historical or current advancements in ovarian tissue cryopreservation and auto-transplantation techniques. Ovarian tissue auto-transplantation in post-pubertal women is capable of restoring fertility with over 80 live births currently reported with a corresponding pregnancy rate of 23 to 37%. The recently reported successes of live births from transplants, both in orthotopic and heterotopic locations, as well as the emerging methods of in vitro maturation (IVM), in vitro culture of primordial follicles, and possibility of in vitro activation (IVA) suggest new fertility options for many women and girls. Vitrification, as an ovarian tissue cryopreservation technique, has also demonstrated successful live births and may be a more cost-effective method to freezing with less tissue injury. Further, transplantation via the artificial ovary with an extracellular tissue matrix (ECTM) scaffolding as well as the effects of sphingosine-1-phosphate (SIP) and fibrin modified with heparin-binding peptide (HBP), heparin, and a vascular endothelial growth factor (VEGF) have demonstrated important advancements in fertility preservation. As a fertility preservation method, ovarian tissue cryopreservation and auto-transplantation are currently considered experimental, but future research may pave the way for these modalities to become a standard of care for women facing the prospect of sterility from ovarian damage.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohta, Kengo, E-mail: yesterday.is.yesterday@gmail.com; Shimohira, Masashi, E-mail: mshimohira@gmail.com; Sasaki, Shigeru, E-mail: ssasaki916@yahoo.co.jp

PurposeThe aim of this study is to analyze the technical and clinical success rates and safety of transarterial fiducial marker placement for image-guided proton therapy for malignant liver tumors.Methods and MaterialsFifty-five patients underwent this procedure as an interventional treatment. Five patients had 2 tumors, and 4 tumors required 2 markers each, so the total number of procedures was 64. The 60 tumors consisted of 46 hepatocellular carcinomas and 14 liver metastases. Five-mm-long straight microcoils of 0.018 inches in diameter were used as fiducial markers and placed in appropriate positions for each tumor. We assessed the technical and clinical success ratesmore » of transarterial fiducial marker placement, as well as the complications associated with it. Technical success was defined as the successful delivery and placement of the fiducial coil, and clinical success was defined as the completion of proton therapy.ResultsAll 64 fiducial coils were successfully installed, so the technical success rate was 100 % (64/64). Fifty-four patients underwent proton therapy without coil migration. In one patient, proton therapy was not performed because of obstructive jaundice due to bile duct invasion by hepatocellular carcinoma. Thus, the clinical success rate was 98 % (54/55). Slight bleeding was observed in one case, but it was stopped immediately and then observed. None of the patients developed hepatic infarctions due to fiducial marker migration.ConclusionTransarterial fiducial marker placement appears to be a useful and safe procedure for proton therapy for malignant liver tumors.« less

Sedation protocol with fasting and shorter sleep leads to magnetic resonance imaging success.

PubMed

Kimiya, Takahisa; Sekiguchi, Shinichiro; Yagihashi, Tatsuhiko; Arai, Mie; Takahashi, Hirotaka; Takahashi, Takao

2017-10-01

Young children undergoing magnetic resonance imaging (MRI) require sedation. In June 2013, Tokyo Metropolitan Ohtsuka Hospital (TMOH) introduced an oral sedation protocol for young children undergoing MRI; the protocol included instructions on fasting before sedation, and recommended a shorter duration of sleep the night before MRI. We compared the MRI success rate before and after the introduction of this protocol. The eligible subjects were children under 3 years old who underwent MRI by appointment at TMOH between October 2012 and March 2014, under sedation with triclofos sodium. All those who underwent MRI in or after June 2013 were enrolled prospectively as a post-protocol group. All patients who underwent MRI before June 2013 were enrolled retrospectively as a pre-protocol group, with data collected from chart review. Seventy-four patients were enrolled in the post-protocol group, and 42 in the pre-protocol group. The MRI success rate was significantly higher in the post-protocol group than in the pre-protocol group (98.7% vs 88.1%), as was the rate of on-time starting of MRI (86.5% vs 71.4%). The post-protocol group woke up earlier on the day of examination (6:18 a.m. vs 6:43 a.m.), resulting in a significantly longer time between awakening and the beginning of sedation (289.8 min vs 265.9 min), and a significantly shorter average duration of sleep on the previous night (504.8 min vs 532.3 min). Implementation of a hospital-wide sedation protocol for young children undergoing MRI significantly improved the MRI success rate. © 2017 Japan Pediatric Society.

Cryo-image Analysis of Tumor Cell Migration, Invasion, and Dispersal in a Mouse Xenograft Model of Human Glioblastoma Multiforme

PubMed Central

Qutaish, Mohammed Q.; Sullivant, Kristin E.; Burden-Gulley, Susan M.; Lu, Hong; Roy, Debashish; Wang, Jing; Basilion, James P.; Brady-Kalnay, Susann M.; Wilson, David L.

2012-01-01

Purpose The goals of this study were to create cryo-imaging methods to quantify characteristics (size, dispersal, and blood vessel density) of mouse orthotopic models of glioblastoma multiforme (GBM) and to enable studies of tumor biology, targeted imaging agents, and theranostic nanoparticles. Procedures Green fluorescent protein-labeled, human glioma LN-229 cells were implanted into mouse brain. At 20–38 days, cryo-imaging gave whole brain, 4-GB, 3D microscopic images of bright field anatomy, including vasculature, and fluorescent tumor. Image analysis/visualization methods were developed. Results Vessel visualization and segmentation methods successfully enabled analyses. The main tumor mass volume, the number of dispersed clusters, the number of cells/cluster, and the percent dispersed volume all increase with age of the tumor. Histograms of dispersal distance give a mean and median of 63 and 56 μm, respectively, averaged over all brains. Dispersal distance tends to increase with age of the tumors. Dispersal tends to occur along blood vessels. Blood vessel density did not appear to increase in and around the tumor with this cell line. Conclusion Cryo-imaging and software allow, for the first time, 3D, whole brain, microscopic characterization of a tumor from a particular cell line. LN-229 exhibits considerable dispersal along blood vessels, a characteristic of human tumors that limits treatment success. PMID:22125093

First 60 fetal in-utero myelomeningocele repairs at Saint Louis Fetal Care Institute in the post-MOMS trial era: hydrocephalus treatment outcomes (endoscopic third ventriculostomy versus ventriculo-peritoneal shunt).

PubMed

Elbabaa, Samer K; Gildehaus, Anne M; Pierson, Matthew J; Albers, J Andrew; Vlastos, Emanuel J

2017-07-01

The published results of the Management of Myelomeningocele Study (MOMS) trial in 2011 showed improved outcomes (reduced need for shunting, decreased incidence of Chiari II malformation, and improved scores of mental development and motor function) in the fetal prenatal repair group compared to the postnatal group. Historically, endoscopic third ventriculostomy (ETV) remains as a controversial hydrocephalus treatment option with high failure rates in pediatric patients with a history of myelomeningocele (MMC). We report hydrocephalus treatment outcomes in the fetal in-utero myelomeningocele repair patients who underwent repair at our Saint Louis Fetal Care Institute following the MOMS trial. We looked carefully at ETV outcomes in this patient population and we identified risk factors for failure. At our Saint Louis Fetal Care Institute, we followed the maternal and fetal inclusion and exclusion criteria used by the MOMS trial. The records of our first 60 fetal MMC repairs performed at our institute between 2011 and 2017 were examined. We retrospectively reviewed the charts, prenatal fetal magnetic resonance imaging (MRI) and ultrasound (US) imaging findings, postnatal brain MRI, and Bayley neurodevelopment testing results for infants and children who underwent surgical treatment of symptomatic hydrocephalus (VP shunt versus ETV). Multiple variables possibly related to ETV failure were considered for identifying risk factors for ETV failure. Between May 2011 and March 2017, 60 pregnant female patients underwent the prenatal MMC repair for their fetuses between 20 and 26 weeks' gestational age (GA) utilizing the standard hysterotomy for exposure of the fetus, and microsurgical repair of the MMC defect. All MMC defects underwent successful in-utero repair, with subsequent progression of the pregnancy. At the time of this study, 58 babies have been born, 56 are alive since there were 2 mortalities in the neonatal period due to prematurity. One patient was excluded given lack of consent for research purposes. From the remaining 55 patient included in this study, a total of 30 infants and toddlers underwent treatment of hydrocephalus (ETV and VPS groups). Twenty-five patients underwent ETV (24 primary ETV and 1 after shunt failure). Nineteen patients underwent shunt placements (6 primary/13 after ETV failure). Mean GA at time of MMC repair for the ETV group was 24 + 6/7 weeks (range 22 + 4/7 to 25 + 6/7). Mean follow up for patients who had a successful ETV was 17.25 months (range 4-57 months). Bayley neurodevelopmental testing results were examined pre- and post-ETV. Overall ETV success rate was 11/24 (45.8%) at the time of this study. The total number of patients who underwent shunt placement was 19/55 (34.5%), while shunting rate was 40% in the MOMS trial. Using a simple logistic regression analysis to identify predictors of ETV failure, ETV age ≤6 months and gestational age ≥23 weeks at repair of myelomeningocele were significant predictors for ETV failure while in-utero ventricular stability ≤4 mm and in-utero ventricular size post-repair ≤15.5 mm were significant predictors for ETV success. None of the listed variables independently predicted classification into ETV success versus ETV failure groups when entered into multiple logistic regression analysis. ETV, as an alternative to initial shunting, may continue to show promising results for treating fetal MMC repair patient population who present with symptomatic hydrocephalus during infancy and early childhood. Although our overall CSF diversion rate (ETV and VPS groups) in our fetal MMC group is higher than the MOMS trial, our shunting rate is lower given our higher incidence of patients with successful ETV. To our knowledge, this is the largest reported ETV series in patients who underwent fetal MMC repair. ETV deserves a closer look in the setting of improved hindbrain herniation in fetal in-utero MMC repair patients. In our series, young age (less than 6 months) and late GA at time of fetal MMC repair (after 23 weeks GA) were predictors for ETV failure, while in-utero stability of ventricular size (less than 4 mm) and in-utero ventricular size post-repair ≤15.5 mm were predictors for ETV success. Larger series and potential prospective randomized studies are required for further evaluation of risk factors for ETV failure in the fetal MMC patient population.

Immunotherapy in new pre-clinical models of HPV-associated oral cancers.

PubMed

Paolini, Francesca; Massa, Silvia; Manni, Isabella; Franconi, Rosella; Venuti, Aldo

2013-03-01

Cervical, anal, penile and a sub-set of head and neck (HN) tumors are critical health problems caused by high risk Human Papilloma Viruses (HPVs), like HPV type 16. No specific/effective pharmacological treatments exist. A valid preventive vaccination as well as the immunotherapy of persistent infections, pre-cancerous lesions or early-stage cancers could drive the HPV disease burden down. These treatments might be featured through low-cost platforms like those based on DNA and plant biotechnologies to produce tailored and enhanced formulations taking profit from the use of plants as bio-factories and as a source of immune-stimulators. Finally, and regardless of the formulation type, pre-clinical tests and models are crucial to foresee efficacy of immunotherapy before clinical trials.   In this study, we created an orthotopic mouse model for HPV-related oral tumors, a subset of HN tumors for which no models have been generated before. The model was obtained by inducing the stable expression of the HPV16 E7 protein into the mouse oral squamous cell carcinoma (OSCC) AT-84 (AT-84 E7). The AT-84 E7 cells were injected into the mouth pavement of C3H mice via an extra-oral route to obtain orthotopic tumors. The model turned out to mimic the natural history of the human HPV oral cancer. From AT-84 E7, through engineering to express luciferase, the bioluminescent AT-84 E7-Luc cells were obtained for a fast and easy monitoring by imaging. The AT-84 E7 and the AT-84 E7-Luc tumors were used to test the efficacy of E7-based therapeutic vaccines that we had previously generated and that had been already proven to be active in mice against non-orthotopic E7-expressing tumors (TC-1 cells). In particular, we used genetic and plant-derived formulations based on attenuated HPV16 E7 variants either fused to plant virus genes with immunological activity or produced by tobacco plants. Mice were monitored by imaging allowing to test the size reduction of the mouth implanted experimental tumors in function of the different regimens used. The proposed tumor model is easy to handle and to reproduce and it is efficacious in monitoring immunotherapy. Furthermore, it is expected to be more predictive of clinical outcome of therapeutic vaccines than non-orthotopic models that are currently used. Finally, imaging offers unique opportunities to predict formulation efficacy through measuring tumor growth in vivo.

On the Edge: A Study of Small Private Colleges That Have Made a Successful Financial Turnaround

ERIC Educational Resources Information Center

Carey, Amy Bragg

2014-01-01

This article describes a qualitative study that involved two small private universities, examining their process of transformation from institutions headed toward closure to institutions that underwent a successful turnaround. The primary questions that guided the study included the issues and circumstances that led to the need for a turnaround,…

Living donor lobar lung transplantation: a longstanding concept being revisited with the same old NEMESIS.

PubMed

Hayes, Don; Baker, Peter B

2014-06-01

Living donor lobar lung transplantation (LDLLT) has been successfully used in select patient populations. A 29-year-old male, who underwent bilateral LDLLT 12 years earlier with allografts donated by father and paternal uncle, developed bronchiolitis obliterans syndrome at distinctly different rates. LDLLT can be done successfully with unique management issues.

Outcomes of reintervention after failed urethroplasty.

PubMed

Ekerhult, Teresa Olsen; Lindqvist, Klas; Peeker, Ralph; Grenabo, Lars

2017-02-01

Urethroplasty is a procedure that has a high success rate. However, there exists a small subgroup of patients who require multiple procedures to achieve an acceptable result. This study analyses the outcomes of a series of patients with failed urethroplasty. This is a retrospective review of 82 failures out of 407 patients who underwent urethroplasty due to urethral stricture during the period 1999-2013. Failure was defined as the need for an additional surgical procedure. Of the failures, 26 patients had penile strictures and 56 had bulbar strictures. Meatal strictures were not included. The redo procedures included one or multiple direct vision internal urethrotomies, dilatations or new urethroplasties, all with a long follow-up time. The patients underwent one to seven redo surgeries (mean 2.4 procedures per patient). In the present series of patients, endourological procedures cured 34% (28/82) of the patients. Ten patients underwent multiple redo urethroplasties until a satisfactory outcome was achieved; the penile strictures were the most difficult to cure. In patients with bulbar strictures, excision with anastomosis and substitution urethroplasty were equally successful. Nevertheless, 18 patients were defined as treatment failures. Of these patients, nine ended up with clean intermittent self-dilatation as a final solution, five had perineal urethrostomy and four are awaiting a new reintervention. Complicated cases need centralized professional care. Despite the possibility of needing multiple reinterventions, the majority of patients undergoing urethroplasty have a good chance of successful treatment.

Sizing of patent ductus arteriosus in adults for transcatheter closure using the balloon pull-through technique.

PubMed

Shafi, Nabil A; Singh, Gagan D; Smith, Thomas W; Rogers, Jason H

2018-05-01

To describe a novel balloon sizing technique used during adult transcatheter patent ductus arteriosus (PDA) closure. In addition, to determine the clinical and procedural outcomes in six patients who underwent PDA balloon sizing with subsequent deployment of a PDA occluder device. Transcatheter PDA closure in adults has excellent safety and procedural outcomes. However, PDA sizing in adults can be challenging due to variable defect size, high flow state, or anatomical complexity. We describe a series of six cases where the balloon- pull through technique was successfully performed for PDA sizing prior to transcatheter closure. Consecutive adult patients undergoing adult PDA closure at our institution were studied retrospectively. A partially inflated sizing balloon was pulled through the defect from the aorta into the pulmonary artery and the balloon waist diameter was measured. Procedural success and clinical outcomes were obtained. Six adult patients underwent successful balloon pull-through technique for PDA sizing during transcatheter PDA closure, since conventional angiography often gave suboptimal opacification of the defect. All PDAs were treated with closure devices based on balloon PDA sizing with complete closure and no complications. In three patients that underwent preprocedure computed tomography, the balloon size matched the CT derived measurements. The balloon pull-through technique for PDA sizing is a safe and accurate sizing modality in adults undergoing transcatheter PDA closure. © 2017 Wiley Periodicals, Inc.

Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD).

PubMed

Czigany, Zoltan; Schöning, Wenzel; Ulmer, Tom Florian; Bednarsch, Jan; Amygdalos, Iakovos; Cramer, Thorsten; Rogiers, Xavier; Popescu, Irinel; Botea, Florin; Froněk, Jiří; Kroy, Daniela; Koch, Alexander; Tacke, Frank; Trautwein, Christian; Tolba, Rene H; Hein, Marc; Koek, Ger H; Dejong, Cornelis H C; Neumann, Ulf Peter; Lurje, Georg

2017-10-10

Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. In an attempt to improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with a higher incidence of primary graft non-function and/or delayed graft function. As such, several strategies have been developed aiming at reconditioning poor quality ECD liver allografts. Hypothermic oxygenated machine perfusion (HOPE) has been successfully tested in preclinical experiments and in few clinical series of donation after cardiac death OLT. HOPE ECD-DBD is an investigator-initiated, open-label, phase-II, prospective multicentre randomised controlled trial on the effects of HOPE on ECD allografts in donation after brain death (DBD) OLT. Human whole organ liver grafts will be submitted to 1-2 hours of HOPE (n=23) via the portal vein before implantation and are going to be compared with a control group (n=23) of patients transplanted after conventional cold storage. Primary (peak and Δ peak alanine aminotransferase within 7 days) and secondary (aspartate aminotransferase, bilirubin and international normalised ratio, postoperative complications, early allograft dysfunction, duration of hospital and intensive care unit stay, 1-year patient and graft survival) endpoints will be analysed within a 12-month follow-up. Extent of ischaemia-reperfusion (I/R) injury will be assessed using liver tissue, perfusate, bile and serum samples taken during the perioperative phase of OLT. The study was approved by the institutional review board of the RWTH Aachen University, Aachen, Germany (EK 049/17). The current paper represent the pre-results phase. First results are expected in 2018. NCT03124641. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Endovascular reconstruction of popliteal and infrapopliteal arteries for limb salvage and wound healing in patients with critical limb ischemia – A retrospective analysis

PubMed Central

Khanolkar, Uday B.; Ephrem, Biju

2016-01-01

Background Advancement in endovascular techniques has led to rapid growth in endovascular revascularization, and it has emerged as a treatment for critical limb ischemia (CLI). Clinical effectiveness of revascularization has been frequently judged by vessel patency and limb salvage, but there is paucity of reports on outcomes of the wound. We present a retrospective analysis of immediate angiographic and 3-month clinical outcome of patients who underwent endovascular reconstruction of popliteal and infrapopliteal arteries for CLI. Methods All patients who underwent endovascular reconstruction of popliteal and/or infrapopliteal arteries for CLI and >70% stenosis on digital subtraction angiography between March 2010 and November 2014 and had a clinical follow-up of at least 3 months were selected for analysis. Results 34 patients underwent endovascular reconstruction. 9 patients (26%) underwent only POBA and remaining 25 (74%) underwent additional stenting. 13 patients (38%) had multiple segmental revascularization. 24 patients (71%) had successful vessel recanalization. Linear flow to foot in at least one artery could be achieved in 20 patients (59%) post revascularization. Successful wound healing occurred in 11 (35%) patients with an additional 7 (21%) patients showing clinical improvement in their wounds. Limb salvage was achieved in 33 patients (97%) at 3-month follow-up. Conclusion Endovascular revascularization of popliteal and infrapopliteal arteries is a feasible, safe, and effective procedure for the treatment of CLI. Normal inflow and outflow with at least one of the three infrapopliteal vessels being patent is essential for adequate healing of chronic ulcers and prevention of major amputation. PMID:26896272

Anastomotic fibrous ring as cause of stricture recurrence after bulbar onlay graft urethroplasty.

PubMed

Barbagli, Guido; Guazzoni, Giorgio; Palminteri, Enzo; Lazzeri, Massimo

2006-08-01

We retrospectively reviewed patterns of failure after bulbar substitution urethroplasty. In particular we investigated the prevalence and location of anastomotic fibrous ring strictures occurring at the apical anastomoses between the graft and urethral plate after 3 types of onlay graft techniques. We reviewed the records of 107 patients who underwent bulbar urethroplasty between 1994 and 2004. Mean patient age was 44 years. Patients with lichen sclerosus, failed hypospadias repair or urethroplasty and panurethral strictures were excluded. A total of 45 patients underwent dorsal onlay skin graft urethroplasty, 50 underwent buccal mucosa onlay graft urethroplasty and 12 underwent augmented end-to-end urethroplasty. The clinical outcome was considered a success or failure at the time that any postoperative procedure was needed, including dilation. Mean followup was 74 months (range 12 to 130). Of 107 cases 85 (80%) were successful and 22 (20%) failed. Failure in 12 patients (11%) involved the whole grafted area and in 10 (9%) it involved the anastomotic site, which was distal and proximal in 5 each. Urethrography, urethral ultrasound and urethroscopy were fundamental for determining the difference between full-length and focal extension of re-stricture. Failures were treated with multistage urethroplasty in 12 cases, urethrotomy in 7 and 1-stage urethroplasty in 3. Of the patients 16 had a satisfactory final outcome and 6 underwent definitive perineal urinary diversion. The prevalence and location of anastomotic ring strictures after bulbar urethroplasty were uniformly distributed in after 3 surgical techniques using skin or buccal mucosa. Further studies are necessary to clarify the etiology of these fibrous ring strictures.

Predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation for critical lower limb ischemia.

PubMed

Tshomba, Yamume; Psacharopulo, Daniele; Frezza, Serena; Marone, Enrico Maria; Astore, Domenico; Chiesa, Roberto

2014-04-01

The aim of this study was to determine predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation (SCS) for critical lower limb ischemia. We retrospectively analyzed 101 consecutive patients with few meter claudication and nonhealing ulcer who underwent definitive SCS. These patients were selected among 274 SCS patients treated at our center from 1995 to 2012. All presented with non-reconstructable critical leg ischemia (NR-CLI) and underwent supervised exercise therapy, best medical care and regular ulcers standard or advanced medications for at least 1 month before SCS implantation. We measured self-perceived quality of life using the SF-36 questionnaire. Patients with an improved walking distance of at least 30 meters after SCS had significant improvement on SF-36 questionnaire scores. We considered 30 meters as the cut-off for clinically significant improvement in pain-free walking distance, and we defined this value as functional success. Logistic regression was applied to assess baseline and other patient variables as possible predictors of functional success. Neither perioperative mortality nor significant complications were found. At a median follow-up of 69 months (range 1-202 months), mortality, major amputation, and minor amputation were 8.9%, 5.9%, and 6.9%, respectively. Functional clinical success was reported in 25.7% of cases. Independent predictors of functional success at univariate analysis included delay between the onset of the ulcer and SCS (P < 0.001) and the pain-free walking distance before SCS (P < 0.002). The only predictive factor of functional success at multivariate analysis was the delay between the onset of ulcer and SCS (median delay in patients with and without functional success was 3 and 15 months, respectively). In particular, comparable to pain-free walking distance before SCS, the success rate decreased by 40% for each month elapsed from onset of ulcer to SCS. In our series of patients who underwent SCS, reduced delay between the onset of ulcer and SCS was associated with improved quality of life and walking distance. Larger series are required to confirm these data and to assess clinical implications. Copyright © 2014 Elsevier Inc. All rights reserved.

The use of postoperative slit-lamp optical coherence tomography to predict primary failure in descemet stripping automated endothelial keratoplasty.

PubMed

Shih, Carolyn Y; Ritterband, David C; Palmiero, Pat-Michael; Seedor, John A; Papachristou, George; Harizman, Noga; Liebmann, Jeffrey M; Ritch, Robert

2009-05-01

To determine if central donor lenticle thickness as measured by slit-lamp optical coherence tomography (SL OCT; Heidelberg Engineering, Heidelberg, Germany) is predictive of primary donor failure in patients undergoing Descemet stripping automated endothelial keratoplasty (DSAEK). Retrospective cross-sectional study. Eighty-four patients who underwent DSAEK surgery by 2 surgeons (D.C.R. and J.A.S.) were enrolled. At each postoperative visit (postoperative day 1, week 1, month 1, and month 2), an SL OCT scan was obtained. Statistical differences in SL OCT measurements of successful and failed DSAEK procedures were measured using the Student t test. A successful DSAEK surgery was defined as having an anatomically attached, clear recipient corneal stroma and donor lenticle compatible with good vision 2 months after surgery. A failed DSAEK surgery was defined as an attached donor lenticle with SL evidence of corneal edema and thickening visible at 2 months or more. Ninety-three eyes of 84 consecutive patients who underwent DSAEK surgery also underwent postoperative SL OCT. After 2 months of follow-up, 82 (88%) procedures were successful and 11 (12%) procedures were failures. The average donor lenticle thickness in successful DSAEK eyes was 314 +/- 128 microm on postoperative day 1 as compared with failed DSAEK eyes, which averaged 532 +/- 259 microm (P = .0013). This was independent regardless of whether the lenticle was attached on the first postoperative visit. Seventy-nine (98%) successful DSAEK eyes had a lenticle thickness of < or = 350 microm at the 1-week visit. All of the failed DSAEK eyes (11 eyes) had a lenticle thickness > or = 350 microm at the 1-week postoperative visit. Statistically significant differences in SL OCT thickness measurements were seen between successful and failed DSAEK cases at all examinations after postoperative week 1. Corneal thickness measurements made with SL OCT are an important predictor of DSAEK failure in both attached and detached lenticles within the first week of surgery. DSAEK lenticle thickness of 350 microm or less at 1 week had a predictability of success of more than 98%.

Liver Transplantation for Budd-Chiari Syndrome

PubMed Central

Putnam, Charles W.; Porter, Kendrick A.; Well, Richard; Reid, H. A. S.; Starzl, Thomas E.

2011-01-01

Orthotopic liver transplantation was accomplished in a 22-year-old woman dying of the Budd-Chiarl syndrome. She Is well and has normal liver function 16 months postoperatively. In view of the good early result, it will be appropriate to consider liver replacement for this disease in further well-selected cases. PMID:781334

Experience with extracorporeal renal operations and autotransplantation in the management of complicated urologic disorders.

PubMed

Novick, A C; Straffon, R A; Stewart, B H

1981-07-01

Renal autotransplantation with or without an extracorporeal renal operation was performed 45 times upon 43 patients. Twenty-one patients underwent renal autotransplantation as surgical treatment for renovascular hypertension, all of whom are cured or have improved postoperatively. Sixteen renal autotransplants were performed upon 14 patients with extensive ureteral disease, 14 of which were successful. Six patients with carcinoma centrally located in a solitary kidney underwent extracorporeal partial nephrectomy and autotransplantation. Three of these patients are alive with functioning autografts and are tumor-free from one to five years postoperatively. Two patients with multiple recurrent renal calculi were successfully treated by extracorporeal pyelolithotomy and autotransplantation with pyelovesicostomy. An extracorporeal renal operation and autotransplantation can provide the best solution for selected urologic problems not correctable by conventional methods.

The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model.

PubMed

Garcia, Celina; Dubois, Luiz Gustavo; Xavier, Anna Lenice; Geraldo, Luiz Henrique; da Fonseca, Anna Carolina Carvalho; Correia, Ana Helena; Meirelles, Fernanda; Ventura, Grasiella; Romão, Luciana; Canedo, Nathalie Henriques Silva; de Souza, Jorge Marcondes; de Menezes, João Ricardo Lacerda; Moura-Neto, Vivaldo; Tovar-Moll, Fernanda; Lima, Flavia Regina Souza

2014-12-08

Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood-brain barrier disruption. This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.

Intratumoral INF-γ triggers an antiviral state in GL261 tumor cells: a major hurdle to overcome for oncolytic vaccinia virus therapy of cancer.

PubMed

Kober, Christina; Weibel, Stephanie; Rohn, Susanne; Kirscher, Lorenz; Szalay, Aladar A

2015-01-01

Oncolytic vaccinia virus (VACV) therapy is an alternative treatment option for glioblastoma multiforme. Here, we used a comparison of different tumor locations and different immunologic and genetic backgrounds to determine the replication efficacy and oncolytic potential of the VACV LIVP 1.1.1, an attenuated wild-type isolate of the Lister strain, in murine GL261 glioma models. With this approach, we expected to identify microenvironmental factors, which may be decisive for failure or success of oncolytic VACV therapy. We found that GL261 glioma cells implanted subcutaneously or orthotopically into Balb/c athymic, C57BL/6 athymic, or C57BL/6 wild-type mice formed individual tumors that respond to oncolytic VACV therapy with different outcomes. Surprisingly, only Balb/c athymic mice with subcutaneous tumors supported viral replication. We identified intratumoral IFN-γ expression levels that upregulate MHCII expression on GL261 cells in C57BL/6 wild-type mice associated with a non-permissive status of the tumor cells. Moreover, this IFN-γ-induced tumor cell phenotype was reversible.

Systemic administration of bevacizumab prolongs survival in an in vivo model of platinum pre-treated ovarian cancer

PubMed Central

REIN, DANIEL T.; VOLKMER, ANNE KATHRIN; VOLKMER, JENS; BEYER, INES M.; JANNI, WOLFGANG; FLEISCH, MARKUS C.; WELTER, ANNE KATHRIN; BAUERSCHLAG, DIRK; SCHÖNDORF, THOMAS; BREIDENBACH, MARTINA

2012-01-01

Ovarian cancer patients often suffer from malignant ascites and pleural effusion. Apart from worsening the outcome, this condition frequently impairs the quality of life in patients who are already distressed by ovarian cancer. This study investigated whether single intraperitoneal administration of the anti-VEGF antibody bevacizumab is capable of reducing the ascites-related body surface and prolonging survival. The study was performed in an orthotopic murine model of peritoneal disseminated platin-resistant ovarian cancer. Mice were treated with bevacizumab and/or paclitaxel or buffer (control). Reduction of body surface and increased survival rates were assessed as therapeutic success. Survival of mice in all treatment groups was significantly enhanced when compared to the non-treatment control group. The combination of paclitaxel plus bevacizumab significantly improved body surface as well as overall survival in comparison to a treatment with only one of the drugs. Treatment of malignant effusion with a single dose of bevacizumab as an intraperitoneal application, with or without cytostatic co-medication, may be a powerful alternative to systemic treatment. PMID:22740945

Total Artificial Heart as Bridge to Heart Transplantation in Chagas Cardiomyopathy: Case Report.

PubMed

Ruzza, A; Czer, L S C; De Robertis, M; Luthringer, D; Moriguchi, J; Kobashigawa, J; Trento, A; Arabia, F

2016-01-01

Chagas disease (CD) is becoming an increasingly recognized cause of dilated cardiomyopathy outside of Latin America, where it is endemic, due to population shifts and migration. Heart transplantation (HTx) is a therapeutic option for end-stage cardiomyopathy due to CD, but may be considered a relative contraindication due to potential reactivation of the causative organism with immunosuppression therapy. The total artificial heart (TAH) can provide mechanical circulatory support in decompensated patients with severe biventricular dysfunction until the time of HTx, while avoiding immunosuppressive therapy and removing the organ most affected by the causative organism. We report herein a patient with CD and severe biventricular dysfunction, who had mechanical circulatory support with a TAH for more than 6 months, followed by successful orthotopic HTx and treatment with benznidazole for 3 months. The patient had no evidence of recurrent disease in the transplanted heart based on endomyocardial biopsy up to 1 year post-transplantation, and remains alive more than 30 months after insertion of a TAH and 24 months after HTx. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac Transplantation in a Jehovah's Witness

PubMed Central

Lammermeier, David E.; Duncan, J. Michael; Kuykendall, R. Craig; Macris, Michael P.; Frazier, O. Howard

1988-01-01

Between July 1982 and October 1987, surgeons at our institution performed 215 cardiac transplantation procedures, 1 of which was in a 46-year-old Jehovah's Witness with congestive cardiomyopathy, who required preoperative intra-aortic balloon pump support. At surgery, the cardiopulmonary bypass system was primed with 1600 ml of Ringer's lactate solution and dextrose. In the 57 minutes during which the patient was on cardiopulmonary bypass, the intra-aortic balloon was removed and successful orthotopic heart transplantation was performed. No supplemental blood or blood product was used, either during or after the procedure. The estimated intraoperative blood loss was 300 ml, and the postoperative chest tube drainage amounted to 1495 ml. Postoperative hematologic abnormalities (mild hypoprothrombinemia, mild thrombocytopenia, mild platelet dysfunction, and moderate hypochromic microcytic anemia) were corrected with Imferon, vitamin K, and desmopressin acetate administered intravenously, and with ferrous sulfate administered orally. This case, which to our knowledge is only the 2nd cardiac transplant in a Jehovah's Witness, further establishes that these patients can undergo even the most major of open-heart procedures without supplemental blood. (Texas Heart Institute Journal 1988;15:189-191) PMID:15227251

Successful surgical management of bilateral epiretinal membrane in a child with only café-au-lait spots.

PubMed

Philip, Swetha Sara; Kuriakose, Thomas; Chacko, Geeta

2017-06-01

A 6-year-old boy diagnosed as anisometropic amblyopia, with only café-au-lait spots and a family history of neurofibromatosis, presented with decrease in vision in the both eyes. Dilated fundus examination showed epiretinal membrane in both eyes over the macula. He underwent successful surgical management of the epiretinal membrane.

Ultrasound-guided lumbar puncture in pediatric patients: technical success and safety.

PubMed

Pierce, David B; Shivaram, Giri; Koo, Kevin S H; Shaw, Dennis W W; Meyer, Kirby F; Monroe, Eric J

2018-06-01

Disadvantages of fluoroscopically guided lumbar puncture include delivery of ionizing radiation and limited resolution of incompletely ossified posterior elements. Ultrasound (US) allows visualization of critical soft tissues and the cerebrospinal fluid (CSF) space without ionizing radiation. To determine the technical success and safety of US-guided lumbar puncture in pediatric patients. A retrospective review identified all patients referred to interventional radiology for lumbar puncture between June 2010 and June 2017. Patients who underwent lumbar puncture with fluoroscopic guidance alone were excluded. For the remaining procedures, technical success and procedural complications were assessed. Two hundred and one image-guided lumbar punctures in 161 patients were included. Eighty patients (43%) had previously failed landmark-based attempts. One hundred ninety-six (97.5%) patients underwent lumbar puncture. Five procedures (2.5%) were not attempted after US assessment, either due to a paucity of CSF or unsafe window for needle placement. Technical success was achieved in 187 (95.4%) of lumbar punctures attempted with US guidance. One hundred seventy-seven (90.3%) were technically successful with US alone (age range: 2 days-15 years, weight range: 1.9-53.1 kg) and an additional 10 (5.1%) were successful with US-guided thecal access and subsequent fluoroscopic confirmation. Three (1.5%) cases were unsuccessful with US guidance but were subsequently successful with fluoroscopic guidance. Of the 80 previously failed landmark-based lumbar punctures, 77 (96.3%) were successful with US guidance alone. There were no reported complications. US guidance is safe and effective for lumbar punctures and has specific advantages over fluoroscopy in pediatric patients.

Direct Vision Internal Urethrotomy for Short Anterior Urethral Strictures and Beyond: Success Rates, Predictors of Treatment Failure, and Recurrence Management.

PubMed

Kluth, Luis A; Ernst, Lukas; Vetterlein, Malte W; Meyer, Christian P; Reiss, C Philip; Fisch, Margit; Rosenbaum, Clemens M

2017-08-01

To determine success rates, predictors of recurrence, and recurrence management of patients treated for short anterior urethral strictures by direct vision internal urethrotomy (DVIU). We identified 128 patients who underwent DVIU of the anterior urethra between December 2009 and March 2016. Follow-up was conducted by telephone interviews. Success rates were assessed by Kaplan-Meier estimators. Predictors of stricture recurrence and different further therapy strategies were identified by uni- and multivariable Cox regression analyses. The mean age was 63.8 years (standard deviation: 16.3) and the overall success rate was 51.6% (N = 66) at a median follow-up of 16 months (interquartile range: 6-43). Median time to stricture recurrence was six months (interquartile range: 2-12). In uni- and multivariable analyses, only repeat DVIU (hazard ratio [HR] = 1.87, 95% confidence interval (CI) = 1.13-3.11, P= .015; and HR=1.78, 95% CI = 1.05-3.03, P = .032, respectively) was a risk factor for recurrence. Of 62 patients with recurrence, 35.5% underwent urethroplasty, 29% underwent further endoscopic treatment, and 33.9% did not undergo further interventional therapy. Age (HR = 1.05, 95% CI = 1.01-1.09, P = .019) and diabetes (HR = 2.90, 95% CI = 1.02-8.26, P = .047) were predictors of no further interventional therapy. DVIU seems justifiable in short urethral strictures as a primary treatment. Prior DVIU was a risk factor for recurrence. In case of recurrence, about one-third of the patients did not undergo any further therapy. Higher age and diabetes predicted the denial of any further treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Interventional Radiology-Operated Cholecystoscopy for the Management of Symptomatic Cholelithiasis: Approach, Technical Success, Safety, and Clinical Outcomes.

PubMed

Patel, Nishant; Chick, Jeffrey Forris Beecham; Gemmete, Joseph J; Castle, Jordan C; Dasika, Narasimham; Saad, Wael E; Srinivasa, Ravi N

2018-05-01

The objective of our study was to report the technique, complications, and clinical outcomes of interventional radiology-operated cholecystoscopy with stone removal for the management of symptomatic cholelithiasis. Ten (77%) men and three (23%) women (mean age, 65 years) with symptomatic cholelithiasis underwent cholecystostomy followed by interventional radiology-operated cholecystoscopy with stone removal. Major comorbidities precluding cholecystectomy included prior cardiac, pulmonary, or abdominal surgery; cirrhosis; sepsis with hyponatremia; seizure disorder; developmental delay; and cholecystoduodenal fistula. Cholecystostomy access, time between cholecystostomy and cholecystoscopy, endoscopic and fragmentation devices used, technical success, procedure time, fluoroscopy time, complications, length of hospital stay, time between cholecystoscopy and cholecystostomy removal, follow-up, and acute cholecystitis recurrence were recorded. Eleven (85%) patients underwent transhepatic cholecystostomy, and two (15%) patients underwent transperitoneal cholecystostomy. The mean time from cholecystostomy to cholecystoscopy was 151 days. Flexible endoscopy was used in eight (62%) patients, rigid endoscopy in three (23%), and both flexible and rigid in two (15%). Electrohydraulic lithotripsy was used in eight procedures, nitinol baskets in seven, ultrasonic lithotripsy in two, and percutaneous thrombectomy devices in one. Primary technical success was achieved in 11 (85%) patients, and secondary technical success was achieved in 13 (100%) patients. The mean procedure time was 164 minutes, and the mean number of procedures required to clear all gallstones was 1. One (8%) patient developed acute pancreatitis, and one (8%) patient died of gastrointestinal hemorrhage. The median hospital length of stay after cholecystoscopy was 1 day for postoperative monitoring. The mean time between cholecystoscopy and cholecystostomy removal was 39 days. One (8%) patient developed recurrent acute cholecystitis 1095 days after cholecystoscopy. Interventional radiology-operated cholecystoscopy may serve as an effective method for percutaneous gallstone removal in patients with multiple comorbidities precluding cholecystectomy.

Relevance of testicular histopathology on prediction of sperm retrieval rates in case of non-obstructive and obstructive azoospermia.

PubMed

Cito, Gianmartin; Coccia, Maria E; Dabizzi, Sara; Morselli, Simone; Della Camera, Pier A; Cocci, Andrea; Criscuoli, Luciana; Picone, Rita; De Carlo, Candida; Nesi, Gabriella; Micelli, Elisabetta; Serni, Sergio; Carini, Marco; Natali, Alessandro

2018-03-01

The aim of our research was to establish the relevance of testicular histopathology on sperm retrieval after testicular sperm extraction in patients with non-obstructive azoospermia and in patients with obstructive azoospermia, who already underwent a previous failure testicular fine needle aspiration. We evaluated a total of 82 azoospermic men, underwent testicular sperm extraction, referring to the Assisted Reproductive Technology Centre of the University of Florence, Italy between January 2008 and March 2017. A general and genital physical examination, scrotal and trans-rectal ultrasound, semen analysis, hormone measurements, including follicle-stimulating hormone, luteinizing hormone and total testosterone, were collected. Successful sperm retrieval was obtained in 36 men of total (43.9%). Successful sperm retrieval was 29.5% in non-obstructive azoospermia patients, while men with obstructive azoospermia, who, underwent a previous failure testicular fine needle aspiration, had sperm retrieval in 86% of cases. Mean luteinizing hormone was 6.55 IU/L, total testosterone 4.70 ng/mL, right testicular volume 13.7 mL and left testicular volume 13.6 mL. Mean Follicle-stimulating hormone was 13.45 IU/L in patients with negative sperm retrieval and 8.18 IU/L in men with successful sperm retrieval. According to histology, 20.7% had normal spermatogenesis, 35.3% hypospermatogenesis, 35.3% maturation arrest and 8.5% Sertoli cell-only syndrome. Successful sperm retrieval was 88.2% in patients with normal spermatogenesis, 24.1% in the maturation arrest group and 48.27% in patients with hypospermatogenesis, while negative sperm retrieval was reported in Sertoli cell-only syndrome patients. Seven cases with maturation arrest showed a successful sperm retrieval. Testicular histopathology after testicular sperm extraction offers important information on prediction of sperm retrieval and can guide the surgeon in choosing the more suitable therapeutic practice.

Resurfacing the Penis of Complex Hypospadias Repair ("Hypospadias Cripples").

PubMed

Fam, Mina M; Hanna, Moneer K

2017-03-01

After the creation of a neourethra in a "hypospadias cripple," resurfacing the penis with healthy skin is a significant challenge because local tissue is often scarred and unusable. We reviewed our experience with various strategies to resurface the penis of hypospadias cripples. We retrospectively reviewed the records of 215 patients referred after multiple unsuccessful hypospadias repairs from 1981 to 2014. In 130 of 215 patients we performed resurfacing using local penile flaps using various techniques, including Byars flaps, Z-plasty or double Z-plasty, or a dorsal relaxing incision. Of the 215 patients 85 did not have adequate healthy local penile skin to resurface the penis after urethroplasty. Scrotal skin was used to resurface the penis in 54 patients, 6 underwent tissue expansion of the dorsal penile skin during a 12 to 16-week period prior to penile resurfacing, 23 underwent full-thickness skin grafting and another 4 received a split-thickness skin graft. Of the 56 patients who underwent fasciomyocutaneous rotational flaps, tissue expansion or a combination of both approaches 54 (96.4%) finally had a successful outcome. All 6 patients who underwent tissue expansion had a successful outcome without complications and were reported on previously. All 23 full-thickness skin grafts took with excellent results. All 4 patients who underwent fenestrated split-thickness skin grafting had 100% graft take but secondary contraction and ulceration were associated with sexual activity. In our experience scrotal skin flaps, tissue expansion of the dorsal penile skin and full-thickness skin grafts serve as reliable approaches in resurfacing the penis in almost any hypospadias cripple lacking healthy local skin. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Unusual biliary scan appearance in a child with a transplanted liver with hepatic arterial thrombosis: a case report.

PubMed

Porn, U; Howman-Giles, R; Shun, A; Dorney, S; Uren, R

2000-02-01

A 5-year-old girl with biliary atresia and a subsequent Kasai procedure is described. She had clinical symptoms suggestive of rejection after a recent orthotopic liver transplant A hepatobiliary scan showed partial hepatic infarction and a biloma in the infarcted area.

Evaluation of Heterogeneous Metabolic Profile in an Orthotopic Human Glioblastoma Xenograft Model Using Compressed Sensing Hyperpolarized 3D 13C Magnetic Resonance Spectroscopic Imaging

PubMed Central

Park, Ilwoo; Hu, Simon; Bok, Robert; Ozawa, Tomoko; Ito, Motokazu; Mukherjee, Joydeep; Phillips, Joanna J.; James, C. David; Pieper, Russell O.; Ronen, Sabrina M.; Vigneron, Daniel B.; Nelson, Sarah J.

2013-01-01

High resolution compressed sensing hyperpolarized 13C magnetic resonance spectroscopic imaging was applied in orthotopic human glioblastoma xenografts for quantitative assessment of spatial variations in 13C metabolic profiles and comparison with histopathology. A new compressed sensing sampling design with a factor of 3.72 acceleration was implemented to enable a factor of 4 increase in spatial resolution. Compressed sensing 3D 13C magnetic resonance spectroscopic imaging data were acquired from a phantom and 10 tumor-bearing rats following injection of hyperpolarized [1-13C]-pyruvate using a 3T scanner. The 13C metabolic profiles were compared with hematoxylin and eosin staining and carbonic anhydrase 9 staining. The high-resolution compressed sensing 13C magnetic resonance spectroscopic imaging data enabled the differentiation of distinct 13C metabolite patterns within abnormal tissues with high specificity in similar scan times compared to the fully sampled method. The results from pathology confirmed the different characteristics of 13C metabolic profiles between viable, non-necrotic, nonhypoxic tumor, and necrotic, hypoxic tissue. PMID:22851374

Evaluation of heterogeneous metabolic profile in an orthotopic human glioblastoma xenograft model using compressed sensing hyperpolarized 3D 13C magnetic resonance spectroscopic imaging.

PubMed

Park, Ilwoo; Hu, Simon; Bok, Robert; Ozawa, Tomoko; Ito, Motokazu; Mukherjee, Joydeep; Phillips, Joanna J; James, C David; Pieper, Russell O; Ronen, Sabrina M; Vigneron, Daniel B; Nelson, Sarah J

2013-07-01

High resolution compressed sensing hyperpolarized (13)C magnetic resonance spectroscopic imaging was applied in orthotopic human glioblastoma xenografts for quantitative assessment of spatial variations in (13)C metabolic profiles and comparison with histopathology. A new compressed sensing sampling design with a factor of 3.72 acceleration was implemented to enable a factor of 4 increase in spatial resolution. Compressed sensing 3D (13)C magnetic resonance spectroscopic imaging data were acquired from a phantom and 10 tumor-bearing rats following injection of hyperpolarized [1-(13)C]-pyruvate using a 3T scanner. The (13)C metabolic profiles were compared with hematoxylin and eosin staining and carbonic anhydrase 9 staining. The high-resolution compressed sensing (13)C magnetic resonance spectroscopic imaging data enabled the differentiation of distinct (13)C metabolite patterns within abnormal tissues with high specificity in similar scan times compared to the fully sampled method. The results from pathology confirmed the different characteristics of (13)C metabolic profiles between viable, non-necrotic, nonhypoxic tumor, and necrotic, hypoxic tissue. Copyright © 2012 Wiley Periodicals, Inc.

Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice.

PubMed

Aozuka, Yasushi; Koizumi, Keiichi; Saitoh, Yurika; Ueda, Yasuji; Sakurai, Hiroaki; Saiki, Ikuo

2004-12-08

We investigated the effect of bestatin, an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B, on the angiogenesis induced by B16-BL6 melanoma cells. Oral administration of bestatin (100-200 mg/kg/day) was found to significantly inhibit the melanoma cell-induced angiogenesis in a mouse dorsal air sac assay. Additionally, anti-APN/CD13 mAb (WM15), which neutralizes the aminopeptidase activity in tumor cells, as well as bestatin inhibited the tube-like formation of human umbilical vein endothelial cells (HUVECs) in vitro. Furthermore, the intraperitoneal administration of bestatin (50-100 mg/kg/day) after the orthotopic implantation of B16-BL6 melanoma cells into mice reduced the number of vessels oriented towards the established primary tumor mass on the dorsal side of mice. These findings suggest that bestatin is an active anti-angiogenic agent that may inhibit tumor angiogenesis in vivo and tube-like formation of endothelial cells in vitro through its inhibition of APN/CD13 activity.

Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous β-tricalcium phosphate (β-TCP) material.

PubMed

Uemura, Toshimasa; Kojima, Hiroko

2011-06-01

Overexpression of Cbfa1 (a transcription factor indispensable for osteoblastic differentiation) is expected to induce the formation of bone directly and indirectly in vivo by accelerating osteoblastic differentiation. Adenoviral vectors carrying the cDNA of Cbfa1/til-1(Adv-Cbf1) were allowed to be adsorbed onto porous blocks of β-tricalcium phosphate (β-TCP), a biodegradable ceramic, which were then implanted subcutaneously and orthotopically into bone defects. The adenoviral vectors were released sustainingly by biodegradation, providing long-term expression of the genes. Results of the subcutaneous implantation of Adv-Cbfa1-adsorbed β-TCP/osteoprogenitor cells suggest that a larger amount of bone formed in the pores of the implant than in the control material. Regarding orthotopic implantation into bone defects, the released Adv-Cbfa1 accelerated regeneration in the cortical bone, whereas it induced bone resorption in the marrow cavity. A safer gene transfer using a smaller amount of the vector was achieved using biodegradable porous β-TCP as a carrier.

Bone formation in vivo induced by Cbfa1-carrying adenoviral vectors released from a biodegradable porous β-tricalcium phosphate (β-TCP) material

NASA Astrophysics Data System (ADS)

Uemura, Toshimasa; Kojima, Hiroko

2011-06-01

Overexpression of Cbfa1 (a transcription factor indispensable for osteoblastic differentiation) is expected to induce the formation of bone directly and indirectly in vivo by accelerating osteoblastic differentiation. Adenoviral vectors carrying the cDNA of Cbfa1/til-1(Adv-Cbf1) were allowed to be adsorbed onto porous blocks of β-tricalcium phosphate (β-TCP), a biodegradable ceramic, which were then implanted subcutaneously and orthotopically into bone defects. The adenoviral vectors were released sustainingly by biodegradation, providing long-term expression of the genes. Results of the subcutaneous implantation of Adv-Cbfa1-adsorbed β-TCP/osteoprogenitor cells suggest that a larger amount of bone formed in the pores of the implant than in the control material. Regarding orthotopic implantation into bone defects, the released Adv-Cbfa1 accelerated regeneration in the cortical bone, whereas it induced bone resorption in the marrow cavity. A safer gene transfer using a smaller amount of the vector was achieved using biodegradable porous β-TCP as a carrier.

Indocyanine green plasma disappearance rate during the anhepatic phase of orthotopic liver transplantation.

PubMed

Bruegger, Lukas; Studer, Peter; Schmid, Stefan W; Pestel, Gunther; Reichen, Juerg; Seiler, Christian; Candinas, Daniel; Inderbitzin, Daniel

2008-01-01

Non-invasive pulse spectrophotometry to measure indocyanine green (ICG) elimination correlates well with the conventional invasive ICG clearance test. Nevertheless, the precision of this method remains unclear for any application, including small-for-size liver remnants. We therefore measured ICG plasma disappearance rate (PDR) during the anhepatic phase of orthotopic liver transplantation using pulse spectrophotometry. Measurements were done in 24 patients. The median PDR after exclusion of two outliers and two patients with inconstant signal was 1.55%/min (95% confidence interval [CI]=0.8-2.2). No correlation with patient age, gender, body mass, blood loss, administration of fresh frozen plasma, norepinephrine dose, postoperative albumin (serum), or difference in pre and post transplant body weight was detected. In conclusion, we found an ICG-PDR different from zero in the anhepatic phase, an overestimation that may arise in particular from a redistribution into the interstitial space. If ICG pulse spectrophotometry is used to measure functional hepatic reserve, the verified average difference from zero (1.55%/min) determined in our study needs to be taken into account.

Effects of a non thermal plasma treatment alone or in combination with gemcitabine in a MIA PaCa2-luc orthotopic pancreatic carcinoma model.

PubMed

Brullé, Laura; Vandamme, Marc; Riès, Delphine; Martel, Eric; Robert, Eric; Lerondel, Stéphanie; Trichet, Valérie; Richard, Serge; Pouvesle, Jean-Michel; Le Pape, Alain

2012-01-01

Pancreatic tumors are the gastrointestinal cancer with the worst prognosis in humans and with a survival rate of 5% at 5 years. Nowadays, no chemotherapy has demonstrated efficacy in terms of survival for this cancer. Previous study focused on the development of a new therapy by non thermal plasma showed significant effects on tumor growth for colorectal carcinoma and glioblastoma. To allow targeted treatment, a fibered plasma (Plasma Gun) was developed and its evaluation was performed on an orthotopic mouse model of human pancreatic carcinoma using a MIA PaCa2-luc bioluminescent cell line. The aim of this study was to characterize this pancreatic carcinoma model and to determine the effects of Plasma Gun alone or in combination with gemcitabine. During a 36 days period, quantitative BLI could be used to follow the tumor progression and we demonstrated that plasma gun induced an inhibition of MIA PaCa2-luc cells proliferation in vitro and in vivo and that this effect could be improved by association with gemcitabine possibly thanks to its radiosensitizing properties.

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

PubMed Central

Taut, F J H; Schmidt, H; Zapletal, C M; Thies, J C; Grube, C; Motsch, J; Klar, E; Martin, E

2001-01-01

In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P ≤ 0·02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment. PMID:11422213

Orthotopic heart transplantation in the prince sultan cardiac center.

PubMed

Al Fagih, M R

1996-01-01

In this report we attempt to demonstrate the efforts involved in establishing and organizing the heart transplant program at the Armed Forces Hospital in Riyadh, Saudi Arabia. From 1986 to date, 25 orthotopic heart transplants were performed at this center. Patient age ranged from 22 months to 57 years; 4 patients were below 12 years of age and 4 aged 50 years and above. The incidations for transplantation were cardiomyopathy in 15 patients, ischemic heart disease in 6 patients, and valvular heart disease in 4 patients. Fourteen recipients have died. Three of them were classified as hospital deaths, occuring before the patient could be discharged after the procedure; the reminder died from rejection and associated problems. Eight patients of them died within the first year. The longest survival period was almost 8 years. The overall 8 years survival rate was 45%, which is comparable to the international figures. Shortage of donors may affect the future of the transplant programs. Increasing the awareness of the public about the importance of organ donation and transplantation is crucial in this regard.

Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents.

PubMed

Kroesen, Michiel; Brok, Ingrid C; Reijnen, Daphne; van Hout-Kuijer, Maaike A; Zeelenberg, Ingrid S; Den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J

2015-05-01

In around half of the patients with neuroblastoma (NBL), the primary tumor is located in one of the adrenal glands. We have previously reported on a transplantable TH-MYCN model of subcutaneous (SC) growing NBL in C57Bl/6 mice for immunological studies. In this report, we describe an orthotopic TH-MYCN transplantable model where the tumor cells were injected intra-adrenally (IA) by microsurgery. Strikingly, 9464D cells grew out much faster in IA tumors compared to the subcutis. Tumors were infiltrated by equal numbers of lymphocytes and myeloid cells. Within the myeloid cell population, however, tumor-infiltrating macrophages were more abundant in IA tumors compared to SC tumors and expressed lower levels of MHC class II, indicative of a more immunosuppressive phenotype. Using 9464D cells stably expressing firefly luciferase, enhanced IA tumor growth could be confirmed using bioluminescence. Collectively, these data show that the orthotopic IA localization of TH-MYCN cells impacts the NBL tumor microenvironment, resulting in a more stringent NBL model to study novel immunotherapeutic approaches for NBL.

Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy, and tumor-targeting S. typhimurium A1-R is superior to first-line chemotherapy.

PubMed

Miyake, Kentaro; Kiyuna, Tasuku; Miyake, Masuyo; Kawaguchi, Kei; Yoon, Sang Nam; Zhang, Zhiying; Igarashi, Kentaro; Razmjooei, Sahar; Wangsiricharoen, Sintawat; Murakami, Takashi; Li, Yunfeng; Nelson, Scott D; Russell, Tara A; Singh, Arun S; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Singh, Shree Ram; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2018-01-01

Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy.

Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool.

PubMed

Loggi, Elisabetta; Micco, Lorenzo; Ercolani, Giorgio; Cucchetti, Alessandro; Bihl, Florian K; Grazi, Gian Luca; Gitto, Stefano; Bontadini, Andrea; Bernardi, Mauro; Grossi, Paolo; Costa, Alessandro Nanni; Pinna, Antonio Daniele; Brander, Christian; Andreone, Pietro

2012-03-01

The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42 months (range 12-60). All recipients were HBcAb positive and were given antiviral prophylaxis. Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hypertrophic Cardiomyopathy in Liver Transplantation Patients.

PubMed

Pai, S-L; Aniskevich, S; Logvinov, I I; Matcha, G V; Palmer, W C; Blackshear, J L

2018-06-01

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder that presents with a hypertrophied nondilated left ventricle. In the absence of other known causes of cardiomyopathy, it is often associated with left ventricular outflow tract obstruction during systole, systolic anterior motion of the mitral valve, mitral regurgitation, and increased risk of sudden cardiac death. When HCM coexists with end-stage liver disease, it can be further complicated by cirrhosis-associated cardiovascular abnormalities, including hyperdynamic circulation, systolic and diastolic dysfunction, and electrophysiologic abnormalities. We retrospectively examined patient characteristics, comorbidities, preoperative echocardiogram results, sudden cardiac death risk prediction model score, and 1-year postoperative mortality of patients with HCM who underwent liver transplantation at our institution from January 1, 2000, through January 1, 2015. Of the 2,812 liver transplantations performed during the study period, we identified 15 patients with a preoperative diagnosis of HCM. When comparing the patients who did vs did not survive the first year after orthotopic liver transplantation, we identified significant differences in maximal left ventricular wall thickness (P = .004) and resting left ventricular outflow tract gradient (P = .004). Preoperative left atrium size (measured by echocardiography; P = .66) and the sudden cardiac death risk prediction model score (P = .32) were not significantly associated with 1-year survival. Preoperative left ventricular outflow tract gradient exceeding 60 mm Hg was strongly associated with death during the first year after transplant. These results suggest that the severity of HCM influences patient outcomes. Copyright © 2018 Elsevier Inc. All rights reserved.

Orlistat-induced fulminant hepatic failure.

PubMed

Sall, D; Wang, J; Rashkin, M; Welch, M; Droege, C; Schauer, D

2014-12-01

Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. © 2014 The Authors. Clinical Obesity © 2014 World Obesity.

Clinical outcomes of liver transplantation for HBV-related hepatocellular carcinoma: data from the NIH HBV OLT study.

PubMed

Han, Steven-Huy; Reddy, K Rajender; Keeffe, Emmet B; Soldevila-Pico, Consuelo; Gish, Robert; Chung, Raymond T; Degertekin, Bulent; Lok, Anna

2011-01-01

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is an indication for orthotopic liver transplantation (OLT) in patients with tumor stage within the United Network for Organ Sharing criteria. The number of patients listed for HBV-related HCC is increasing, while the number of patients listed for HBV-related cirrhosis is declining presumptively because of the availability of more effective oral nucleos(t)ide analogues. This study presents the final, long-term outcome of patients transplanted for HBV-related HCC in the National Institutes of Health (NIH) HBV OLT Study Group. Ninety-eight patients (52.4%) in the NIH HBV OLT cohort underwent OLT for HBV-related HCC. With a mean follow-up of 36.5 months post-OLT, 12 (12.2%) patients developed recurrence of HCC. Multivariate analysis did not find a statistically significant role of gender, tumor stage at OLT, pre-OLT HCC treatment, recurrence of HBV, or duration of HCC diagnosis pre-OLT in predicting HCC recurrence. Serum alpha-fetoprotein (AFP) level >200 ng/mL at transplant was found to be statistically significant in predicting HCC recurrence (p=0.003). HCC recurrence was significantly associated with decreased post-OLT survival. HCC is the most common indication for OLT in patients with chronic hepatitis B in the era of more effective oral antivirals. Serum AFP at the time of OLT is significantly associated with HCC recurrence. © 2010 John Wiley & Sons A/S.

Long-term survival after liver transplant for recurrent hepatocellular carcinoma with bile duct tumor thrombus: case report.

PubMed

Liu, Chao; Wang, Jie

2012-12-01

Hepatocellular carcinoma with bile duct tumor thrombus is considered an aggressive malignancy, and the prognosis of liver transplant for it remains obscure. A 42-year-old man with recurrent hepatocellular carcinoma and a history of surgical resection was admitted to our hospital with a 10-day history of yellowish urine and itchy skin. There were 3 lesions in the right lobe with the diameter of 2 cm each. A mass was found in the upper part of common bile duct, and the intrahepatic bile duct was dilated. His serum alpha-fetoprotein level was 2476 μg/L, total bilirubin level was 327 μmol/L, direct bilirubin level was 261 μmol/L, and alanine aminotransferase was 714 U/L. There was no main portal vein thrombus or extrahepatic metastases. Because of his poor liver function, he was listed for a liver transplant. During the wait (30 d), he underwent 9 episodes of plasmapheresis to decrease the serum level of bilirubin. He had an orthotopic liver transplant with the graft from a deceased donor. After the liver transplant, he received 5 cycles of chemotherapy with the regimen of oxaliplatin and 5-fluorouracil. This patient has survived without recurrence of hepatocellular carcinoma for more than 82 months and remains in good condition. Liver transplant may have a favorable result for hepatocellular carcinoma patient with a bile duct tumor thrombus, within the Milan criteria.

Liver transplantation in man: morphometric analysis of the parenchymal alterations following cold ischaemia and warm ischaemia/reperfusion

PubMed Central

VIZZOTTO, LAURA; VERTEMATI, MAURIZIO; DEGNA, CARLO TOMMASINI; ASENI, PAOLO

2001-01-01

Ischaemia and reperfusion phases represent critical events during liver transplantation. The purpose of this study was to describe morphological alterations of both vascular and parenchymal compartments after ischaemia and reperfusion and to evaluate the possible relationship between morphometric parameters and biochemical/clinical data. Three needle biopsies were drawn from 20 patients who underwent orthotopic liver transplantation. The first biopsy was taken before flushing with preservation solution, and the second and the third to evaluate respectively the effects of cold ischaemia and of warm ischaemia/reperfusion. Biopsies were examined by an image analyser and morphometric parameters related to the liver parenchyma were evaluated. At the second biopsy we observed a decrease of the endothelium volume fraction while the same parameter referred to the sinusoidal lumen achieved a peak value. The hepatocytes showed a lower surface parenchymal/vascular sides ratio. This parameter was reversed at the end of the reperfusion phase; furthermore the third biopsy revealed endothelial swelling and a decreased volume fraction of the sinusoidal lumen. The results quantify the damage to the sinusoidal bed which, as already known, is one of the main targets of cold ischaemia; warm ischaemia and reperfusion accentuate endothelial damage. The end of transplantation is characterised by damage chiefly to parenchymal cells. Hepatocytes show a rearrangement of their surface sides, probably related to the alterations of the sinusoidal bed. In addition, the fluctuations of morphometric parameters during ischaemia/reperfusion correlate positively with biochemical data and clinical course of the patients. PMID:11430699

KENNEDY SPACE CENTER, FLA. --Shown upside down to read the names, this plaque commemorating the STS-107 Space Shuttle Columbia crew now looks over the Mars landscape after the successful landing and deployment of the Mars Exploration Rover “Spirit” Jan. 4 onto the red planet. The plaque, mounted on the high-gain antenna, is shown while the rover underwent final checkout March 28, 2003, in the Payload Hazardous Servicing Facility at KSC.

NASA Image and Video Library

2004-01-06

KENNEDY SPACE CENTER, FLA. --Shown upside down to read the names, this plaque commemorating the STS-107 Space Shuttle Columbia crew now looks over the Mars landscape after the successful landing and deployment of the Mars Exploration Rover “Spirit” Jan. 4 onto the red planet. The plaque, mounted on the high-gain antenna, is shown while the rover underwent final checkout March 28, 2003, in the Payload Hazardous Servicing Facility at KSC.

Ensuring excision of intraductal lesions: marker placement at time of ductography.

PubMed

Woodward, Suzanne; Daly, Caroline P; Patterson, Stephanie K; Joe, Annette I; Helvie, Mark A

2010-11-01

To propose grid coordinate marker placement for patients with suspicious ductogram findings occult on routine workup. To compare the success of marker placement and wire localization (WL) with ductogram-guided WL. A retrospective search of radiology records identified all patients referred for ductography between January 2001 and May 2008. Results for 16 patients referred for ductogram-guided WL and 5 patients with grid coordinate marker placement at the time of ductography and subsequent WL were reviewed. Surgical pathology results and clinical follow-up were reviewed for concordance. Nine of 16 patients (56.3%) underwent successful ductogram-guided WL. Eight of nine patients had papillomas, one of which also had atypical ductal hyperplasia (ADH). One of nine patients had ectatic ducts with inspisated debris. Seven patients who failed ductogram-guided WL eventually underwent open surgical biopsy. Four of seven patients had papillomas, one of which also had lobular carcinoma in situ. Remaining patients had ADH (1/7) and fibrocystic changes with chronic inflammation (3/7). All five (100%) patients with grid coordinate marker placement underwent successful WL and marker excision. Pathology results included three papillomas, papillary intraductal hyperplasia, and fibrocystic change. Grid coordinate marker placement at the time of abnormal ductogram provided an accurate method of localizing ductal abnormalities that are occult on routine workup, thus facilitating future WL. Marker placement obviated the need for repeat ductogram on the day of surgery and ensured surgical removal of the ductogram abnormality. Copyright © 2010 AUR. Published by Elsevier Inc. All rights reserved.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats

PubMed Central

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-01-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at −80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs. PMID:29637821

Piggyback technique in adult orthotopic liver transplantation: an analysis of 1067 liver transplants at a single center

PubMed Central

Nakamura, Noboru; Vaidya, Anil; Levi, David M.; Kato, Tomoaki; Nery, Jose R.; Madariaga, Juan R.; Molina, Enrique; Ruiz, Phillip; Gyamfi, Anthony; Tzakis, Andreas G.

2006-01-01

Background. Orthotopic liver transplantation (OLT) in adult patients has traditionally been performed using conventional caval reconstruction technique (CV) with veno-venous bypass. Recently, the piggyback technique (PB) without veno-venous bypass has begun to be widely used. The aim of this study was to assess the effect of routine use of PB on OLTs in adult patients. Patients and methods. A retrospective analysis was undertaken of 1067 orthotopic cadaveric whole liver transplantations in adult patients treated between June 1994 and July 2001. PB was used as the routine procedure. Patient demographics, factors including cold ischemia time (CIT), warm ischemia time (WIT), operative time, transfusions, blood loss, and postoperative results were assessed. The effects of clinical factors on graft survival were assessed by univariate and multivariate analyses.In all, 918 transplantations (86%) were performed with PB. Blood transfusion, WIT, and usage of veno-venous bypass were less with PB. Seventy-five (8.3%) cases with PB had refractory ascites following OLT (p=NS). Five venous outflow stenosis cases (0.54%) with PB were noted (p=NS). The liver and renal function during the postoperative periods was similar. Overall 1-, 3-, and 5-year patient survival rates were 85%, 78%, and 72% with PB. Univariate analysis showed that cava reconstruction method, CIT, WIT, amount of transfusion, length of hospital stay, donor age, and tumor presence were significant factors influencing graft survival. Multivariate analysis further reinforced the fact that CIT, donor age, amount of transfusion, and hospital stay were prognostic factors for graft survival. Conclusions. PB can be performed safely in the majority of adult OLTs. Results of OLT with PB are as same as for CV. Liver function, renal function, morbidity, mortality, and patient and graft survival are similar to CV. However, amount of transfusion, WIT, and use of veno-venous bypass are less with PB. PMID:18333273

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models

PubMed Central

Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H.; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D’Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag

2017-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O’Neill (J Neurooncol 107: 359–364, 2012). An extract from the winter cherry plant (Withania somnifera), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985–1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3–5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 μM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 μM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM. PMID:26650066

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

PubMed

Chang, Edwin; Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D'Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag; Gambhir, Sanjiv S

2016-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.

High vascular delivery of EGF, but low receptor binding rate is observed in AsPC-1 tumors as compared to normal pancreas.

PubMed

Samkoe, Kimberley S; Sexton, Kristian; Tichauer, Kenneth M; Hextrum, Shannon K; Pardesi, Omar; Davis, Scott C; O'Hara, Julia A; Hoopes, P Jack; Hasan, Tayyaba; Pogue, Brian W

2012-08-01

Cellular receptor targeted imaging agents present the potential to target extracellular molecular expression in cancerous lesions; however, the image contrast in vivo does not reflect the magnitude of overexpression expected from in vitro data. Here, the in vivo delivery and binding kinetics of epidermal growth factor receptor (EGFR) was determined for normal pancreas and AsPC-1 orthotopic pancreatic tumors known to overexpress EGFR. EGFR in orthotopic xenograft AsPC-1 tumors was targeted with epidermal growth factor (EGF) conjugated with IRDye800CW. The transfer rate constants (k(e), K₁₂, k₂₁, k₂₃, and k₃₂) associated with a three-compartment model describing the vascular delivery, leakage rate and binding of targeted agents were determined experimentally. The plasma excretion rate, k (e), was determined from extracted blood plasma samples. K₁₂, k₂₁, and k₃₂ were determined from ex vivo tissue washing studies at time points ≥ 24 h. The measured in vivo uptake of IRDye800CW-EGF and a non-targeted tracer dye, IRDye700DX-carboxylate, injected simultaneously was used to determined k₂₃. The vascular exchange of IRDye800CW-EGF in the orthotopic tumor (K₁₂ and k₂₁) was higher than in the AsPC-1 tumor as compared to normal pancreas, suggesting that more targeted agent can be taken up in tumor tissue. However, the cellular associated (binding) rate constant (k₂₃) was slightly lower for AsPC-1 pancreatic tumor (4.1 × 10(-4) s(-1)) than the normal pancreas (5.5 × 10(-4) s(-1)), implying that less binding is occurring. Higher vascular delivery but low cellular association in the AsPC-1 tumor compared to the normal pancreas may be indicative of low receptor density due to low cellular content. This attribute of the AsPC-1 tumor may indicate one contributing cause of the difficulty in treating pancreatic tumors with cellular targeted agents.

ESTABLISHMENT AND EVALUATION OF ORTHOTOPIC HEPATOCELLULAR CARCINOMA AND DRUG-INDUCED HEPATOCELLULAR CARCINOMA IN MICE WITH SPLEEN-DEFICIENCY SYNDROME IN TRADITIONAL CHINESE MEDICINE.

PubMed

Luo, Haoxuan; Chen, Yan; Sun, Baoguo; Xiang, Ting; Zhang, Shijun

2017-01-01

Spleen-deficiency syndrome (SDS) in Traditional Chinese Medicine (TCM) played pivotal roles on the development of hepatocellular carcinoma (HCC). This study was performed to establish and evaluate HCC model in mice with SDS in TCM. A total of 90 C57BL/6 mice were randomized in six groups (n=15 for each group): A, Control group; B, SDS group; C, orthotopic HCC (OHCC) group; D, OHCC based on SDS (SDS-OHCC) group; E, Drug-induced HCC (DHCC) group; F, DHCC based on SDS (SDS-DHCC) group. The SDS model were established by subcutaneous injection of reserpine, followed by the OHCC or DHCC model establishment. The SDS scores, tumor formation rate and survival time were recorded and calculated, as well as the histochemical stain was performed. The SDS scores of mice in Group B, D, F were 17.57±4.86 (P<0.05 vs. Group A), 18.13±4.53 (P<0.05 vs. Group A and C) and 23.32±4.94 (P<0.05 vs. Group A and E) respectively. The tumor formation rate of mice in Group C, D, E and F were 73.33%, 100%, 60% and 80% respectively. The survival time of mice in Group C, D, E and F were 26.42±5.27, 17.33±4.76 (P<0.05 vs. Group C), 35.77±6.12 and 22.61±5.05 (P<0.05 vs. Group E) respectively. The SDS-oriented HCC mice models were simple and easily-operated models for further studies on SDS oriented tumor. Meanwhile, SDS was a pivotal factor for low outcome of hepatic tumor. Abbreviations: HCC, Hepatocellular carcinoma; OHCC, Orthotopic hepatocellular carcinoma; DHCC, Drug-induced hepatocellular carcinoma; SDS, Spleen-deficiency syndrome; TCM, Traditional Chinese Medicine; SPF, Specific pathogen-free; DEN, Diethylnitrosamine; CCl4, Carbon tetrachloride; HE, Hematoxylin-eosin; IACUC, Institutional Animal Care and Use Committee.

Color-Coded Imaging of Syngeneic Orthotopic Malignant Lymphoma Interacting with Host Stromal Cells During Metastasis.

PubMed

Matsumoto, Takuro; Suetsugu, Atsushi; Hasegawa, Kosuke; Nakamura, Miki; Aoki, Hitomi; Kunisada, Takahiro; Tsurumi, Hisashi; Shimizu, Masahito; Hoffman, Robert M

2016-04-01

The EL4 cell line was previously derived from a lymphoma induced in a C57/BL6 mouse by 9,10-dimethyl-1,2-benzanthracene. In a previous study, EL4 lymphoma cells expressing red fluorescent protein (EL4-RFP) were established and injected into the tail vein of C57/BL6 green fluorescent protein (GFP) transgenic mice. Metastasis was observed at multiple sites which were also enriched with host GFP-expressing stromal cells. In the present study, our aim was to establish an orthotopic model of EL4-RFP. In the present study, EL4-RFP lymphoma cells were injected in the spleen of C57/BL6 GFP transgenic mice as an orthotopic model of lymphoma. Resultant primary tumor and metastases were imaged with the Olympus FV1000 scanning laser confocal microscope. EL4-RFP metastasis was observed 21 days later. EL4-RFP tumors in the spleen (primary injection site), liver, supra-mediastinum lymph nodes, abdominal lymph nodes, bone marrow, and lung were visualized by color-coded imaging. EL4-RFP metastases in the liver, lymph nodes, and bone marrow in C57/BL6 GFP mice were rich in GFP stromal cells such as macrophages, fibroblasts, dendritic cells, and normal lymphocytes derived from the host animal. Small tumors were observed in the spleen, which were rich in host stromal cells. In the lung, no mass formation of lymphoma cells occurred, but lymphoma cells circulated in lung peripheral blood vessels. Phagocytosis of EL4-RFP lymphoma cells by macrophages, as well as dendritic cells and fibroblasts, were observed in culture. Color-coded imaging of the lymphoma microenvironment suggests an important role of stromal cells in lymphoma progression and metastasis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma.

PubMed

Theisen, Emily R; Gajiwala, Snehal; Bearss, Jared; Sorna, Venkataswamy; Sharma, Sunil; Janat-Amsbury, Margit

2014-10-09

Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE. The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509. Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034). Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.

Early Therapy Evaluation of Combined Anti-DR5 Antibody and Gemcitabine in Orthotopic Pancreatic Tumor Xenografts by Diffusion Weighted Magnetic Resonance Imaging

PubMed Central

Kim, Hyunki; Morgan, Desiree E.; Buchsbaum, Donald J.; Zeng, Huadong; Grizzle, William E.; Warram, Jason M.; Stockard, Cecil R.; McNally, Lacey R.; Long, Joshua W.; Sellers, Jeffrey C.; Forero, Andres; Zinn, Kurt R.

2008-01-01

Early therapeutic efficacy of anti-DR5 antibody (TRA-8) combined with gemcitabine was measured using diffusion-weighted magnetic resonance imaging (DWI) in an orthotopic pancreatic tumor model. Groups 1–4 of SCID mice (n=5–7/group) bearing orthotopically implanted, luciferase-positive human pancreatic tumors (MIA PaCa-2) were subsequently (4–5 weeks thereafter) injected with saline (control), gemcitabine (120mg/kg), TRA-8 (200μg), or TRA-8 combined with gemcitabine, respectively, on day 0. DWI, anatomical MRI, and bioluminescence imaging were performed on days 0, 1, 2, and 3 after treatment. Three tumors from each group were collected randomly on day 3 after imaging, and TUNEL staining was performed to quantify apoptotic cellularity. At just 1 day after starting therapy, the changes of apparent diffusion coefficient (ADC) in tumor regions for groups 3 (TRA-8) and 4 (TRA-8/Gem) were 21±9% (mean±SE) and 27±3%, respectively, significantly higher (p <0.05) than those of groups 1 (−1±5%) and 2 (−2±4%). There was no statistical difference in tumor volumes for the groups at this time. The mean ADC values of groups 2–4 gradually increased over 3 days, which were concurrent with tumor-volume regressions and bioluminescence-signal decreases. Apoptotic-cell densities of tumors in groups 1–4 were 0.7±0.4%, 0.6±0.2%, 3.1±0.9%, and 4.7±1.0%, respectively, linearly proportional to the ADC changes on day 1. Further, the ADC changes were highly correlated with the previously reported mean survival times of animals treated with the same agents and doses. This study supports the clinical use of DWI for pancreatic tumor patients for early assessment of drug efficacy. PMID:18922909

‘Obligate’ anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice

PubMed Central

Li, Chang-Xian; Yu, Bin; Shi, Lei; Geng, Wei; Lin, Qiu-Bin; Ling, Chang-Chun; Yang, Mei; Ng, Kevin T. P.; Huang, Jian-Dong; Man, Kwan

2017-01-01

The antitumor properties of bacteria have been demonstrated over the past decades. However, the efficacy is limited and unclear. Furthermore, systemic infection remains a serious concern in bacteria treatment. In this study, the effect of YB1, a rationally designed ‘obligate’ anaerobic Salmonella typhimurium strain, on liver tumor growth and metastasis in a nude mouse orthotopic liver tumor model was investigated. The orthotopic liver tumor model was established in nude mice using the hepatocellular carcinoma cell line MHCC-97L. Two weeks after orthotopic liver tumor implantation, YB1, SL7207 and saline were respectively administered through the tail vein of the mice. Longitudinal monitoring of tumor growth and metastasis was performed using Xenogen IVIS, and direct measurements of tumor volume were taken 3 weeks after treatment. In vitro, MHCC-97L and PLC cells were incubated with YB1 or SL7207 under anaerobic conditions. YB1 was observed to invade tumor cells and induce tumor cell apoptosis and death. The results revealed that all mice in the YB1 group were alive 3 weeks after YB1 injection while all mice in the SL7207 group died within 11 days of the SL7207 injection. The body weight decreased by ~9% on day 1 after YB1 injection and but subsequently recovered. Liver tumor growth and metastases were significantly inhibited following YB1 treatment. By contrast to the control group, a large number of Gr1-positive cells were detected on days 1 to 21 following YB1 treatment. Furthermore, YB1 also effectively invaded tumor cells and induced tumor cell apoptosis and death. In conclusion, YB1 suppressed liver tumor growth and metastasis in a nude mice liver tumor model. The potential mechanism may be through enhancing innate immune response and inducing tumor cell apoptosis and cell death. PMID:28123538

Establishment and characterization of in vivo orthotopic bioluminescent xenograft models from human osteosarcoma cell lines in Swiss nude and NSG mice.

PubMed

Marques da Costa, Maria Eugenia; Daudigeos-Dubus, Estelle; Gomez-Brouchet, Anne; Bawa, Olivia; Rouffiac, Valerie; Serra, Massimo; Scotlandi, Katia; Santos, Conceição; Geoerger, Birgit; Gaspar, Nathalie

2018-03-01

Osteosarcoma is one of the most common primary bone tumors in childhood and adolescence. Metastases occurrence at diagnosis or during disease evolution is the main therapeutic challenge. New drug evaluation to improve patient survival requires the development of various preclinical models mimicking at best the complexity of the disease and its metastatic potential. We describe here the development and characteristics of two orthotopic bioluminescent (Luc/mKate2) cell-derived xenograft (CDX) models, Saos-2-B-Luc/mKate2-CDX and HOS-Luc/mKate2-CDX, in different immune (nude and NSG mouse strains) and bone (intratibial and paratibial with periosteum activation) contexts. IVIS SpectrumCT system allowed both longitudinal computed tomography (CT) and bioluminescence real-time follow-up of primary tumor growth and metastatic spread, which was confirmed by histology. The murine immune context influenced tumor engraftment, primary tumor growth, and metastatic spread to lungs, bone, and spleen (an unusual localization in humans). Engraftment in NSG mice was found superior to that found in nude mice and intratibial bone environment more favorable to engraftment compared to paratibial injection. The genetic background of the two CDX models also led to distinct primary tumor behavior observed on CT scan. Saos-2-B-Luc/mKate2-CDX showed osteocondensed, HOS-Luc/mKate2-CDX osteolytic morphology. Bioluminescence defined a faster growth of the primary tumor and metastases in Saos-2-B-Luc/mKate2-CDX than in HOS-Luc/mKate2-CDX. The early detection of primary tumor growth and metastatic spread by bioluminescence allows an improved exploration of osteosarcoma disease at tumor progression, and metastatic spread, as well as the evaluations of anticancer treatments. Our orthotopic models with metastatic spread bring complementary information to other types of existing osteosarcoma models. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Alterations in NO- and PGI2- dependent function in aorta in the orthotopic murine model of metastatic 4T1 breast cancer: relationship with pulmonary endothelial dysfunction and systemic inflammation.

PubMed

Buczek, E; Denslow, A; Mateuszuk, L; Proniewski, B; Wojcik, T; Sitek, B; Fedorowicz, A; Jasztal, A; Kus, E; Chmura-Skirlinska, A; Gurbiel, R; Wietrzyk, J; Chlopicki, S

2018-05-22

Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI 2 )-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer. BALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI 2 -dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation. As early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI 2 production. In 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI 2 pathway.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats: With or without Incorporation of Autologous Mesenchymal Stem Cells.

PubMed

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-02-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at -80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.

Transjugular intrahepatic porto-systemic shunt in the elderly: Palliation for complications of portal hypertension.

PubMed

Syed, Mubin I; Karsan, Hetal; Ferral, Hector; Shaikh, Azim; Waheed, Uzma; Akhter, Talal; Gabbard, Alan; Morar, Kamal; Tyrrell, Robert

2012-02-27

To present a dedicated series of transjugular intrahepatic porto-systemic shunts (TIPS) in the elderly since data is sparse on this population group. A retrospective review was performed of patients at least 65 years of age who underwent TIPS at our institutions between 1997 and 2010. Twenty-five patients were referred for TIPS. We deemed that 2 patients were not considered appropriate candidates due to their markedly advanced liver disease. Of the 23 patients suitable for TIPS, the indications for TIPS placement was portal hypertension complicated by refractory ascites alone (n = 9), hepatic hydrothorax alone (n = 2), refractory ascites and hydrothorax (n = 1), gastrointestinal bleeding alone (n = 8), gastrointestinal bleeding and ascites (n = 3). Of these 23 attempted TIPS procedure patients, 21 patients had technically successful TIPS procedures. A total of 29 out of 32 TIPS procedures including revisions were successful in 21 patients with a mean age of 72.1 years (range 65-82 years). Three of the procedures were unsuccessful attempts at TIPS and 8 procedures were successful revisions of our existing TIPS. Sixteen of 21 patients who underwent successful TIPS (excluding 5 patients lost to follow-up) were followed for a mean of 14.7 mo. Ascites and/or hydrothorax was controlled following technically successful procedures in 12 of 13 patients. Bleeding was controlled following technically successful procedures in 10 out of 11 patients. We have demonstrated that TIPS is an effective procedure to control refractory complications of portal hypertension in elderly patients.

Bilateral metal stents for hilar biliary obstruction using a 6Fr delivery system: outcomes following bilateral and side-by-side stent deployment.

PubMed

Law, Ryan; Baron, Todd H

2013-09-01

Controversy exists on optimal endoscopic management for palliation of malignant hilar obstruction, with advocates for metal "side-by-side" (SBS) and "stent-in-stent" (SIS) techniques. We sought to evaluate the technical feasibility, efficacy, and outcomes of bilateral biliary self-expanding metal stents (SEMS) for treatment of malignant hilar obstruction using a stent with a 6Fr delivery system. This was a single-center, retrospective review of all patients who underwent bilateral placement of Zilver® biliary SEMS for malignant hilar obstruction from January 2010 to August 2012. Patients underwent endoscopic retrograde cholangiopancreatography with placement of stents using either the SIS or SBS stent techniques. Twenty-four patients (19 men, mean age 63 years) underwent bilateral stenting for malignant hilar obstruction during the study period. Seventeen and seven patients underwent the SBS and SIS technique, respectively. Cholangiocarcinoma (n=14) was the most common cause of hilar obstruction. Initial technical success was achieved in 24/24 (100%) of patients; however, 12 (50%) patients required re-intervention during the study period (median 98 days). Comparison of the SBS and SIS groups revealed no statistical difference with respect to need for re-intervention (P=0.31), successful re-intervention (P=0.60), or procedural length (P=0.89). Use of bilateral Zilver® SEMS in either the SBS or SIS configuration is safe, technically feasible, and effective for drainage of malignant hilar obstruction; however, duration of stent patency and procedure-free survival remain variable.

Substitution urethroplasty of complex and long-segment urethral strictures: a rationale for procedure selection.

PubMed

Xu, Yue-Min; Qiao, Yong; Sa, Ying-Long; Wu, Den-Long; Zhang, Xin-Ru; Zhang, Jion; Gu, Bao-Jun; Jin, San-Bao

2007-04-01

We evaluated the applications and outcomes of substitution urethroplasty, using a variety of techniques, in 65 patients with complex, long-segment urethral strictures. From January 1995 to December 2005, 65 patients with complex urethral strictures >8cm in length underwent substitution urethroplasty. Of the 65 patients, 43 underwent one-stage urethral reconstruction using mucosal grafts (28 colonic mucosal graft, 12 buccal mucosal graft, and 3 bladder mucosal graft), 17 patients underwent one-stage urethroplasty using pedicle flaps, and 5 patients underwent staged Johanson's urethroplasty. The mean follow-up time was 4.8 yr (range; 0.8-10 yr), with an overall success rate of 76.92% (50 of 65 cases). Complications developed in 15 patients (23.08%) and included recurrent stricture in 7 (10.77%), urethrocutaneous fistula in 3 (4.62%), coloabdominal fistula in 1 (1.54%), penile chordee in 2 (3.08%), and urethral pseudodiverticulum in 2 (3.08%). Recurrent strictures and urethral pseudodiverticulum were treated successfully with a subsequent procedure, including repeat urethroplasty in six cases and urethrotomy or dilation in three. Coloabdominal fistula was corrected only by dressing change; five patients await further reconstruction. Penile skin, colonic mucosal, and buccal mucosal grafts are excellent materials for substitution urethroplasty. Colonic mucosal graft urethroplasty is a feasible procedure for complicated urethral strictures involving the entire or multiple portions of the urethra and the technique may also be considered for urethral reconstruction in patients in whom other conventional procedures failed.

Attempted salvage of infected cardiovascular implantable electronic devices: Are there clinical factors that predict success?

PubMed

Peacock, James E; Stafford, Jeanette M; Le, Katherine; Sohail, Muhammad Rizwan; Baddour, Larry M; Prutkin, Jordan M; Danik, Stephan B; Vikram, Holenarasipur R; Hernandez-Meneses, Marta; Miró, José M; Blank, Elisabeth; Naber, Christoph K; Carrillo, Roger G; Greenspon, Arnold J; Tseng, Chi-Hong; Uslan, Daniel Z

2018-03-08

Published guidelines mandate complete device removal in cases of cardiovascular implantable electronic device (CIED) infection. Clinical predictors of successful salvage of infected CIEDs have not been defined. Data from the Multicenter Electrophysiologic Device Infection Collaboration, a prospective, observational, multinational cohort study of CIED infection, were used to investigate whether clinical predictors of successful salvage of infected devices could be identified. Of 433 adult patients with CIED infections, 306 (71%) underwent immediate device explantation. Medical management with device retention and antimicrobial therapy was initially attempted in 127 patients (29%). "Early failure" of attempted salvage occurred in 74 patients (58%) who subsequently underwent device explantation during the index hospitalization. The remaining 53 patients (42%) in the attempted salvage group retained their CIED. Twenty-six (49%) had resolution of CIED infection (successful salvage group) whereas 27 patients (51%) experienced "late" salvage failure. Upon comparing the salvage failure group, early and late (N = 101), to the group experiencing successful salvage of an infected CIED (N = 26), no clinical or laboratory predictors of successful salvage were identified. However, by univariate analysis, coagulase-negative staphylococci as infecting pathogens (P = 0.0439) and the presence of a lead vegetation (P = 0.024) were associated with overall failed salvage. In patients with definite CIED infections, clinical and laboratory variables cannot predict successful device salvage. Until new data are forthcoming, device explantation should remain a mandatory and early management intervention in patients with CIED infection in keeping with existing expert guidelines unless medical contraindications exist or patients refuse device removal. © 2018 Wiley Periodicals, Inc.

Endoscopic Third Ventriculostomy for the Treatment of Hydrocephalus in a Pediatric Population with Myelomeningocele.

PubMed

Rei, Joana; Pereira, Josué; Reis, Carina; Salvador, Sérgio; Vaz, Rui

2017-09-01

Hydrocephalus develops in up to 90% of patients born with myelomeningocele. Although endoscopic third ventriculostomy (ETV) is currently considered the preferred treatment for obstructive hydrocephalus, its results have been inconsistent in patients with myelomeningocele. This study focuses on clinical and radiologic outcomes of ETV in children with hydrocephalus related to myelomeningocele. Medical records of 18 pediatric patients with myelomeningocele treated with ETV from 1998 to 2015 at the Centro Hospitalar São João (Porto, Portugal) were reviewed retrospectively. Patients' caregivers were contacted to evaluate their clinical manifestations before and after surgery regarding signs and symptoms of hydrocephalus and Chiari malformation. Control neuroradiologic imaging of 9 patients was obtained and analyzed. Success of ETV was defined by clinical resolution and radiologic confirmation. ETV was successful in 8 of 18 cases (44.4%). Groups of patients were compared according to age at the time of surgery, with a 40% (2/5) success rate in newborns and a 50% success rate (3/6) in children older than 1 year. Eight patients underwent ETV as a first option, with a 37.5% success rate. Ten patients underwent the procedure after previous ventriculoperitoneal shunt (VPS), 5 for malfunction and 5 for VPS infection with 60% and 40% success rates, respectively. Early postoperative complications occurred in 2 patients. ETV can be performed in patients with myelomeningocele and hydrocephalus with success rates of almost 50%. Prior VPS or VPS malfunction or infection do not contraindicate ETV. If possible, the procedure should be delayed until the patient is at least 1 month old. Copyright © 2017 Elsevier Inc. All rights reserved.

Mechanical Thrombectomy of Occluded Hemodialysis Native Fistulas and Grafts Using a Hydrodynamic Thrombectomy Catheter: Preliminary Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahni, Vikram, E-mail: vassahni@hotmail.com; Kaniyur, Sunil; Malhotra, Anmol

2005-12-15

The purpose of this study was to evaluate the efficacy and safety of a new hydrodynamic percutaneous thrombectomy catheter in the treatment of thrombosed hemodialysis fistulas and grafts. Twenty-two patients (median age: 47 years; range: 31-79 years) underwent mechanical thrombectomy for thrombosed hemodialysis fistulas or polytetrafluoroethylene (PTFE) grafts. In all cases, an Oasis hydrodynamic catheter was used. Five patients had native fistulas and 17 had PTFE grafts. Six patients required repeat procedures. All patients with native fistulas and 15 of the 17 with PTFE grafts also underwent angioplasty of the venous limb following the thrombectomy. Major outcome measures included technicalmore » success, clinical success, primary and secondary patency, and complication rates. Twenty-eight procedures were performed in total. The technical success rate was 100% and 90% and clinical success was 86% and 76% for native fistulas and grafts, respectively. The primary patency at 6 months was 50% and 59% for fistulas and grafts, respectively, and the secondary patency at 6 months was 75% and 70% for fistulas and grafts, respectively. Two patients died of unrelated causes during the follow-up period. The Oasis catheter is an effective mechanical device for the percutaneous treatment of thrombosed hemodialysis access. Our initial success rate showed that the technique is safe in the treatment of both native fistulas and grafts.« less

Electroconvulsive therapy for depression in a patient with an Inspire hypoglossal nerve stimulator device for obstructive sleep apnea: A case report.

PubMed

Mingo, Katie; Kominsky, Alan

2018-04-19

METHODS: This is a case report of a patient who underwent placement and initiation of a hypoglossal nerve stimulator device in the context of receiving electroconvulsive therapy for bipolar depression between February and September 2016. To our knowledge, this has not yet been reported in the literature. Outcome measurements included successful device activation and successful device use throughout electroconvulsive therapy. The patient underwent successful device implantation, activation, and use without disruption throughout electroconvulsive therapy sessions. No special device deactivation was required during electroconvulsive therapy sessions. Obstructive sleep apnea is a common disorder that causes significant reduction in quality of life and is an independent risk factor for multiple comorbidities. Electroconvulsive therapy is an established treatment for medication-refractory depression with minimal risk in most patient populations. This is the first report in the literature of a patient undergoing ECT for bipolar depression with recent activation of Inspire hypoglossal nerve stimulator who had no disruption in the function of his implanted device. Copyright © 2018. Published by Elsevier Inc.

Two horizontal rectus eye muscle surgery combined with botulinum toxin for the treatment of very large angle esotropia. A pilot study.

PubMed

Khan, Arif O

2005-01-01

To evaluate the effectiveness of a proposed new protocol for the primary treatment for very large angle esotropia: two muscle horizontal rectus muscle surgery with simultaneous botulinum toxin A injection in a small pilot study. Eight patients who had esotropia at near (ET') greater than 60 prism diopters (in actuality 70 to 100 prism diopters ET') underwent 2 muscle horizontal rectus surgery with simultaneous botulinum toxin A injection of the medial rectus intraoperatively. This was the only surgical procedure for all patients included in this report. Seven patients underwent bilateral medial rectus recession and bilateral injection, and one patient underwent a unilateral medial rectus recession / lateral rectus resection procedure with unilateral medial rectus injection. Postoperatively, 6 of the 8 patients demonstrated residual esotropia at near of less than 10 prism diopters and were considered "successful" by the conventional criteria of binocular alignment within 8 prism diopters of orthotropia. Two undercorrections occurred in patients with 100 and 85 prism diopters of preop ET' respectively. But 3 other patients with such large deviations had satisfactory results. All patients and families were satisfied with postoperative binocular alignment, so no further surgery was undertaken. The patient who underwent unilateral surgery had the least surgical effect and was the largest undercorrection, probably because only one medial rectus received a Botox injection. Considering only the bilateral cases, results were "successful" in 6 of 7 cases. Most patients suffered an extended period of Botox induced exotropia in the postop' period before recovery from the paresis. One patient had a transient, successfully treated, postoperative strabismic amblyopia while exotropic. Bilateral medial rectus recession with simultaneous botulinum injection is a safe and effective primary surgical procedure for very large angle esotropia. A more extensive study is indicated to confirm these findings.

HCV-RNA quantification in liver bioptic samples and extrahepatic compartments, using the abbott RealTime HCV assay.

PubMed

Antonucci, FrancescoPaolo; Cento, Valeria; Sorbo, Maria Chiara; Manuelli, Matteo Ciancio; Lenci, Ilaria; Sforza, Daniele; Di Carlo, Domenico; Milana, Martina; Manzia, Tommaso Maria; Angelico, Mario; Tisone, Giuseppe; Perno, Carlo Federico; Ceccherini-Silberstein, Francesca

2017-08-01

We evaluated the performance of a rapid method to quantify HCV-RNA in the hepatic and extrahepatic compartments, by using for the first time the Abbott RealTime HCV-assay. Non-tumoral (NT), tumoral (TT) liver samples, lymph nodes and ascitic fluid from patients undergoing orthotopic-liver-transplantation (N=18) or liver resection (N=4) were used for the HCV-RNA quantification; 5/22 patients were tested after or during direct acting antivirals (DAA) treatment. Total RNA and DNA quantification from tissue-biopsies allowed normalization of HCV-RNA concentrations in IU/μg of total RNA and IU/10 6 liver-cells, respectively. HCV-RNA was successfully quantified with high reliability in liver biopsies, lymph nodes and ascitic fluid samples. Among the 17 untreated patients, a positive and significant HCV-RNA correlation between serum and NT liver-samples was observed (Pearson: rho=0.544, p=0.024). Three DAA-treated patients were HCV-RNA "undetectable" in serum, but still "detectable" in all tested liver-tissues. Differently, only one DAA-treated patient, tested after sustained-virological-response, showed HCV-RNA "undetectability" in liver-tissue. HCV-RNA was successfully quantified with high reliability in liver bioptic samples and extrahepatic compartments, even when HCV-RNA was "undetectable" in serum. Abbott RealTime HCV-assay is a good diagnostic tool for HCV quantification in intra- and extra-hepatic compartments, whenever a bioptic sample is available. Copyright © 2017 Elsevier B.V. All rights reserved.

[Primary culture of human malignant meningioma cells and its intracranial orthotopic transplantation in nude mice].

PubMed

Hu, Mei-Xin; Liu, Jia-le; Chen, Xuan-Bo; Xu, An-Qi; Shu, Song-Ren; Wang, Chao-Hu; Liu, Yi

2018-03-20

To obtain stable primary cultures of human malignant meningioma cells and establish an intracranial in-situ tumor model in nude mice. Ten surgical specimens of highly suspected malignant meningioma were obtained with postoperative pathological confirmation. Primary malignant meningioma cells were cultured from the tissues using a modified method and passaged. After identification with cell immunofluorescence, the cultured cells were inoculated into the right parietal lobe of 6 nude mice using stereotaxic apparatus and also transplanted subcutaneously in another 6 nude mice. The nude mice were executed after 6 weeks, and HE staining and immunohistochmistry were used to detect tumor growth and the invasion of the adjacent brain tissues. The primary malignant meningioma cells were cultured successfully, and postoperative pathology reported anaplastic malignant meningioma. Cell immunofluorescence revealed positivity for vimentin and EMA in the cells, which showed a S-shaped growth curve in culture. Flow cytometry revealed a cell percentage in the Q3 area of (95.99∓2.58)%. Six weeks after transplantation, tumor nodules occurred in the subcutaneous tumor group, and the nude mice bearing the in situ tumor showed obvious body weight loss. The xenografts in both groups contained a mean of (36∓5.35)% cells expressing Ki-67, and the intracranial in situ tumor showed obvious invasion of the adjacent peripheral brain tissues. We obtained stable primary cultures of malignant meningioma cells and successfully established a nude mouse model bearing in situ human malignant meningioma.

Vesicovaginal fistula repair with rectus abdominus myofascial interposition flap.

PubMed

Reynolds, W Stuart; Gottlieb, Lawrence J; Lucioni, Alvaro; Rapp, David E; Song, David H; Bales, Gregory T

2008-06-01

Complex, recurrent vesicovaginal fistulas (VVFs) can be very challenging to repair and often require interposition of nonirradiated, well-vascularized tissue between the urinary system and vagina. We report our experience using a rectus abdominus myofascial (RAM) interposition flap for VVF repair. A retrospective analysis was performed to identify patients who had undergone VVF repair with RAM interposition. Data were collected focusing on preoperative patient characteristics, etiology of VVF, intraoperative parameters, including surgical techniques, and postoperative patient outcomes. We used a RAM interposition flap for VVF repair in 5 patients. All VVFs had developed postoperatively; no patient had received radiotherapy. VVF developed after total abdominal hysterectomy (TAH) or radical cystectomy in 3 and 2 cases, respectively. Both cases of VVF after radical cystectomy occurred in conjunction with orthotopic diversion (neobladder-vaginal fistula). In 3 patients with post-TAH VVF, a total of five previous failed repairs were attempted before RAM interposition. In 1 patient with a neobladder-vaginal fistula, who had received adjuvant chemotherapy, RAM interposition failed, and the patient ultimately required cutaneous urinary diversion after two subsequent failed attempts at repair (68 months of follow-up). The remaining 4 patients (80%) had no evidence of recurrent VVF or voiding abnormalities at a mean follow-up of 19 months (range 8 to 32). Rectus abdominus muscle can be a successful interposition flap during repair of complex, recurrent VVF. In our experience, this has been successful in most cases, particularly in younger patients with nonmalignant processes.

Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling.

PubMed

Wen, Shi; Zhan, Bohan; Feng, Jianghua; Hu, Weize; Lin, Xianchao; Bai, Jianxi; Huang, Heguang

2017-11-02

The differentiation of pancreatic ductal adenocarcinoma (PDAC) could be associated with prognosis and may influence the choices of clinical management. No applicable methods could reliably predict the tumor differentiation preoperatively. Thus, the aim of this study was to compare the metabonomic profiling of pancreatic ductal adenocarcinoma with different differentiations and assess the feasibility of predicting tumor differentiations through metabonomic strategy based on nuclear magnetic resonance spectroscopy. By implanting pancreatic cancer cell strains Panc-1, Bxpc-3 and SW1990 in nude mice in situ, we successfully established the orthotopic xenograft models of PDAC with different differentiations. The metabonomic profiling of serum from different PDAC was achieved and analyzed by using 1 H nuclear magnetic resonance (NMR) spectroscopy combined with the multivariate statistical analysis. Then, the differential metabolites acquired were used for enrichment analysis of metabolic pathways to get a deep insight. An obvious metabonomic difference was demonstrated between all groups and the pattern recognition models were established successfully. The higher concentrations of amino acids, glycolytic and glutaminolytic participators in SW1990 and choline-contain metabolites in Panc-1 relative to other PDAC cells were demonstrated, which may be served as potential indicators for tumor differentiation. The metabolic pathways and differential metabolites identified in current study may be associated with specific pathways such as serine-glycine-one-carbon and glutaminolytic pathways, which can regulate tumorous proliferation and epigenetic regulation. The NMR-based metabonomic strategy may be served as a non-invasive detection method for predicting tumor differentiation preoperatively.

Sonography-guided hydrostatic reduction of ileocolic intussusception in children: analysis of failure and success in consecutive patients presenting timely to the hospital.

PubMed

Menke, Jan; Kahl, Fritz

2015-03-01

In children with ileocolic intussusception sonography is increasingly being used for diagnosis, whereas fluoroscopy is frequently used for guiding non-invasive reduction. This study assessed the success rate of radiation-free sonography-guided hydrostatic reduction in children with ileocolic intussusception, using novel well-defined success rate indices. All children were evaluated who presented from 2005 to 2013 to the local university hospital with ileocolic intussusception. The patients were treated with sonography-guided hydrostatic reduction unless primary surgery was clinically indicated. The according success rate was determined by indices of Bekdash et al. They represent the ratio of persistently successful non-surgical reductions versus four different denominators, depending on including/excluding cases with primary surgery and including/excluding cases requiring bowel resection/intervention. Fifty-six consecutive patients were included (age, 3 months to 7.8 years). About 80% of the patients presented until 24 h and 20% until 48 h after the onset of symptoms. Seven patients underwent primary surgery, with bowel resection required in three cases. Hydrostatic reduction was attempted in 49 patients, being permanently successful in 41 cases (selective reduction rate 41/49 = 83.7%; crude reduction rate 41/56 = 73.2%). The remaining eight patients underwent secondary surgery, with just two patients not requiring surgical bowel resection/intervention (corrected selective reduction rate 41/43 = 95.3%). The composite reduction rate was 87.2% (successful/feasible reductions, 41/47). Radiation-free sonography-guided hydrostatic reduction has a good success rate in children with ileocolic intussusception. It may be particularly valuable in centers that are already experienced with using sonography for the diagnosis.

[Thyrotoxicosis in heart recipients].

PubMed

Skirzyńska, Dorota; Garlicki, Mirosław; Plicner, Dariusz; Wysocka, Teresa; Wierzbicki, Karol; Biernat, Marta; Sadowski, Jerzy

2002-01-01

Between 1992 and 2000 in the group of the patients before heart transplantation, amiodarone induced thyrotoxicosis occurred in 5 (4 male and 1 female, average age 45.5 years) patients. In four of the patients of that group orthotopic heart transplantation was done. Postoperative period in the patients with euthyreosis was uncomplicated. One patient died after HTx because of thyroid crisis.

Ovarian Tumor-Stroma Interactions in an In Vivo Orthotopic Model

DTIC Science & Technology

2012-08-01

32. 7. Zheng X, Cui XX, Avila GE, Huang MT, Liu Y, Patel J, Kong AN, Paulino R, Shih WJ, Lin Y, Rabson AB, Reddy BS, Conney AH. Atorvastatin and...Shih WJ, Huang MT, Liu Y, Rabson A, Reddy B, Yang CS, Conney AH. Atorvastatin and celecoxib in combination inhibits the progression of androgen

Acute left main coronary artery occlusion

PubMed Central

Burgazli, K. Mehmet; Bilgin, Mehmet; Soydan, Nedim; Chasan, Ridvan; Erdogan, Ali

2013-01-01

The treatment of an acute left main coronary artery occlusion still poses a challenge. In this case report we present a 50-year-old patient with an acute occlusion of the left main artery. After a successful angioplasty without “stenting” due to the complexity of the stenosis the patient underwent a successful bypass surgery. We discuss the therapeutic options of acute left main occlusion regarding medical, interventional and surgical options. PMID:24353543

Successful Surgical Stabilization of Rib Fractures Despite Candida Colonization of the Mediastinum.

PubMed

Ju, Tammy; Rivas, Lisbi; Sarani, Babak

2018-04-06

Pleural space or chest wall infection is a contraindication for surgical stabilization of rib fractures (SSRF) due to the risk of hardware infection. However, the exact degree of risk is uncertain. SSRF is associated with decreased need for mechanical ventilation and pneumonia. Here, we describe a poly-trauma patient with candida colonization of the mediastinum who successfully underwent SSRF. Copyright © 2018. Published by Elsevier Inc.

Partial nephrectomy in a patient with dwarfism.

PubMed

Farber, Nicholas J; Dubin, Justin; Parihar, Jaspreet; Han, Chris; Lasser, Michael S

2016-08-01

We describe the case of a 50-year-old male with achondroplastic dwarfism who presents with a renal mass in his left kidney concerning for renal cell carcinoma. The patient successfully underwent a robotic partial nephrectomy, which revealed a T1a renal cell carcinoma. The tumor was excised successfully without any intraoperative complications demonstrating that a robotic partial nephrectomy is technically both safe and effective in patients with achondroplastic dwarfism.

Matched cohort study of external cephalic version in women with previous cesarean delivery.

PubMed

Keepanasseril, Anish; Anand, Keerthana; Soundara Raghavan, Subrahmanian

2017-07-01

To evaluate the efficacy and safety of external cephalic version (ECV) among women with previous cesarean delivery. A retrospective study was conducted using data for women with previous cesarean delivery and breech presentation who underwent ECV at or after 36 weeks of pregnancy during 2011-2016. For every case, two multiparous women without previous cesarean delivery who underwent ECV and were matched for age and pregnancy duration were included. Characteristics and outcomes were compared between groups. ECV was successful for 32 (84.2%) of 38 women with previous cesarean delivery and 62 (81.6%) in the control group (P=0.728). Multivariate regression analysis confirmed that previous cesarean was not associated with ECV success (odds ratio 1.89, 95% confidence interval 0.19-18.47; P=0.244). Successful vaginal delivery after successful ECV was reported for 19 (59.4%) women in the previous cesarean delivery group and 52 (83.9%) in the control group (P<0.001). No ECV-associated complications occurred in women with previous cesarean delivery. To avoid a repeat cesarean delivery, ECV can be offered to women with breech presentation and previous cesarean delivery who are otherwise eligible for a trial of labor. © 2017 International Federation of Gynecology and Obstetrics.