Science.gov

Sample records for orthotopic neobladder replacement

  1. Postoperative bacteriuria, pyuria and urinary tract infection in patients with an orthotopic sigmoid colon neobladder replacement.

    PubMed

    Shigemura, Katsumi; Tanaka, Kazushi; Arakawa, Soichi; Miyake, Hideaki; Fujisawa, Masato

    2014-02-01

    The purpose of this study is to investigate the prevalence of postoperative bacteriuria, pyuria and urine culture in patients with an orthotopic sigmoid colon neobladder replacement. Urine samples for bacteriuria, pyuria and urine culture, if necessary, were collected at 1, 3, 6, 9 and 12 months after surgery and the presence of blood culture and antibiotic-resistant strains, and their treatments on positive urine culture cases were investigated. Of 209 for bacteriuria and 207 for pyuria urine samples with evaluable data, 95 (45.5%) were positive for bacteriuria and 76 (36.7%) had pyuria (10 or more white blood cells per high-power field). Totally, 30 bacteria were isolated from urine culture of urinary tract infection (UTI) and Klebisiella pneumoniae, Escherichia coli, Staphylococcos aureus and Enterococcus spp. strains were representatively isolated. The incidence of pyuria significantly decreased over time (P=0.041) but that of bacteriuria did not (P=0.107). In them, there were six bacteria (20.7%) with antibiotic-resistant strains. The antibiotics used for their treatments representatively were levofloxacin in five cases, tazobactam/piperacillin in three cases and sulfamethoxazole/trimethoprim and cefepime, meropenem in two cases, respectively. In conclusion, these findings suggest that physicians taking care of sigmoid colon neobladder patients need to be aware of these high ratios of bacteriuria, pyuria and UTI, including bacteremia.

  2. Endoscopic Treatment of Studer's Orthotopic Neobladder Lithiasis

    PubMed Central

    Gil-Sousa, Diogo; Oliveira-Reis, Daniel; Cavadas, Vitor; Oliveira, Manuel; Soares, José; Fraga, Avelino

    2015-01-01

    Studer's neobladder lithiasis is a rare but important long term complication of this orthotopic bladder substitute technique. We report a case of a 45 year-old male patient, submitted to a radical cystoprostatectomy with a Studer's orthotopic neobladder 4 years before, presenting bad compliance to recommended urinary habits, increased production of mucus and high post voiding residue. CT scan and urethrocystography showed a distended pouch with 2 major sacculations with narrow communication and a stone in each sacculation. A minimally invasive endoscopic technique was successfully used in the treatment of the 2 small calculus. PMID:26793507

  3. Intraneobladder Hem-o-Lok Migration with Stone Formation after Orthotopic Neobladder Cystectomy.

    PubMed

    Shu-Xiong, Zeng; Zhen-Sheng, Zhang; Xiao-Wen, Yu; Hui-Zhen, Li; Xin, Lu; Ying-Hao, Sun; Chuan-Liang, Xu

    2014-01-01

    Introduction. Laparoscopic and robot-assisted laparoscopic surgery are widely performed in urology field, so Hem-o-Lok clips are thus extensively used in the laparoscopic procedures. We describe the first case of Hem-o-Lok clip which migrated into the neobladder with calculus formation 26 months after laparoscopic orthotopic neobladder cystectomy, which causes symptoms of gross hematuria and frequent urination. Case Presentation. A 57-year-old man with T2a muscle invasive bladder cancer underwent laparoscopic orthotopic sigmoid neobladder reconstruction after cystectomy which was complicated by intestinal anastomosis leak and peritoneal abscess requiring transverse colostomy and drainage 15 days postoperatively. Twenty-six months after cystectomy, he complained of gross hematuria and frequent urination. Computerized tomography and plain pelvic X-ray revealed a stone measuring approximately 2.8 cm in diameter in the neobladder. During cystoscopy, a closed whitish Hem-o-Lok clip was seen in the center of the calculi. No anastomotic leak or neoplasm was found during cystoscopy. Conclusion. Hem-o-Lok clip migration into the bladder after laparoscopic orthotopic neobladder cystectomy is a rare complication; the first reported case in the literature. To prevent Hem-o-Lok clip migration, it is recommended to avoid extensive use of Hem-o-Lok clip close to anastomosis site, and any loose Hem-o-Lok clip should be retrieved before closure.

  4. AB047. Clinic therapeutic effect of sigmoid orthotopic neobladder after radical cystectomy

    PubMed Central

    Zhang, Jin; Li, Ranwei; Li, Shengwen

    2016-01-01

    Objective To investigate the clinic therapeutic effect of sigmoid orthotopic neobladder after radical cystectomy. Methods Sixteen patients with invasive bladder cancer (all males; age range from 53 to 75 years) were admitted and underwent radical cystectomy and sigmoid orthotopic neobladder. Results The 16 patients were hospitalized for 37 to 62 d, with an average of 51 d. All the 16 patients were followed up for a mean of 26 months (range from 5 months to 6 years). The serum creatinine and blood urea nitrogen levels were both in the normal range without acidosis in all the cases. No cases had unilateral ureteral urine reflux during cystography. Of the 16 patients 14 cases (87.5%) achieved continence during daytime; 6 cases (37.5%) were incontinent at night, but all of them could control urination by being woken up at night. The capacity of the neobladder was 245 to 380 mL with an average of 316 mL and the maximal pressure of the neobladder during filling was 28 to 57 cmH2O (1 cmH2O =0.098 kPa) with an average of 39 cmH2O. Conclusions As an operation the sigmoid orthotopic neobladder can be performed easily without serious postoperative complications and more reliable results. This operation may be generally applied in clinical practice.

  5. Pregnancy and delivery in a patient with a Studer orthotopic ileal neobladder

    PubMed Central

    Kołodziej, Anna; Tupikowski, Krzysztof; Małkiewicz, Bartosz; Dembowski, Janusz; Zimmer, Mariusz; Szydełko, Tomasz; Zdrojowy, Romuald

    2016-01-01

    Pregnancies in patients after cystectomy with urinary diversion, especially after the construction of a continent urinary reservoir, are rare. Experience in this field is limited and mainly concerns patients with congenital disorders, neurogenic diseases or trauma. In this paper, we report the outcome of pregnancy, delivery and the postpartum period in a 27-year old woman with a Studer ileal orthotopic neobladder after radical cystectomy, performed after the diagnosis of a malignant tumor at the age of 14. PMID:28127463

  6. Laparoscopic radical cystectomy with novel orthotopic neobladder with bilateral isoperistaltic afferent limbs: initial experience

    PubMed Central

    Xing, Nian-Zeng; Kang, Ning; Song, Li-Mming; Niu, Yi-Nong; Wang, Ming-Shuai; Zhang, Jun-Hui

    2017-01-01

    ABSTRACT Purpose To introduce a new method of constructing an orthotopic ileal neobladder with bilateral isoperistaltic afferent limbs, and to describe its clinical outcomes. Materials and Methods From January 2012 to December 2013, 16 patients underwent a new method of orthotopic ileal neobladder after laparoscopic radical cystectomy for bladder cancer. To construct the neobladder, an ileal segment 60cm long was isolated approximately 25cm proximally to the ileocecum. The proximal 20cm of the ileal segment was divided into two parts for bilateral isoperistaltic afferent limbs. The proximal 10cm of the ileal segment was moved to the distal end of the ileal segment for the right isoperistaltic afferent limb, and the remaining proximal 10cm ileal segment was reserved for the left isoperistaltic afferent limb. The remaining length of the 40cm ileal segment was detubularized along its antimesenteric border to form a reservoir. The neobladder was sutured to achieve a spherical configuration. Results All procedures were carried out successfully. The mean operative time was 330 min, mean blood loss was 328mL, and mean hospital stay was 12.5 days. The mean neobladder capacity 6 and 12 months after surgery was 300mL and 401mL, respectively. With a mean follow-up of 22.8 months, all patients achieved daytime continence and 15 achieved nighttime continence. The mean peak urinary flow rate was 11.9mL/s and 12.8mL/s at 6 and 12 months postoperatively, respectively. Conclusions This novel procedure is feasible, safe, simple to perform, and provides encouraging functional outcomes. However, comparative studies with long-term follow-up are required to prove its superiority. PMID:28124527

  7. [Application of modified single port laparoscopic radical cystoprostatectomy and orthotopic ileal neobladder].

    PubMed

    Huang, Jian; Lin, Tian-Zin; Xu, Ke-Wei; Han, Jin-Li; Ye, Feng; Huang, Hai; Jiang, Chun; Zhang, Cai-Xia; Yao, You-Sheng; Xie, Wen-Lian; Liu, Hao

    2010-06-08

    To evaluated the feasibility and therapeutic effect of laparoscopic-endoscopic single-site surgery (LESS) for radical cystoprostatectomy and orthotopic ileal neobladder. Between November 2008 and August 2009, 8 male patients with bladder cancer underwent modified single port laparoscopic cystoprostatectomy and orthotopic ileal neobladder with a home-made multichannel port made up of two stretchable rings and a surgical glove with trocars and valves attached to its fingers. A 4 - 5 cm midline incision was made in lower abdomen and the multichannel port placed into this incision. Laparoscopic instrument was extended through the multichannel port. Another port was placed at the umbilicus site for laparoscope. The investigators performed the modified single port transperitoneal technique neobladder extracorporeally and urethro-pouch anastomosis under laparoscopy with a slipknot running suture technique. The perioperative and postoperative data were collected and analyzed prospectively. In all cases, no conversion into conventional laparoscopic or open surgery was necessary. The mean operative duration, including extended lymph node dissection, was 399 min (range: 355 - 455 min). Mean estimated blood loss was 154 ml (range: 90 -210 ml). The mean postoperative hospital stay was 15 d (range: 14 - 18 d). No peri-operative mortality was reported. One case had delirium 2 days postoperatively and there was no port-related complication. The pathological report confirmed surgical margins were tumor-free for all cases. The average number of removed lymph node was 20. The mean follow-up period was 6.1 months (range: 2.0 -10.0 months). All patients remained disease-free until the last follow-up. With a reduction of 4 ports, modified single port laparoscopic radical cystectomy with orthotopic ileal neobladder is technically feasible with a low complication rate. Our initial outcome is encouraging, but additional work and a further follow-up are warranted to critically compare the

  8. [Orthotopic ileal neobladder: urodynamic and metabolic aspects. Our experience].

    PubMed

    Mangiarotti, B; Ceresoli, A; Del Nero, A; Parravicini, M; Prati, G; Currò, A; Zanetti, G P; Trinchieri, A; Pisani, E

    1996-12-01

    We subjected to a functional and metabolic evaluation (urodynamic examination + cystography) 10 patients underwent to radical cystectomy with a ileal orthotopic reservoir (VIP) for bladder cancer. At the moment patients have a minimum 3-years follow-up and they are out of disease. The medium capacity of the reservoir is about 447 ml, with a low pressure flow, a medium pressure of ureteral closing of 62.5 cm of H2O. At the cystography neither ureteral reflux nor post miction residuum have been proved. All the patients are continent, with the exception of one patient suffering from episodes of nocturnal enuresis. The metabolic evaluation hasn't proved substantial changes except the presence of hypocitraturia in the only patient in metabolic acidosis. In conclusion the ileal orthotopic reservoir showed a good long-term functionality without considerable complication of metabolism.

  9. 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

  10. Long-term urodynamic evaluation of laparoscopic radical cystectomy with orthotopic ileal neobladder for bladder cancer

    PubMed Central

    WANG, DONG; LI, LI-JUN; LIU, JING; QIU, MING-XING

    2014-01-01

    The long-term urodynamics of laparoscopic radical cystectomy with orthotopic ileal neobladder for bladder cancer remain unclear in the clinical setting. The present prospective observational study was conducted between January 2010 and December 2012 to evaluate the 6-month and 12-month follow-up data of urodynamic changes of bladder cancer patients who were initially treated by laparoscopic radical cystectomy with orthotopic ileal neobladder. A total of 53 eligible patients were included, and all patients were followed up for at least 12 months, with a median time of 18 months. During the follow-up period, no patients reported difficulty urinating, and the daily frequency of urination and the urine output were gradually improved with time. Dynamic urodynamic examinations showed that the maximum flow rate (11.4±1.1 vs. 7.3±1.4 ml/sec; P<0.001), residual urine content (22.8±10.5 vs. 40.7±12.7 ml; P<0.001), maximum bladder capacity (373.8±62.2 vs. 229.7±56.3 ml; P<0.001) and maximum bladder pressure during filling (35.8±6.7 vs. 26.4±7.0 cm H2O; P<0.001) at 12 months were all improved significantly compared with that at 6 months after the initial surgical treatment. However, there were no significant differences in maximum bladder pressure during voiding (75.7±24.7 vs. 73.1±24.7 cm H2O; P=0.618) and bladder compliance (26.9±13 vs. 27.4±13.1 cm H2O; P=0.848) at 12 and 6 months after initial surgical treatment. In conclusion, the urodynamics of this orthotopic ileal neobladder gradually improve, and its long-term urine storage and voiding functions are acceptable. PMID:25120652

  11. [Orthotopic ileal neobladder: technical procedures and long-term follow-up].

    PubMed

    Leidi, G L; Berti, G L; Giola, V; Longoni, E; Paccaduscio, A; Raimoldi, A; Bacchioni, A M

    1999-06-01

    From January 1992 to September 1997, 29 male patients between the age of 39 and 71 affected by localized bladder cancer underwent radical cystectomy and received detubularized orthotopic ileal neobladder. In most cases we performed the ileal neobladder utilizing the Studer technique, preferring the Wallace 1 method for the uretero-ileal anastomosis, that seems to reduce the risk of stenosis. In some patients we experimented different techniques. One of these was the utilization of staplers but, at present, we are no longer using this procedure due to its high costs without any real advantage in operative time. Another technique is the performance of continuous suture in catgut 000 on the ileal aperture edges for the anastomosis with the urethra, because we believe that this method makes the ileal wall stronger. Usually we apply 6 stitches in vicryl 000 for the urethro-ileal anastomosis. In 14-28 days, after a cystography to exclude the presence of urinary fistula, the catheter was removed. 6 months later an evaluation was made utilizing an auto-evaluation questionnaire, biochemical, radiological and urodynamic examinations. The diurnal continence (96%), the nocturnal continence (71%), the renal function preservation (normal in 86% of patients), the radiological, biochemical and urodynamic (low pressure and high capacity of the neobladder) results were comparable with those published in literature. The discrete percentage of urinary refluxes observed (39%) puts in doubt the real efficacy of the undetubularized ileal tract as an antireflux mechanism, however it does not seem to determine an important reduction of renal function, as confirmed in the check up five years later. In our experience, this operation reduces the risk of stenosis of the uretero-ileal anastomosis.

  12. Orthotopic ileal neobladder in female patients after radical cystectomy: 2-year experience.

    PubMed

    Cancrini, A; De Carli, P; Fattahi, H; Pompeo, V; Cantiani, R; Von Heland, M

    1995-03-01

    We describe a surgical technique to conserve urinary continence in 7 women who underwent radical cystectomy with construction of an orthotopic ileal neobladder for infiltrating bladder carcinoma. The selection of the patients and the surgical procedure to preserve the anatomical and functional integrity of the female urethra are described. Followup ranged from 7 to 28 months. There were no postoperative deaths or serious clinical complications. The urinary continence rate was 100% during the day and 71% at night with micturition at regular 3-hour intervals. The vesical capacity varied from 250 to 400 cc and pressure at maximum capacity from 10 to 25 cm. water. Urinary flow was satisfactory and the urethral pressure profile showed a normal sphincteric mechanism at rest. Two patients died of metastases at 14 and 8 months postoperatively, and 5 are alive and disease-free. We believe that these results confirm the possibility of obtaining micturition in women via the urethra following radical cystectomy.

  13. Robotic Intracorporeal Orthotopic Neobladder: Urodynamic Outcomes, Urinary Function, and Health-related Quality of Life.

    PubMed

    Satkunasivam, Raj; Santomauro, Michael; Chopra, Sameer; Plotner, Elisabeth; Cai, Jie; Miranda, Gus; Salibian, Salpi; Aron, Monish; Ginsberg, David; Daneshmand, Siamak; Desai, Mihir; Gill, Inderbir S

    2016-02-01

    Intracorporeal orthotopic neobladder (iONB) creation following robotic radical cystectomy is an emerging procedure and robust functional data are required. To evaluate urodynamic features of iONB and bladder cancer-specific and general health-related quality-of-life (HRQOL) outcomes. We retrospectively assessed 28 men who underwent iONB creation (January 2012 to October 2013) and compared results to a previously characterized cohort of 79 of open ONB procedures. iONB pressure-volume properties were characterized using multichannel urodynamics (UDS). The Bladder Cancer Index (BCI) questionnaire, modified with mucus- and pad-related questions, and the Short Form Health Survey (SF-36) were used to evaluate urinary function and HRQOL. ONB cohorts were compared for functional outcomes and BCI score. Multivariable linear regression was used to assess predictors of BCI score. The median follow-up was 9.4 mo for the iONB and 62.1 mo for the open ONB group (p<0.0001); ≥2-yr follow-up had been completed for one (4%) patient in the iONB group compared to 75 (95%) patients in the open ONB group (p<0.0001). In UDS tests, the iONB group had minimal postvoid residual volume, normal compliance, and a mean capacity of 514 cm(3) (range 339-1001). BCI mean scores for urinary function (p=0.58) and urinary bother (p=0.31) were comparable between the groups. The surgical approach was not associated with the BCI score on multivariable analysis. Rates of 24-h pad use were comparable between iONB and open ONB groups (pad-free 17% vs. 19%; ≤2 pads 84% vs. 79%), as reflected by total pad usage (p=0.1); pad size and daytime wetness were worse in the iONB group. The clean intermittent catheterization rate was 10.7% in the iONB and 6.3% in the open ONB group. Limitations include the retrospective comparison, small number of patients and short follow-up for the iONB group. iONB had adequate UDS characteristics and comparable bladder cancer-specific HRQOL scores to open ONB. However, pad size

  14. Can we predict the need for clean intermittent catheterization after orthotopic neobladder construction?

    PubMed

    Murray, Katie S; Arther, Andrew R; Zuk, Keegan P; Lee, Eugene K; Lopez-Corona, Ernesto; Holzbeierlein, Jeffrey M

    2015-01-01

    We aimed to identify peri-operative and pathologic characteristics that may predict the need for clean intermittent catheterization (CIC) following radical cystectomy (RC) with orthotopic neobladder (ONB) in order to improve patient counseling on choice of urinary diversion. Between July 2004 and February 2013, all patients who underwent RC with ONB were identified. Peri-operative clinical and pathological features were evaluated and correlated with patients reported need for CIC. The independent T-test was performed for continuous variables and Chi-square test was performed for categorical variables. Multivariate forward stepwise logistic regression analysis was used to identify variables that correlated with need for CIC after ONB. During the study period, 114 patients underwent RC with ONB creation. On univariate analysis, patients with higher body mass index, younger age, and non-vaginal or non-nerve-sparing procedures were more likely to require catheterization for complete emptying. Multivariate analysis demonstrates that conservative surgery (nerve sparing in males or vaginal sparing in females) was associated with a significantly lower rate of requiring CIC (Odds Ratio [OR] 0.20, P < 0.01). Surprisingly, older age was also associated with a slightly lower, but statistically significant, rate of requiring CIC (OR 0.92,P < 0.01). When counseling patients regarding the different types of diversions after RC, the potential need for long-term CIC after ONB must be discussed. The clinical factors that appear to increase the need for CIC include non-conservative RC (non-nerve sparing in males and non-vaginal sparing in females) and, to a certain degree, younger age.

  15. Cystectomy and orthotopic ileal neobladder in a male patient 12 years after kidney transplantation; good preservation of the renal function.

    PubMed

    Selli, Cesare; Boggi, Ugo; Travaglini, Fabrizio; Vistoli, Fabio; Del Chiaro, Marco; Mosca, Franco

    2004-02-01

    In case of cystectomy, some forms of urinary diversion can impair the graft function of renal transplant patients. Here we present the case of a 70-year-old male with carcinoma of the bladder 12 years after renal transplantation. Immunosuppression was achieved with Cyclosporin A (200 mg/day) and Prednisone (5 mg/day). The patient's serum creatinine level was 1.4 mg/dl. Following cystectomy, an orthotopic ileal neobladder was constructed by means of Studer technique, and the afferent ileal loop was anastomosed to the graft ureter. Pathology revealed pT1 G3 N+ transitional cell carcinoma. Ten months later, periaortic nodal recurrences necessitated four cycles of chemotherapy with Epidoxorubicyn and Gemcytabine. To date, 20 months after cystectomy, the patient is stable, with day and night-time urinary continence. His serum creatinine level is 1.3 mg/dl, and there is no evidence of hydronephrosis or acidosis. We conclude that the orthotopic ileal neobladder is an effective form of urinary diversion in renal transplant patients requiring cystectomy, allowing good preservation of the renal function.

  16. Development of a questionnaire specifically for patients with Ileal Orthotopic Neobladder (IONB).

    PubMed

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

    2014-09-01

    The ileal orthotopic neobladder (IONB) is often used in patients undergoing radical cystectomy. The IONB allows to void avoiding the disadvantages of the external urinary diversion.In IONB patients the quality of life (QoL) appears compromised by the need to urinate voluntarily. The patients need to wake up at night interrupting the sleep-wake rhythm with consequences on social and emotional life.At present the QoL in IONB patients is evaluated by generic questionnaires. These are useful when IONB patients are compared with patients with different urinary diversions but they are less effective when only IONB patients are evaluated. To address this problem a specific questionnaire-the IONB-PRO-was developed. A) Based on a conceptual framework, narrative-based interviews were conducted on 35 IONB patients. A basic pool of 43 items was produced and organized throughout two clinical and four QoL dimensions. An additional 15 IONB patients were interviewed for face validity testing.B) Psychometric testing was conducted on 145 IONB patients. Both classic test strategy and Rasch analysis were applied. Psychometric properties of the resulting scales were comparatively tested against other QoL-validated scales. The IONB-PRO questionnaire includes two sections: one on the QoL and a second section on the capability of the patient to manage the IONB. For evaluation of the QoL, three versions were delivered: 1) a basic 23-item QoL version (3 domains 23-items; alpha 0.86÷ 9.69), 2) a short-form 12-item QoL scale (alpha = 0.947), and 3) a short-form 15-item Rasch QoL scale (alpha = 0.967). Correlations of the long version scales with the corresponding dimensions of the EORTC-QLQ C30 and the EORTC-BLM30 were significant. The short forms exhibited significant correlations with the global health dimension of the EORTC-QLQ and with the urinary subscales of the EORTC-BLM30. The effect size was approximately 1.00 between patients at the 1-year follow-up period and those with 3, 5, and

  17. Hybrid laparoscopic endoscopic single-site surgery for radical cystoprostatectomy and orthotopic ileal neobladder: an initial experience of 12 cases.

    PubMed

    Lin, Tianxin; Huang, Jian; Han, Jinli; Xu, Kewei; Huang, Hai; Jiang, Chun; Liu, Hao; Zhang, Caixia; Yao, Yousheng; Xie, Wenlian; Shah, Arvind Kumar; Huang, Li

    2011-01-01

    Laparoscopic endoscopic single-site surgery (LESS) has recently emerged as an attempt to enhance cosmetic benefits and reduce morbidity; however, LESS for radical cystectomy is still not well established. Here we describe the technique of hybrid LESS for radical cystoprostatectomy and orthotopic ileal neobladder (RC-OIN), and evaluate its feasibility and safety. Between November 2008 and October 2009, 12 men with bladder cancer underwent hybrid LESS for RC-OIN. A homemade multichannel port, made from two stretchable rings and a surgical glove with trocars and valves attached to its fingers, was placed into a 4- to 5-cm midline incision in the lower abdomen and was used for laparoscopic instruments. Another subumbilical port was placed for the laparoscope. Extended bilateral pelvic lymphadenectomy was performed by the lateral view; radical cystoprostatectomy was completed laparoscopically; construction of the ileal neobladder was performed extracorporeally; and the neobladder was anastomosed to the urethral stump laparoscopically, with a slipknot running suture technique. Perioperative, functional, oncologic data and complications were collected and analyzed. All operations were performed successfully without conversion to conventional laparoscopic radical cystectomy or open surgery. There was no perioperative mortality or port-related complications. The median operative time was 383 minutes. Median blood loss was 150 mL. A median of 25 lymph nodes were removed. Surgical margins were tumor free in all cases. Hybrid LESS for RC-OIN is technically feasible with effects similar to those of conventional laparoscopic procedures. Further instrument and technique improvement are necessary to shorten operative time and reduce intraoperative difficulties.

  18. Cystectomy with orthotopic ileal neobladder reconstruction for treatment of bladder contracture after intravesical bacillus Calmette-Guerin therapy

    PubMed Central

    Vetorazzo, José Eduardo; Bahia, Leandro Augusto Costa; Vedovato, Bruno César; Maron, Paulo Eduardo Goulart; Esteves, Paulo Ebert; Fernandes, Roni de Carvalho; Perez, Marjo Deninson Cardenuto

    2014-01-01

    Bladder cancer is an important health problem worldwide due to high prevalence rates and costs related to treatment. A reduction in recurrence rates has been observed since the introduction of adjuvant intravesical immunotherapy with bacillus Calmette-Guerin. There are mild complications that are easily solved by local measures and orientations. Bladder contracture, a rare and severe local complication, in some cases leading to disability, is observed primarily in patients in a maintenance program. In this article we reported the case of a male patient who underwent transurethral resection of the bladder because of a high-grade T1 urothelial carcinoma and developed this complication during treatment with bacillus Calmette-Guerin. For this reason he was submitted to cystoprostatectomy with orthotopic ileal neobladder reconstruction. PMID:25628205

  19. Cystectomy with orthotopic ileal neobladder reconstruction for treatment of bladder contracture after intravesical bacillus Calmette-Guerin therapy.

    PubMed

    Vetorazzo Filho, José Eduardo; Bahia, Leandro Augusto Costa; Vedovato, Bruno César; Maron, Paulo Eduardo Goulart; Esteves, Paulo Ebert; Fernandes, Roni de Carvalho; Perez, Marjo Deninson Cardenuto

    2014-01-01

    Bladder cancer is an important health problem worldwide due to high prevalence rates and costs related to treatment. A reduction in recurrence rates has been observed since the introduction of adjuvant intravesical immunotherapy with bacillus Calmette-Guerin. There are mild complications that are easily solved by local measures and orientations. Bladder contracture, a rare and severe local complication, in some cases leading to disability, is observed primarily in patients in a maintenance program. In this article we reported the case of a male patient who underwent transurethral resection of the bladder because of a high-grade T1 urothelial carcinoma and developed this complication during treatment with bacillus Calmette-Guerin. For this reason he was submitted to cystoprostatectomy with orthotopic ileal neobladder reconstruction.

  20. Quality of Life Assessment With Orthotopic Ileal Neobladder Reconstruction After Radical Cystectomy: Results From a Prospective Italian Multicenter Observational Study.

    PubMed

    Imbimbo, Ciro; Mirone, Vincenzo; Siracusano, Salvatore; Niero, Mauro; Cerruto, Maria Angela; Lonardi, Cristina; Artibani, Walter; Bassi, Pierfrancesco; Iafrate, Massimo; Racioppi, Marco; Talamini, Renato; Ciciliato, Stefano; Toffoli, Laura; Visalli, Francesco; Massidda, Davide; D'Elia, Carolina; Cacciamani, Giovanni; De Marchi, Davide; Silvestri, Tommaso; Creta, Massimiliano; Belgrano, Emanuele; Verze, Paolo

    2015-11-01

    To assess health-related quality of life (HRQoL) parameters in patients who received radical cystectomy (RC) with ileal orthotopic neobladder (IONB) reconstruction and to identify clinic-pathologic predictors of HRQoL. From January 2010 to December 2013, a multicenter, retrospective on 174 RC-IONB patients was carried out. All patients completed the following questionnaires: the European Organization for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and bladder cancer-specific instruments (QLQ-BLM30) and the IONB-Patient Reported Outcome (IONB-PRO). Univariate and multivariate analyses were computed to identify clinic-pathologic predictors of HRQoL. Median age was 66 years (range, 31-83), and 91.4% of patients were men. Median follow-up period was 37 months (range, 3-247). The EORTC QLQ-C30 revealed that age >65 years, absence of urinary incontinence, and absence of peripheral vascular disease were independent predictors of deteriorated body image. A follow-up > 36 months and the presence of urinary incontinence were independent predictors of worsened urinary symptoms, whereas the absence of urinary incontinence was an independent predictor of a worsened body image according to EORTC QLQ-BLM30 results. A follow-up >36 months and the absence of urinary incontinence were independent predictors of better functioning in terms of relational life, emotional life, and fatigue as revealed by the IONB-PRO. Age, presence of urinary incontinence, length of follow-up, and comorbidity status may influence postoperative HRQoL and should all be taken into account when counseling RC-IONB patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. [A case of metabolic acidosis and tetany after ileal neobladder replacement].

    PubMed

    Nomura, Hironori; Kou, Yohko; Kinjyo, Takanori; Nonomura, Daichi; Yoneda, Suguru; Yamamoto, Yoshiyuki; Tei, Norihide; Takada, Shingo; Matsumiya, Kiyomi

    2013-08-01

    A 64-year-old man visited our hospital with the complaint of macrohematuria and bilateral hydronephrosis. He had undergone total cystectomy and ileal neobladder replacement under the diagnosis of muscle invasive bladder cancer (cT2bN0M0). Tetany due to hyperventilation syndrome appeared on postoperative day 42. Blood gas analysis showed metabolic acidosis (pH 7.260, pO2 148.1 mmHg, pCO2 20.7 mmHg, HCO3 9.1 mmHg, BE -16.0 mmol/l). His condition was immediately improved after a urethral catheter was placed and sodium bicarbonate was administered. After re-removal of the urethral catheter, however, hyperventilation syndrome recurred. He was discharged from the hospital with the urethral catheter placed.

  2. 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.

  3. 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.

  4. 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

  5. Systematic review and meta-analysis of non RCT's on health related quality of life after radical cystectomy using validated questionnaires: Better results with orthotopic neobladder versus ileal conduit.

    PubMed

    Cerruto, M A; D'Elia, C; Siracusano, S; Gedeshi, X; Mariotto, A; Iafrate, M; Niero, M; Lonardi, C; Bassi, P; Belgrano, E; Imbimbo, C; Racioppi, M; Talamini, R; Ciciliato, S; Toffoli, L; Rizzo, M; Visalli, F; Verze, P; Artibani, W

    2016-03-01

    The current literature on the impact of different urinary diversions on patients' health related quality of life (HR-QoL) showed a marginally better quality of life scores of orthotopic neobladder (ONB) compared to ileal conduit (IC). The aim of this study was to update the review of all relevant published studies on the comparison between ONB and IC. Studies were identified by searching multiple literature databases, including MEDLINE, CINAHL, the Cochrane Library, PubMed Data were synthesized using meta-analytic methods conformed to the PRISMA statement. The current meta-analysis was based on 18 papers that reported a HR-QoL comparison between IC and ONB using at least a validate questionnaire. Pooled effect sizes of combined QoL outcomes for IC versus ONB showed a slight, but not significant, better QoL in patients with ONB (Hedges' g = 0.150; p = 0.066). Patients with ileal ONB showed a significant better QoL than those with IC (Hedges' g = 0.278; p = 0.000); in case series with more than 65% males, ONB group showed a slight significant better QoL than IC (Hedges' g = 0.190; p = 0.024). Pooled effects sizes of all EORTC-QLQ-C30 aspects showed a significant better QoL in patients with ONB (Hedges' g = 0.400; p = 0.0000). This meta-analysis of not-randomized comparative studies on the impact of different types of urinary diversions on HR-QoL showed demonstrated a significant advantage of ileal ONB compared to IC in terms of HR-QoL. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Functional Assessment of the Hautmann Ileal Neobladder with Chimney Modification Using Uroflowmetry and a Questionnaire

    PubMed Central

    Jung, Ha Bum; Choi, Don Kyoung; Cho, Sung Tae; Kim, Ki Kyung

    2016-01-01

    Urinary diversion reconstruction is essential after radical cystectomy and neobladder reconstruction is accepted as a fine option. This study included 51 patients, who underwent radical cystectomy with orthotopic neobladder reconstruction by a Hautmann ileal neobladder with chimney modification from 2006 to 2014. Functional outcomes were evaluated using a questionnaire and uroflowmetry. Perioperative complications were analyzed retrospectively. The mean follow-up period was 36.1 months. Eighty-six percent of patients voided without clean intermittent catheterization (CIC) assistance. CIC was used 1-2x per day or every time they voided in 8% and 6% of patients, respectively, and 71% of patients were continent. The percentages of patients who used 1, 2, 3-4, and ≥5 pads per day were 15%, 6%, 2%, and 6%, respectively. Daytime and nighttime continence were achieved in 86% and 69% of patients, respectively. Daily mucus leakage was reported in 69% of patients. The mean maximum neobladder capacity, voided volume, postvoid residual volume, and maximum flow rate were 413.2 mL, 370.6 mL, 43.7 mL, and 20.8 mL/s, respectively. Eighteen early and 5 late complications developed in 13 and 5 patients, respectively. Reoperations were needed in 7 patients. The Hautmann ileal neobladder with chimney modification provided satisfactory results regarding functional outcomes. PMID:28025648

  7. Management of Voiding Dysfunction After Female Neobladder Creation.

    PubMed

    Hoy, Nathan Y; Cohn, Joshua A; Kowalik, Casey G; Kaufman, Melissa R; Stuart Reynolds, W; Dmochowski, Roger R

    2017-05-01

    Functional complications after orthotopic neobladder urinary diversion (ONB), including urinary incontinence and urinary retention, present unique challenges. The purpose of this review is to outline contemporary treatment options for voiding dysfunction after ONB in females. Meticulous surgical technique in the form of urethral nerve-sparing has been shown to play an important role in maintaining continence, as has sparing the uterus when possible. Data supporting the effectiveness of lifestyle measures, urethral bulking, pubovaginal slings, and transobturator slings in the treatment of urinary incontinence are widely variable and limited to case reports. Urinary retention is still most effectively managed with self-catheterization. Voiding dysfunction after ONB can be devastating. Recent advances focus on improving surgical techniques to decrease the risk of incontinence and retention, as post-operative management options are limited.

  8. The 'pitcher pot' ileal neobladder: early experiences.

    PubMed

    Rawal, Sudhir; Kumar, Prem; Kaul, Rakesh; Raghunath, S K; Julka, Saurabh

    2006-11-01

    To analyse initial results of newly designed ileal neobladder-a modification of Studer neobladder Twenty-four patients with urinary bladder cancer underwent radical cystoprostatectomy from February 2005 to March 2006. Twenty-one of them had urinary diversion using ileal neobladder in spherical configuration with ileal neourethra (giving the shape of an inverted Indian earthenware container called a 'pitcher pot') to circumvent the problem of short mesentery and construct a low-pressure spherical ileal neobladder. Early post-operative complications occurred in 42% of patients. Late complications occurred in 23% of patients. Most of these complications were minor, mainly as a result of wound infection, urine leak or urinary tract infections and were managed conservatively. No early post-operative mortality was observed. Daytime continence was achieved in 100% of patients who completed the 1 year follow-up. Night-time continence was variable as it depended on timed voiding--75% of patients achieved nocturnal continence by 1 year. The functional neobladder capacity was 426 ml. The mean post-operative residual volume was 36 ml. Three patients required cystoscopic mucus evacuation and catheterization. None of them required clean intermittent catheterization. No significant metabolic disturbance occurred in any patient. Length of mesentery remains one of the factors in deciding the segment of intestine to be taken for neobladder. Ileal neourethra gives about 2-3 cm extra length to perform tensionless anastomosis, which is a key factor in the smooth recovery after such major surgery and also maintains optimum urodynamic features of neobladder.

  9. Febrile Urinary Tract Infection after Radical Cystectomy and Ileal Neobladder in Patients with Bladder Cancer.

    PubMed

    Kim, Kwang Hyun; Yoon, Hyun Suk; Yoon, Hana; Chung, Woo Sik; Sim, Bong Suk; Lee, Dong Hyeon

    2016-07-01

    Urinary tract infection (UTI) is one of the most common complications after radical cystectomy and orthotopic neobladder reconstruction. This study investigated the incidence and implicated pathogen of febrile UTI after ileal neobladder reconstruction and identify clinical and urodynamic parameters associated with febrile UTI. From January 2001 to May 2015, 236 patients who underwent radical cystectomy and ileal neobladder were included in this study. Fifty-five episodes of febrile UTI were identified in 46 patients (19.4%). The probability of febrile UTI was 17.6% and 19.8% at 6 months and 24 months after surgery, respectively. While, Escherichia coli was the most common implicated pathogen (22/55, 40.0%), Enterococcus spp. were the most common pathogen during the first month after surgery (18/33, 54.5%). In multivariate logistic regression analysis, ureteral stricture was an independent risk factor associated with febrile UTI (OR 5.93, P = 0.023). However, ureteral stricture accounted for only 6 episodes (10.9%, 6/55) of febrile UTI. Most episodes of febrile UTI occurred within 6 months after surgery. Thus, to identify risk factors associated with febrile UTI in the initial postoperative period, we assessed videourodynamics within 6 months after surgery in 38 patients. On videourodyamic examination, vesicoureteral reflux (VUR) was identified in 16 patients (42.1%). The rate of VUR presence in patients who had febrile UTI was not significantly different from those in patients without febrile UTI (50% vs. 39.3%, P = 0.556). Patients with febrile UTI had significantly larger residual urine volume (212.0 ± 193.7 vs. 90.5 ± 148.2, P = 0.048) than those without. E. coli and Enterococcus spp. are common pathogens and ureteral stricture and residual urine are risk factors for UTI after ileal neobladder reconstruction.

  10. Incisional hernia involving the neobladder: technical considerations to avoid complications.

    PubMed

    Katkoori, Devendar; Jayathillake, Anuradha; Eldefrawy, Ahmed; Manoharan, Murugesan

    2009-06-30

    The management of incisional hernia following radical cystectomy (RC) and neobladder diversion poses a special challenge. Mesh erosion into the neobladder is a potential complication of hernia repair in this setting. We describe our experience and steps to avoid this complication. Three patients developed incisional hernias following RC involving the neobladder. The incisional hernias were repaired by the same surgeon. A systematic dissection and repair of the hernias with an onlay dual-layer mesh (made of polyglactin and polypropylene) was carried out. The critical steps were placing the polyglactin side of the mesh deeper and positioning of an omental flap anterior to the neobladder. The omental flap adds a protective layer that prevents adhesions between the neobladder and abdominal wall, and prevents erosion of the mesh into the fragile neobladder wall. All of these patients had received two cycles of neoadjuvant chemotherapy prior to RC. The time duration from RC to the repair of hernia was 7, 42, and 54 months. No intraoperative injury to the neobladder or other complication was noted during hernia repair. The patients were followed after hernia repair for 20, 22, and 42 months with no recurrence, mesh erosion, or other complications. Careful understanding and attention to details of the technique can minimize the risk of complications, especially incisional hernia recurrence, injury to the neobladder, and erosion of mesh into the neobladder wall.

  11. 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

  12. Ileocolic neobladder post-cystectomy: continence and potency.

    PubMed

    Marshall, F F; Mostwin, J L; Radebaugh, L C; Walsh, P C; Brendler, C B

    1991-03-01

    Incontinence and impotence are 2 of the primary complications associated with total bladder reconstruction after cystectomy for carcinoma. These and other features are addressed in 25 patients who underwent total neobladder reconstruction following cystectomy for transitional cell carcinoma. Of these patients 20 had a urethral anastomosis. No patient had to wear a pad or device. Enuresis was rare. When the radical cystoprostatectomy population was contrasted with a radical prostatectomy patient population, continence was achieved more rapidly in the neobladder group. Potency was maintained in 15 of 21 (71%) evaluable patients. This ileocolic neobladder produces a large volume and low pressure, and provides excellent day and night continence. With preservation of the neurovascular bundle potency can be maintained in the majority of patients.

  13. Orthotopic bladder substitution after radical cystectomy: 5 years of experience with a novel personal modification of the ileal s pouch.

    PubMed

    Constantinides, C; Manousakas, T; Chrisofos, M; Giannopoulos, A

    2001-08-01

    We report a 5-year experience with 52 patients who underwent radical cystoprostatectomy for bladder cancer and orthotopic bladder substitution using a novel personal modification of the S pouch. From September 1995 to December 1999, 52 men 36 to 72 years old (mean age 63) underwent bladder substitution with an S pouch. They were followed until September 2000. The pouch was constructed with a 36 cm. segment of ileum with the whole length used for the reservoir. The ureters were directly anastomosed with one above the other in the mid segment of the pouch without any antireflux procedure. Complications were documented and classified as early or up to 3 months postoperatively and late, and further subdivided by the relationship to neobladder construction. Continence and voiding pattern were evaluated by personal interview and neobladder function was urodynamically assessed. Mean followup in our patients was 30 months. The most common of the 5 early and 9 late neobladder related complications were persistent urine leakage and reflux, respectively. There was no reflux greater than grade III in the 4 patients with reflux (5 refluxing ureters) and no functional disorders. We observed 12 early and 5 late complications unrelated to the neobladder. Open reoperation was required in 5 cases. Good or satisfactory daytime and nighttime continence was reported by 95% and 88% of our patients, respectively. By year 1 postoperatively 91% of our patients voided at an interval of 3 to 5 hours during the day. Mean maximum neobladder capacity was 672 ml. and mean post-void residual was 30 ml. by year 3 postoperatively. Two patients required self-catheterization once daily and mild hyperchloremia without acidosis developed in 2. The advantages of our modified S pouch are technical simplicity, substantially shorter operative time and decreased bowel length required. It is associated with an acceptable complication rate and functional parameters with subsequent patient satisfaction and

  14. 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

  15. The effect of N-acetyl-L-cysteine on the viscosity of ileal neobladder mucus.

    PubMed

    Schrier, B P; Lichtendonk, W J; Witjes, J A

    2002-05-01

    N-acetyl-L-cysteine (NAC) proved to be an effective mucolytic in pulmonary secretions. Our goal was to investigate the in vitro effect of NAC on viscosity of ileal neobladder mucus. The urine of a patient with an ileal neobladder was collected during the first 7 days postoperatively and stored in a refrigerator. After precipitation, the urine was decanted. The residue was stirred to a homogeneous suspension. To samples of 4.5 ml mucus, 0.5 ml NAC 10% was added. To the control sample, 0.5 ml water was added. The samples were incubated in a water bath at 37 degrees C for 5, 30 and 60 min. Viscosity was measured in the Bohlin VOR Rheometer. The viscosity of the ileal neobladder mucus decreased quickly after incubating with NAC 10%. Viscosity increased slightly after I h of incubation. The viscosity in the control sample was higher than in the other incubated samples. NAC was found to decrease the viscosity of ileal neobladder mucus, supporting the in vivo experience that NAC can be useful in patients with an ileal neobladder to facilitate the evacuation of mucus by decreasing viscosity.

  16. Laparoscopic radical cystectomy: neobladder or ileal conduit, debate still goes on

    PubMed Central

    Drewa, Tomasz; Olejniczak, Pawel; Chlosta, Piotr L.

    2014-01-01

    Objective To compare the pre, intra, and post–operative data between ileal conduit and neobladder urinary diversions during laparoscopic radical cystectomy(LRC). Material and methods Between 2006 and 2011, 63 patients who underwent LRC and urinary diversion had their data input prospectively into a database and said data used for the analysis. The outcome comparators were the patient demographics, operative time, conversion rate, blood loss, transfusion rate, morphine analgesic requirement, length of hospital stay, complication rates, follow up, and quality of life assessments. A Mantel–Haenszel test was used for dichotomous data and an inverse variance method was used for continuous data. P values less than 0.5 were considered significant Results Thirty–nine patients (60 ±7.11 years) had ileal conduits and 24 patients (57 ±8.68 years) had neobladder urinary diversion. No difference was found (P >0.05) regarding age, BMI, smoking history, TURBT pathology result, blood loss, blood transfusion requirement, conversion rates, length of hospital stay, morphine requirement, complications, or follow–up and quality of life. The neobladder groups did have more previous abdominal operations and had significantly longer operative time. Conclusions We found no difference between either types of diversion in all comparative aspects except that the neobladder had longer operative times. This is the first comparative study between ileal conduit and neobladder urinary diversion after laparoscopic radical cystectomy and can pose as a bench mark for future comparisons. PMID:24982773

  17. Comparison of postoperative acute kidney injury between ileal conduit and neobladder urinary diversions after radical cystectomy

    PubMed Central

    Joung, Kyoung-Woon; Kong, Yu-Gyeong; Yoon, Syn-Hae; Kim, Yeon Ju; Hwang, Jai-Hyun; Hong, Bumsik; Kim, Young-Kug

    2016-01-01

    Abstract Ileal conduit and neobladder urinary diversions are frequently performed after radical cystectomy. However, complications after radical cystectomy may be different according to the type of urinary diversion. Acute kidney injury (AKI) is a common complication after surgery and increases costs, morbidity, and mortality of hospitalized patients. This study was performed to compare the incidence of postoperative AKI between ileal conduit and neobladder urinary diversions after radical cystectomy. All consecutive patients who underwent radical cystectomy in 2004 to 2014 in a single tertiary care center were identified. The patients were divided into the ileal conduit and ileal neobladder groups. Preoperative variables, including demographics, cancer-related data and laboratory values, as well as intraoperative data and postoperative outcomes, including AKI, intensive care unit admission rate, and the duration of hospital stay, were evaluated between the groups. Postoperative AKI was defined according to the Kidney Disease: Improving Global Outcome criteria. Propensity score matching analysis was performed to reduce the influence of possible confounding variables and adjust for intergroup differences. After performing 1:1 propensity score matching, the ileal conduit and ileal neobladder groups each included 101 patients. The overall incidence of AKI after radical cystectomy was 30.7% (62 out of 202) and the incidences did not significantly differ between the groups (27 [26.7%], ileal conduit group vs 35 [34.7%], ileal neobladder group, P = 0.268). Intraoperative data, intensive care unit admission rate, and the duration of hospital stay were not significantly different between the groups. Postoperative AKI did not significantly differ between ileal conduit and neobladder urinary diversions after radical cystectomy. This finding provides additional information useful for appropriate selection of the urinary diversion type in conjunction with radical cystectomy

  18. Robot-assisted radical cystectomy with intracorporeal neobladder diversion: The Karolinska experience

    PubMed Central

    Collins, Justin W.; Sooriakumaran, P.; Sanchez-Salas, R.; Ahonen, R.; Nyberg, T.; Wiklund, N. P.; Hosseini, A.

    2014-01-01

    Introduction: The aim of this report is to describe our surgical technique of totally intracorporeal robotic assisted radical cystectomy (RARC) with neobladder formation. Materials and Methods: Between December 2003 and March 2013, a total of 147 patients (118 male, 29 female) underwent totally intracorporeal RARC for urinary bladder cancer. We also performed a systematic search of Medline, Embase and PubMed databases using the terms RARC, robotic cystectomy, robot-assisted, totally intracorporeal RARC, intracorporeal neobladder, intracorporeal urinary diversion, oncological outcomes, functional outcomes, and complication rates. Results: The mean age of our patients was 64 years (range 37-87). On surgical pathology 47% had pT1 or less disease, 27% had pT2, 16% had pT3 and 10% had pT4. The mean number of lymph nodes removed was 21 (range 0-60). 24% of patients had lymph node positive dAQ1isease. Positive surgical margins occurred in 6 cases (4%). Mean follow-up was 31 months (range 4-115 months). Two patients (1.4%) died within 90 days of their operation. Using Kaplan-Meier analysis, overall survival and cancer specific survival at 60 months was 68% and 69.6%, respectively. 80 patients (54%) received a continent diversion with totally intracorporeal neobladder formation. In the neobladder subgroup median total operating time was 420 minutes (range 265-760). Daytime continence and satisfactory sexual function or potency at 12 months ranged between 70-90% in both men and women. Conclusions: Our experience with totally intracorporeal RARC demonstrates acceptable oncological and functional outcomes that suggest this is a viable alternative to open radical cystectomy. PMID:25097318

  19. Mitomycin-C suppresses mucus secretion in an ileal neobladder rat model.

    PubMed

    Fan, Weiwei; Yu, Yang; Shu, Junjie; Ming, Hao; Li, Weiping; Fan, Zhilu

    2015-08-01

    The aim of the present study was to investigate the mucus secretion status of mature goblet cells following the application of mitomycin-C (MMC) in ileal neobladder rat models. Bladder substitution models were established in Sprague Dawley rats, which had been divided into five groups, namely the control (sham), normal saline (NS), high-dose MMC (HMMC), low-dose MMC (LMMC) and dehydrated alcohol (DA) groups. To evaluate the total protein concentration and level of sialic acid following the therapy, urine from the rats in each group was collected on days 8, 11 and 14. In addition, to observe the variances between mucus secretion and the ileum goblet cells, immunohistochemistry and hematoxylin and eosin staining were conducted in the different groups on day 17. The results indicated that the ileal neobladder mucosas in the MMC groups were clearly undamaged, as compared with the DA group. Furthermore, the MMC and DA groups were shown to inhibit the proliferation of goblet cells. The concentration of protein and sialic acid in the LMMC group was found to be lower compared with the NS group, while the concentration in the HMMC group was considerably lower. In conclusion, HMMC was demonstrated to evidently reduce the mucin and sialic acid concentration in the urine, without visible damage to the ileal neobladder mucus membrane. Therefore, MMC may provide a novel therapeutic approach for the treatment of certain bladder conditions.

  20. Mitomycin-C suppresses mucus secretion in an ileal neobladder rat model

    PubMed Central

    FAN, WEIWEI; YU, YANG; SHU, JUNJIE; MING, HAO; LI, WEIPING; FAN, ZHILU

    2015-01-01

    The aim of the present study was to investigate the mucus secretion status of mature goblet cells following the application of mitomycin-C (MMC) in ileal neobladder rat models. Bladder substitution models were established in Sprague Dawley rats, which had been divided into five groups, namely the control (sham), normal saline (NS), high-dose MMC (HMMC), low-dose MMC (LMMC) and dehydrated alcohol (DA) groups. To evaluate the total protein concentration and level of sialic acid following the therapy, urine from the rats in each group was collected on days 8, 11 and 14. In addition, to observe the variances between mucus secretion and the ileum goblet cells, immunohistochemistry and hematoxylin and eosin staining were conducted in the different groups on day 17. The results indicated that the ileal neobladder mucosas in the MMC groups were clearly undamaged, as compared with the DA group. Furthermore, the MMC and DA groups were shown to inhibit the proliferation of goblet cells. The concentration of protein and sialic acid in the LMMC group was found to be lower compared with the NS group, while the concentration in the HMMC group was considerably lower. In conclusion, HMMC was demonstrated to evidently reduce the mucin and sialic acid concentration in the urine, without visible damage to the ileal neobladder mucus membrane. Therefore, MMC may provide a novel therapeutic approach for the treatment of certain bladder conditions. PMID:26622360

  1. 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

  2. Orthotopic urinary diversion after radical cystectomy in treatment of muscle invasive bladder cancer.

    PubMed

    Jovan, Hadži-Djokić; Vladan, Andrejević; Tomislav, Pejčić; Miodrag, Aćimović; Uroš, Babić; Miodrag, Stanić; Zoran, Džamić

    2014-01-01

    Surgical treatment of invasive carcinoma of the bladder in males includes total cystectomy removal of the prostate, seminal vesicles, and the distal parts of the urethers and the pelvic lymph node dissection as well. At this moment it is not possible to recommend a particular type of urinary diversion, but today in clinical practice commonly used derivative are ileal orthotopic neobladder as the continent one and ileal conduit as non-continent urinary diversion. Continent urinary diversion after radical cystectomy are the result of the application of technological innovation in surgery, but also knowledge, imagination and skill of well trained urologist. This type of operation significantly improves the quality of life in patients who underwent radical cystectomy, and the proposal is to operate whenever there is a possibility for this type of procedure. Also it is very important, during surgery to respect oncological principles, of complete removal of tumorous tissue and that the functional principle of ensur- ing that the patients have daytime and also nighttime continence later on after the surgery.

  3. Risk Factors for Developing Metabolic Acidosis after Radical Cystectomy and Ileal Neobladder.

    PubMed

    Kim, Kwang Hyun; Yoon, Hyun Suk; Yoon, Hana; Chung, Woo Sik; Sim, Bong Suk; Ryu, Dong-Ryeol; Lee, Dong Hyeon

    2016-01-01

    To investigate the serial changes of metabolic acidosis and identify associated risk factors in patients who underwent radical cystectomy and ileal neobladder. From January 2010 to August 2014, 123 patients who underwent radical cystectomy and ileal neobladder reconstruction for bladder cancer were included in this study. Metabolic acidosis was defined as a serum bicarbonate level less than 22 mEq/L and impaired renal function was defined as a GFR <50ml/min. The presence of metabolic acidosis was evaluated at 1 month, 1 year, and 2 years after surgery. Multivariate logistic regression analysis was conducted to identify risk factors associated with development of metabolic acidosis. Metabolic acidosis was observed in 52%, 19.5%, and 7.3% of patients at 1 month, 1 year, and 2 years after surgery, respectively. At 1 month after surgery, impaired renal function was the only independent risk factor associated with metabolic acidosis (OR 3.87, P = 0.046). At 1 year after surgery, diabetes was the only independent risk factor associated with metabolic acidosis (OR 5.68, P = 0.002). At 2 years post-surgery, both age and diabetes were significant risk factors associated with metabolic acidosis. Approximately, half of patients experienced metabolic acidosis one month after ileal neobladder reconstruction. Preoperative impaired renal function was the most significant risk factor for developing metabolic acidosis in the early postoperative period. However, the incidence of metabolic acidosis decreased to less than 20% 1 year after surgery, and diabetes was an independent risk factor during this period.

  4. A history of orthotopic heart transplantation.

    PubMed

    Meine, Trip J; Russell, Stuart D

    2005-01-01

    Orthotopic human heart transplantation today is performed at more than 150 U.S. centers, and the average survival is more than 10 years. Its prevalence and success, however, belies the fact that just 40 years ago, no one had ever attempted the procedure in humans and that the procedure seemed destined for failure just a year after the first transplant. This article reviews the history of orthotopic heart transplantation, beginning with ancient Greek legends and culminating in modern successes.

  5. Perineal herniation of an ileal neobladder following radical cystectomy and consecutive rectal resection for recurrent bladder carcinoma

    PubMed Central

    Neumann, PA; Mehdorn, AS; Puehse, G; Senninger, N; Rijcken, E

    2016-01-01

    Secondary perineal herniation of intraperitoneal contents represents a rare complication following procedures such as abdominoperineal rectal resection or cystectomy. We present a case of a perineal hernia formation with prolapse of an ileum neobladder following radical cystectomy and rectal resection for recurrent bladder cancer. Following consecutive resections in the anterior and posterior compartment of the lesser pelvis, the patient developed problems emptying his neobladder. Clinical examination and computed tomography revealed perineal herniation of his neobladder through the pelvic floor. Through a perineal approach, the hernial sac could be repositioned, and via a combination of absorbable and non-absorbable synthetic mesh grafts, the pelvic floor was stabilised. Follow-up review at one year after hernia fixation showed no signs of recurrence and no symptoms. In cases of extensive surgery in the lesser pelvis with associated weakness of the pelvic compartments, meshes should be considered for closure of the pelvic floor. Development of biological meshes with reduced risk of infection might be an interesting treatment option in these cases. PMID:26985818

  6. Pulmonary artery rupture in a patient receiving an orthotopic heart transplant after total artificial heart explant.

    PubMed

    Nomoto, Koichi; Weiner, Menachem M; Evans, Adam

    2014-02-01

    Our case illustrates a patient who suffered a pulmonary artery rupture despite previous total artificial heart implantation and replacement with orthotopic heart transplant. Pulmonary artery rupture during or following cardiac surgery has been reported to occur due to both pulmonary artery catheter use and surgical technique. Our case is the first to demonstrate the occurrence of this complication in the total artificial heart patient population.

  7. Survival up to 5–15 years in young women following genital sparing radical cystectomy and neobladder: oncological outcome and quality of life. Single–surgeon and single–institution experience

    PubMed Central

    Elganozoury, Hossam

    2015-01-01

    Introduction This is an observational retrospective study utilising long term patient follow–up for 15 years to determine the survival and quality of life in women (age range 20–54 years) after having been treated for carcinoma of the bladder by radical cystectomy with preservation of genital organs. Material and methods The study included 13 female patients with urothelial carcinoma of the bladder treated with genital sparing radical cystectomy during the period of 1995 until 2006. They had orthotopic ileal neobladder. Follow–up included recurrence–free survival, metastases–free survival, overall survival, continence, and sexual function. Results Genital sparing cystectomy was done in 13 women. Seven women were between the ages of 20–37, and 6 women were aged 38–54. Overall survival of 10–15 years was 61.53%, survival from 5 to 9 years was 38.46%. The procedure was done in 9 women with a muscle–invasive tumor of stage T2– T3a. Non–muscle invasive T1 tumor was present in four patients. Quality of life was assessed by continence, which was good in 10/13 patients. Three women needed CIC. Sexual function was tested by female sexual function index >20–30 and was scored at 84.61%. Conclusions The study provides evidence of safety and efficacy of radical cystectomy with sparing of genital organs in women aged 20 to 54 with urothelial carcinoma of the bladder. Oncological outcome for 5–15 years was good; continence and sexual function were good. This procedure should be considered when surgical approach appears to be feasible. The limitation of our findings is the small sample size of this case series. PMID:26251729

  8. Fluorescent Orthotopic Mouse Model of Pancreatic Cancer.

    PubMed

    Moreno, Jonathan A; Sanchez, Antonio; Hoffman, Robert M; Nur, Saima; Lambros, Maria P

    2016-09-20

    Pancreatic cancer remains one of the cancers for which survival has not improved substantially in the last few decades. Only 7% of diagnosed patients will survive longer than five years. In order to understand and mimic the microenvironment of pancreatic tumors, we utilized a murine orthotopic model of pancreatic cancer that allows non-invasive imaging of tumor progression in real time. Pancreatic cancer cells expressing green fluorescent protein (PANC-1 GFP) were suspended in basement membrane matrix, high concentration, (e.g., Matrigel HC) with serum-free media and then injected into the tail of the pancreas via laparotomy. The cell suspension in the high concentration basement membrane matrix becomes a gel-like substance once it reaches room temperature; therefore, it gels when it comes in contact with the pancreas, creating a seal at the injection site and preventing any cell leakage. Tumor growth and metastasis to other organs are monitored in live animals by using fluorescence. It is critical to use the appropriate filters for excitation and emission of GFP. The steps for the orthotopic implantation are detailed in this article so researchers can easily replicate the procedure in nude mice. The main steps of this protocol are preparation of the cell suspension, surgical implantation, and whole body fluorescent in vivo imaging. This orthotopic model is designed to investigate the efficacy of novel therapeutics on primary and metastatic tumors.

  9. Left Diaphragmatic Herniation following Orthotopic Liver Transplantation in an Adult

    PubMed Central

    Rosat, Adriá; Alonso, Ayaya; Padilla, Javier; Sanz, Pablo; Varona, M. Aránzazu; Méndiz, Javier; Moneva, Enrique; Barrera, Manuel

    2015-01-01

    Diaphragmatic herniation is an uncommon complication in the postquirurgic follow of the liver transplant. The associated symptoms are unspecific and may not suggest the correct diagnosis. It may explain why in many patients the diagnosis remains unmade or it is made only after a long interval of time. We present the case of a fifty-seven-year-old male who required an orthotopic liver transplant in 2010 due to a trifocal hepatocarcinoma. In postoperatory follow-up the patient showed alimentary regurgitation, vomiting, and dyspepsia. The diagnosis was made by an oesophagogastroduodenal transit with barium and an abdominal CT scan that showed a left diaphragmatic herniation with the gastric fundus into the thorax. With these findings we decided to perform a programmed surgery. After takedown of adhesions and replacement of the stomach into the upper abdomen, the palm-sized diaphragmatic opening was closed with a synthetic material. The patient's condition remained stable throughout the entire operation. The postoperative course was uneventful and he was discharged at the fifth day after surgery with a normal digestive intake. In a 12-month follow-up the patient shows no symptoms. PMID:26064764

  10. The hepatic artery in orthotopic liver transplantation

    PubMed Central

    Lerut, J. P.; Gordon, R. D.; Tzakis, A. G.; Stieber, A. C.; Iwatsuki, S.; Starzl, T. E.

    2011-01-01

    Summary Hepatic artery thrombosis (HAT) is a dreadful complication of orthotopic liver transplantation (OLT). This complication occurred in 27 grafts (68% = 27/393 grafts) in 25 patients (9% = 25/313 patients). HAT was responsible for a high mortality (64% = 16/25 patients) despite a high retransplantation rate (70% = 19/27 grafts). HAT should be suspected in case of fulminant liver failure, delayed bile leak or unexplained fever of sepsis of unknown etiology occurring after liver transplantation. Pulsed doppler examination and arteriogram are the decisive diagnostic procedures. Patients presenting HAT can only be rescued by early diagnosis and retransplantation. Aneurysms of the hepatic arterial supply must also be treated urgently, either by conventional vascular repair if possible or by retransplantation, because or the high incidence of fatal rupture (3/4 patients = 75%). PMID:3049463

  11. Cryopreservation and orthotopic transplantation of rat ovaries.

    PubMed

    Dorsch, Martina; Wedekind, Dirk

    2010-01-01

    The number of rat strains increased considerably in the last decade and will increase continuously during the next years. This requires enough space for maintaining vital strains and techniques for cryobanking, which can be applied not only in specialised rat resource centres but also in regular animal houses. Here we describe an easy and fast method for the cryopreservation and transplantation of frozen-thawed ovaries of the rat. With dimethyl sulfoxide as cryoprotectant rat ovaries can be stored at -196 degrees C for unlimited time. For revitalisation thawed ovaries have to be orthotopically transplanted into appropriate ovarectomised recipients. Reestablishment of the reproductive cycle in the recipients can be confirmed by vaginal cytology shortly after transplantation. The recipients are able to produce 2-3 litters after mating with males of an appropriate strain. Cyropreservation of ovaries thus can be considered a reliable method to preserve scientifically and economically important stocks and strains of rats that are currently not required.

  12. Cyclosporine Absorption Following Orthotopic Liver Transplantation

    PubMed Central

    Burckart, Gilbert J.; Venkataramanan, Raman; Ptachcinski, Richard J.; Starzl, Thomas E.; Gartner, J. Carlton; Zitelli, Basil J.; Malatack, Jeffrey J.; Shaw, Byers W.; Iwatsuki, Shunzaburo; Van Thiel, David H.

    2010-01-01

    Blood concentrations of cyclosporine were determined in adult and pediatric patients following orthotopic liver transplantation to quantitate cyclosporine blood clearance and oral absorption. Seventeen bioavailability studies were performed following transplantation surgery in nine children and seven adults. The intravenous cyclosporine study was performed following an average dose of 2.1 mg/kg. The patients were again studied when they received the same intravenous dose plus an oral dose of cyclosporine of 8.6 mg/kg or an oral dose alone. Blood samples were collected and analyzed for cyclosporine using high-performance liquid chromatography. Cyclosporine blood clearance ranged from 29 to 203 mL/min (1.9–21.5 mL/min/kg) in children and from 253 to 680 mL/min (3.2–7.6 mL/min/kg) in adults. The mean cyclosporine clearance value was 9.3 mL/min/kg in the pediatric patients and 5.5 mL/min/kg in the adults. Cyclosporine bioavailability was less than 5% in six studies on five pediatric patients in the immediate postoperative period. The bioavailability varied from 8% to 60% in adult liver transplant patients (mean, 27%). We conclude that: (1) cyclosporine clearance is highly variable between patients, (2) pediatric patients clear the drug more rapidly than adults and therefore need a higher cyclosporine dose on a body weight basis, (3) cyclosporine is poorly and variably absorbed in liver transplant patients, and (4) cyclosporine blood concentration monitoring is essential following orthotopic liver transplantation. PMID:3540030

  13. VIP neobladder (Padovana) reconstruction following radical cystectomy for bladder cancer Complications, functional outcome and quality of life evaluation in 95 cases.

    PubMed

    Kostakopoulos, Nikolaos; Protogerou, Vassilis; Skolarikos, Andreas; Varkarakis, Ioannis; Papatsoris, Athanasios; Troupis, Theodore; Piagou, Maria; Deliveliotis, Charalambos

    2015-01-01

    The Authors report a complete study concerning complications, the imaging and functional results, the clinical outcome and the quality of life in patients treated with VIP. 95 patients with localized bladder TCC (T2N0M0) were evaluated. Follow up points were 1st, 3rd, 6th, 12th, 18th, 24th and 36th month with clinical and ultrasound evaluation. At 6th, 12th and 36th month CT pyelography and urodynamic evaluation were performed and we used a questionnaire for subjective bladder function and the EORTC QLQ C-30 questionnaire to evaluate quality of life. Perioperative complications were ileus (2 patients; 2.1%) (Clavien Grade IIIb), one postoperative death (1.0%) (Clavien Grade V) and a resuscitated cardiac arrest (1.0%) (Clavien Grade IVa). Postoperative complications were incisional hernias (n=4 patients; 4.21%) (Clavien Grade I) and hydronephrosis in five patients (5.26%) due to ureteric/neobladder stricture (Clavien Grade IIIb). Urine retention due to neobladder neck stenosis was observed in one patient (1.0%) (Clavien Grade IIIb) and an ileo-neobladder fistula in one (1.0%) patient (Clavien Grade IIIb). During follow up there were two cancer related deaths (2.1%). According to urodynamic evaluations neobladder capacity increased, end-filling pressure and Qmax decreased while residual urine and the number of intrinsic contractions remained stable. Continence rates and quality of life were high and stable during follow up. VIP technique for bladder substitution is a relatively easy technique with low rate of complications, good functional results which respect the patient's quality of life.

  14. Total and immediate daytime and nighttime continence with a right colonic neobladder--What makes it possible? An 11-year followup.

    PubMed

    D'Orazio, Osvaldo R; Lambert, Osvaldo L; Vallati, Juan C; Franco, Francisco L; Romano, Salomón V; de Lasa Stewart, Tomás A; Saenz, Carlos A

    2005-11-01

    We report the long-term functional results of the colonic neobladder and provide the physiological and urodynamic foundations for them. From March 1993 to February 2004, 38 patients with cystectomy received a neobladder constructed from detubularized, remodeled right colon and intact cecum following our design at the urology service at our institution. Most patients underwent urodynamics and videourodynamics as postoperative followup. We defined total continence as not using any protection whatsoever (neither pads nor a night alarm), which was immediate upon removing the urethral catheter. A total of 37 patients achieved total daytime continence immediately and the remaining 1 was totally continent after 30 days (100%). Nighttime continence was total and immediate in 36 patients (92%) and satisfactory in 2. Micturition was immediate, satisfactory and total in 37 patients with an average maximum flow of more than 26 ml per second. The patient who did not achieve micturition required clean intermittent catheterization. Videourodynamic studies revealed that continence resulted from the low pressure developed in the large capacity reservoir (more than 600 ml) and from intact intestine haustral contractions, which ejected urine toward the detubularized and remodeled area. In turn, micturition was attained through a combination of abdominal wall tension and mass contractions of the nondetubularized segment, which generated a pressure of more than 100 cm. The functional results of this new neobladder are significantly greater than those achieved with other procedures already described in the literature because of the different way in which it functions.

  15. Societal reintegration following cadaveric orthotopic liver transplantation

    PubMed Central

    Kelly, Ryan; Hurton, Scott; Ayloo, Subhashini; Cwinn, Mathew; De Coutere-Bosse, Sarah

    2016-01-01

    Background Studies on patients’ societal reintegration following orthotopic liver transplantation (OLT) are scarce. Methods Between September 2006 and January 2008, all adults who were alive after 3 years post OLT were included in this prospective cohort study. Validated questionnaires were administered to all candidates with the primary aim of investigating the rate of their social re-integration following OLT and potential barriers they might have encountered. Results Among 157 eligible patients 110 (70%) participated. Mean participants’ age was 57 years (SD 11.4) and 43% were females. Prior to OLT, 75% of patients were married and 6% were divorced. Following OLT there was no significant difference in marital status. Employment rate fell from 72% to 30% post-OLT. Patients who had been employed in either low-skill or advanced-skill jobs were less likely to return to work. After OLT, personal income fell an average of 4,363 Canadian dollars (CAN$) (SD 20,733) (P=0.03) but the majority of recipients (80%) reported high levels of satisfaction for their role in society. Conclusions Although patients’ satisfaction post-OLT is high, employment status is likely to be negatively affected for individuals who are not self-employed. Strategies to assist recipients in returning to their pre-OLT jobs should be developed to improve patients’ economical status and societal ability to recoup resources committed for OLT. PMID:27275465

  16. External biliary fistula in orthotopic liver transplantation.

    PubMed

    Gilbo, N; Mirabella, S; Strignano, P; Ricchiuti, A; Lupo, F; Giono, I; Sanna, C; Fop, F; Salizzoni, M

    2009-05-01

    During orthotopic liver transplantation (OLT), various situations may occur in which biliary reconstruction is neither technically feasible nor recommended. One bridge to a delayed anastomosis can be an external biliary fistula (EBF). This procedure allows the surgeon to execute hemostatic maneuvers, such as abdominal packing; therefore, biliary reconstruction can be subsequently performed in a bloodless operative field without edematous tissues. EBF can be made by placing in the donor biliary tract a cannula that is fixed to the bile duct using 2-0 silk ties and secured outside the abdominal wall. The biliary anastomosis will be performed within 2 days after the OLT. The aim of this study was to examine the safety of EBF in terms of the incidence of biliary complications compared with a direct anastomosis. Among 1,634 adult OLTs performed in 17 years in our center, 1,322 were carried out with termino-terminal hepaticocholedochostomy (HC-TT); two with side-to-side hepaticocholedochostomy; 208 with hepaticojejunostomy (HJ); 31 with EBF and delayed HC-TT, and 71 with EBF and delayed HJ. Biliary complication rates in the EBF group were 24.5%, including 23.9% in the delayed HJ and 25.8% in the delayed HC-TT. Biliary complication incidence among all OLTs was 24.6% (P = NS). No complications related to the procedure were observed. Therefore, EBF is a safe technique without a higher biliary complication rate. It may be useful when a direct biliary anastomosis is dangerous.

  17. Percutaneous venovenous bypass in orthotopic liver transplantation.

    PubMed

    Washburn, W K; Lewis, W D; Jenkins, R L

    1995-11-01

    Since January 1994, we have used percutaneous placement of both the subclavian and femoral cannulae to establish access for venovenous bypass during orthotopic liver transplantation. Percutaneous subclavian and femoral cannulae were used in 36 patients of which 5 had portal decompression by placement of a cannula in inferior mesenteric vein percutaneously through the abdominal wall. Intraoperative placement of the subclavian cannula is facilitated by placing a subclavian central venous line before the abdominal incision. One patient underwent exploration for femoral vein bleeding early in our experience. Another patient sustained hypotension as a result of a kinked subclavian cannula. In 4 patients, early in this experience, we had difficulty placing the subclavian cannula and resorted to axillary vein cut-down. There were no episodes of deep venous thrombosis detected by routine postoperative duplex ultrasonography. Minimum and maximum flow rates were significantly better (P < .01), with percutaneously placed cannulae in comparison to a control group of patients who underwent transplantation in whom we used the standard venous cut-down approach with a #7 Gott shunt (2.14 and 3.17 L/min v 1.65 and 2.41 L/min, respectively). Percutaneous placement of cannulae for venovenous bypass during liver transplantation is quick, safe, and effective. We would advocate this technique as an alternative approach for patients in whom bypass is deemed necessary.

  18. Societal reintegration following cadaveric orthotopic liver transplantation.

    PubMed

    Kelly, Ryan; Hurton, Scott; Ayloo, Subhashini; Cwinn, Mathew; De Coutere-Bosse, Sarah; Molinari, Michele

    2016-06-01

    Studies on patients' societal reintegration following orthotopic liver transplantation (OLT) are scarce. Between September 2006 and January 2008, all adults who were alive after 3 years post OLT were included in this prospective cohort study. Validated questionnaires were administered to all candidates with the primary aim of investigating the rate of their social re-integration following OLT and potential barriers they might have encountered. Among 157 eligible patients 110 (70%) participated. Mean participants' age was 57 years (SD 11.4) and 43% were females. Prior to OLT, 75% of patients were married and 6% were divorced. Following OLT there was no significant difference in marital status. Employment rate fell from 72% to 30% post-OLT. Patients who had been employed in either low-skill or advanced-skill jobs were less likely to return to work. After OLT, personal income fell an average of 4,363 Canadian dollars (CAN$) (SD 20,733) (P=0.03) but the majority of recipients (80%) reported high levels of satisfaction for their role in society. Although patients' satisfaction post-OLT is high, employment status is likely to be negatively affected for individuals who are not self-employed. Strategies to assist recipients in returning to their pre-OLT jobs should be developed to improve patients' economical status and societal ability to recoup resources committed for OLT.

  19. Intraoperative fluid management during orthotopic liver transplantation.

    PubMed

    Schroeder, Rebecca A; Collins, Bradley H; Tuttle-Newhall, Elizabeth; Robertson, Kerri; Plotkin, Jeffrey; Johnson, Lynt B; Kuo, Paul C

    2004-08-01

    To assess clinical safety of a low central venous pressure (CVP) fluid management strategy in patients undergoing liver transplantation. Retrospective record review comparing 2 transplant centers, one using the low CVP method and the other using the normal CVP method. University-based, academic, tertiary care centers. Patients undergoing orthotopic cadaveric liver transplantation. Each center practiced according to its own standard of care. Center 1 maintained an intraoperative CVP <5 mmHg using fluid restriction, nitroglycerin, forced diuresis, and morphine. If pressors were required to maintain systolic arterial pressure >90 mmHg, phenylephrine or norepinephrine was used. At center 2, CVP was kept 7 to 10 mmHg and mean arterial pressure >75 mmHg with minimal use of vasoactive drugs. Data collected included United Network for Organ Sharing status, surgical technique, intraoperative transfusion rate, preoperative and peak postoperative creatinine, time spent in intensive care unit and hospital, incidence of death, and postoperative need for hemodialysis. Principal findings include an increased rate of transfusion in the normal CVP group but increased rates of postoperative renal failure (elevated creatinine and more frequent need for dialysis) and 30-day mortality in the low CVP group. Despite success in lowering blood transfusion requirements in liver resection patients, a low CVP should be avoided in patients undergoing liver transplantation.

  20. 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

  1. Pulmonary complications following orthotopic liver transplant.

    PubMed

    Durán, F G; Piqueras, B; Romero, M; Carneros, J A; de Diego, A; Salcedo, M; Santos, L; Ferreiroa, J; Cos, E; Clemente, G

    1998-01-01

    Pulmonary complications after orthotopic liver transplant (OLT) are frequent, involving high morbidity and mortality. We have determined the pulmonary complication incidence in 187 patients submitted to OLT at the General University Hospital "Gregorio Marañón" in the last 4 years, analyzing the type of infection, evolution, diagnostic and therapeutic measures and their influence on OLT mortality. A total of 120 patients had pulmonary complications, the most frequent being pleural effusion (61.94%), pneumonia (43.36%), and pneumothorax (11.5%). Serious pulmonary hypertension was diagnosed by invasive methods in two patients at the time of surgery (unidentified before OLT); both died at early post postoperative times. Pleural effusion was noted in 70 patients, 31.42% of them requiring thoracic tube drainage, complications developing in 22.72%. Thirteen patients were diagnosed of pneumothorax, the most frequent etiologies being percutaneous liver biopsy, thoracic tube drainage for pleural effusion, and postoperative complications in 41.6, 33.3, and 23.3%, respectively. Pneumonia was diagnosed in the 1st month after OLT in 45 patients. Tests to diagnose and identify the etiological agent were made in 71.1% of diagnosed pneumonia patients, identification being obtained in 62.5%. Telescope catheter culture identified the agent in 48%, fiber optic bronchoscopy in 50%, and lung or pleural biopsy in 100%. Respiratory insufficiency was noted in 64 patients (34.22% of transplanted patients). Factors involved in their development were pneumonia (42.18%), graft dysfunction (39.06%, pleural effusion (34.37%), sepsis (28.18%), and poor nutritional status (7.81%). Fifty patients (41.66%) died, pulmonary pathology being the determinant factor in 28.8%. Patient mortality with respiratory insufficiency was greater, especially in those with three factors involved the development of respiratory insufficiency.

  2. Self-assembled tumor-targeting hyaluronic acid nanoparticles for photothermal ablation in orthotopic bladder cancer.

    PubMed

    Lin, Tingsheng; Yuan, Ahu; Zhao, Xiaozhi; Lian, Huibo; Zhuang, Junlong; Chen, Wei; Zhang, Qing; Liu, Guangxiang; Zhang, Shiwei; Chen, Wei; Cao, Wenmin; Zhang, Chengwei; Wu, Jinhui; Hu, Yiqiao; Guo, Hongqian

    2017-02-15

    Bladder cancer is one of the most frequent malignancies in the urinary system. Radical cystectomy is inevitable when bladder cancer progresses to a muscle-invasive disease. However, cystectomy still causes a high risk of death and a low quality of life (such as ureter-abdomen ostomy, uroclepsia for ileal-colon neobladder). Therefore, more effective treatments as well as bladder preservation are needed. We developed self-assembled tumor-targeting hyaluronic acid-IR-780 nanoparticles for photothermal ablation in over-expressing CD44 (the receptor for HA) bladder cancer, which show high tumor selectivity, high treatment efficacy, good bioavailability, and excellent biocompatibility. The nanoparticles demonstrated a stable spherical nanostructure in aqueous conditions with good mono-dispersity, and their average size was 171.3±9.14nm. The nanoparticles can be degraded by hyaluronidase when it is over-expressed in bladder cells; therefore, they appear to have a hyaluronidase-responsive "OFF/ON" behavior of a fluorescence signal. HA-IR-780 NPs also showed high photothermal efficiency; 2.5, 5, 10 and 20μg/mL of NPs had a maximum temperature increase of 11.2±0.66°C, 18.6±0.75°C, 26.8±1.11°C and 32.3±1.42°C. The in vitro cell viability showed that MB-49 cells could be efficiently ablated by combining HA-IR-780 NPs with 808nm laser irradiation. Then, in vivo biodistribution showed the HA-IR-780 NPs are targeted for accumulation in bladder cancer cells but have negligible accumulation in normal bladder wall. The photothermal therapeutic efficacy of HA-IR-780 NPs in the orthotopic bladder cancer model showed tumors treated with NPs had a maximum temperature of 48.1±1.81°C after 6min of laser irradiation. The tumor volume was approximately 65-75mm(3) prior to treatment. After 12days, the tumor sizes for the PBS, PBS plus laser irradiation and HA-IR-780 NPs-treated groups were 784.75mm(3), 707.5mm(3), and 711.37mm(3), respectively. None of the tumors in the HA-IR-780

  3. Orthotopic and heterotopic lower leg reimplantation. Evaluation of seven patients.

    PubMed

    Daigeler, A; Fansa, H; Schneider, W

    2003-05-01

    Reimplantation is a well-established procedure in reconstructive surgery. This is especially so after amputation of the upper limb since prostheses provide limited function. In unilateral amputation of the lower leg orthotopic reimplantation is the treatment of choice. With bilateral amputation, in which orthotopic reimplantation is not possible because of the complexity of the trauma, heterotopic reimplantation is an option. We report five patients who received orthotopic and two who received heterotopic reimplantations of the lower leg. We assessed the functional outcomewith reference to cutaneous sensation, mobility, pain, and the cosmetic result. The functional outcome was good, as was the patients' satisfaction. Their mobility, stability, and psychological state were satisfactory. Patients with heterotopic reimplantations preferred the reimplanted leg to a prosthesis. Although reimplantation of the lower leg requires prolonged hospitalisation, delayed mobilisation and secondary operations, we conclude that there is an indication for this operation in order to improve the patient's quality of life.

  4. Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats.

    PubMed

    Sjöqvist, Sebastian; Jungebluth, Philipp; Lim, Mei Ling; Haag, Johannes C; Gustafsson, Ylva; Lemon, Greg; Baiguera, Silvia; Burguillos, Miguel Angel; 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

    2014-04-15

    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.

  5. 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

  6. Fatal Emmonsia sp. Infection and Fungemia after Orthotopic Liver Transplantation

    PubMed Central

    Adams, Jason Y.; Luo, Robert; Banaei, Niaz; Concepcion, Waldo; Ho, Dora Y.

    2017-01-01

    We report a fatal case of disseminated Emmonsia sp. infection in a 55-year-old man who received an orthotopic liver transplant. The patient had pneumonia and fungemia, and multisystem organ failure developed. As human habitats and the number of immunocompromised patients increase, physicians must be aware of this emerging fungal infection. PMID:28098544

  7. Ankle replacement

    MedlinePlus

    ... is surgery to replace the damaged bone and cartilage in the ankle joint. Artificial joint parts (prosthetics) ... Your surgeon will remove the damaged bone and cartilage. Your surgeon will replace the damaged part of: ...

  8. Hip Replacement

    MedlinePlus

    ... replacement is an operation in which a damaged hip joint is removed and replaced with an artificial joint. ... are many medical conditions that can damage the hip joint. (Watch the video to learn about what goes ...

  9. Optimizing a canine survival model of orthotopic lung transplantation.

    PubMed

    Farivar, A S; Yunusov, M Y; Chen, P; Leone, R J; Madtes, D K; Kuhr, C S; Spector, M R; Abrams, K; Hwang, B; Nash, R A; Mulligan, M S

    2006-06-01

    While acute models of orthotopic lung transplantation have been described in dogs, the technical considerations of developing a survival model in this species have not been elaborated. Herein, we describe optimization of a canine survival model of orthotopic lung transplantation. Protocols of orthotopic left lung transplantation and single lung ventilation were established in acute experiments (n=9). Four dogs, serving as controls, received autologous, orthotopic lung transplants. Allogeneic transplants were performed in 16 DLA-identical and 16 DLA-mismatched unrelated recipient dogs. Selective right lung ventilation was utilized in all animals. A Malecot tube was left in the pleural space connected to a Heimlich valve for up to 24 hours. To date, animals have been followed up to 24 months by chest radiography, pulmonary function tests, bronchoscopy with lavage, and open biopsies. Long-term survival was achieved in 34/36 animals. Two recipients died intraoperatively secondary to cardiac arrest. All animals were extubated on the operating table, and in all cases the chest tube was removed within 24 hours. Major complications included thrombosis of the pulmonary artery and subcritical stenosis of bronchial anastamosis. One recipient underwent successful treatment of a small bowel intussusception. We report our experience in developing a survival canine model of orthotopic single lung transplantation. While short-term survival following canine lung transplantation is achievable, we report particular considerations that facilitate animal comfort, early extubation, and lung reexpansion in the immediate postoperative period, further optimizing use of this species for experimental modeling of long-term complications after lung transplantation.

  10. Pre-clinical Orthotopic Murine Model of Human Prostate Cancer.

    PubMed

    Shahryari, Varahram; Nip, Hannah; Saini, Sharanjot; Dar, Altaf A; Yamamura, Soichiro; Mitsui, Yozo; Colden, Melissa; Bucay, Nathan; Tabatabai, Laura Z; Greene, Kirsten; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir; Majid, Shahana

    2016-08-29

    To study the multifaceted biology of prostate cancer, pre-clinical in vivo models offer a range of options to uncover critical biological information about this disease. The human orthotopic prostate cancer xenograft mouse model provides a useful alternative approach for understanding the specific interactions between genetically and molecularly altered tumor cells, their organ microenvironment, and for evaluation of efficacy of therapeutic regimens. This is a well characterized model designed to study the molecular events of primary tumor development and it recapitulates the early events in the metastatic cascade prior to embolism and entry of tumor cells into the circulation. Thus it allows elucidation of molecular mechanisms underlying the initial phase of metastatic disease. In addition, this model can annotate drug targets of clinical relevance and is a valuable tool to study prostate cancer progression. In this manuscript we describe a detailed procedure to establish a human orthotopic prostate cancer xenograft mouse model.

  11. 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.

  12. A murine model of orthotopic periorbital subunit transplantation.

    PubMed

    Gao, Bowen; Li, Bin; Li, Xinxin; Bae, Jinhong; Xiao, Kaiyan; Li, Qingfeng; Zhu, Hainan

    2017-03-01

    Conventional reconstructive methods fail to achieve satisfactory results in total eyelid defect cases. Vascularized composite tissue allotransplantation might provide both good appearance and function for these patients. We developed an orthotopic periorbital transplantation model in rats to facilitate further experimentation in this field. In anatomical studies, the vascular distribution to and innervation of the periorbital unit were identified and recorded. Then, according to the anatomical studies, eight orthotopic transplantations and two transplantations with pedicle ligation were performed. The posterior facial vein and the external carotid artery were selected as the graft pedicles, while the temporal and upper zygomatic facial nerves were used for graft innervation. All transplanted eyelids were assessed daily. Micro-CT scanning and hematoxylin and eosin staining of the grafts were performed 60 days after the operation. In total, 90% of recipients tolerated the operation well. All grafts without pedicle ligation survived, and new hair growth was observed. The position of the eyelid was maintained, and eyelid function was partially restored. In the recipients with graft pedicle ligation, the grafts became necrotic and mummified within four to five days. Micro-CT of the surviving grafts showed a good blood supply, and histological staining revealed normal morphology. A periorbital subunit orthotopic transplantation model was established, which might facilitate future eyelid allotransplantation-related experimentation. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

  13. Transcatheter aortic valve replacement for bicuspid aortic stenosis 13years post heart transplant.

    PubMed

    Julien, Maureen B; Desai, Nimesh; Brozena, Susan; Herrmann, Howard C

    2016-12-16

    Despite the widespread use of transcatheter aortic valve replacement (TAVR) for moderate and high-risk patients with severe aortic stenosis, it is utilized less frequently in patients with bicuspid aortic valves (BAV). Orthotopic heart transplant (OHT) donors tend to be younger and may have undiagnosed BAV. We present a case of successful TAVR in a patient with BAV thirteen years after OHT.

  14. Shoulder replacement

    MedlinePlus

    ... the opening at the end of the shoulder blade, called the socket. This type of joint allows ... head. The socket part (glenoid) of your shoulder blade will be replaced with a smooth plastic shell ( ...

  15. An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation.

    PubMed

    Perrin, George Q; Li, Hua; Fishbein, Lauren; Thomson, Susanne A; Hwang, Min S; Scarborough, Mark T; Yachnis, Anthony T; Wallace, Margaret R; Mareci, Thomas H; Muir, David

    2007-11-01

    Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth.

  16. Ectopic goitrous submandibular thyroid with goitrous orthotopic thyroid gland.

    PubMed

    Bhardwaj, Avinash Kumar; Mani, Vinayaga; Dixit, Rashmi; Garg, Anju

    2016-01-01

    Ectopic thyroid is a rare developmental anomaly with lingual thyroid accounting for majority of the cases. The presence of ectopic thyroid tissue lateral to the midline is very rare, and very few cases located in the submandibular region have been reported. The simultaneous finding of submandibular ectopic thyroid tissue and a functional orthotopic thyroid gland is even rarer. In the differential diagnosis of an ectopic submandibular thyroid, it is fundamental to exclude a metastasis from well-differentiated thyroid cancer, even when primary thyroid carcinoma is not demonstrable.

  17. Liver replacement for alpha1-antitrypsin deficiency

    PubMed Central

    Putnam, Charles W.; Porter, Kendrick A.; Peters, Robert L.; Ashcavai, Mary; Redeker, Allan G.; Starzl, Thomas E.

    2010-01-01

    A 16-year-old girl with advanced cirrhosis and severe alpha1-antitrypsin deficiency of the homozygous PiZZ phenotype was treated by orthotopic liver transplantation. After replacement of the liver with a homograft from a donor with the normal PiMM phenotype, the alpha1-antitrypsin concentration in the recipient’s serum rose to normal; it had the PiMM phenotype. Two and a third years later, chronic rejection necessitated retransplantation. Insertion of a homograft from a heterozygous PiMZ donar was followed by the identification of that phenotype in the recipient’s serum. Neither liver graft developed the alpha1-antitrypsin glycoprotein deposits seen with the deficiency state. These observations confirm that this hepatic- based inborn error metabolism is metabolically cured by liver replacement. PMID:320694

  18. Esophageal replacement.

    PubMed

    Kunisaki, Shaun M; Coran, Arnold G

    2017-04-01

    This article focuses on esophageal replacement as a surgical option for pediatric patients with end-stage esophageal disease. While it is obvious that the patient׳s own esophagus is the best esophagus, persisting with attempts to retain a native esophagus with no function and at all costs are futile and usually detrimental to the overall well-being of the child. In such cases, the esophagus should be abandoned, and the appropriate esophageal replacement is chosen for definitive reconstruction. We review the various types of conduits used for esophageal replacement and discuss the unique advantages and disadvantages that are relevant for clinical decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Orthotopic heart transplant: a therapeutic option for unresectable cardiac fibroma in infants.

    PubMed

    Kobayashi, Daisuke; L'Ecuyer, Thomas J; Aggarwal, Sanjeev

    2012-01-01

    Primary cardiac tumors are rare lesions in childhood, with the two most common being rhabdomyoma and fibroma. We report two infants who successfully underwent orthotopic heart transplant for massive interventricular septal cardiac fibromas. For unresectable infantile cardiac fibroma, orthotopic heart transplant may be considered a therapeutic option.

  20. Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts.

    PubMed

    Hoffman, Robert M

    2015-08-01

    The majority of human solid tumours do not metastasize when grown subcutaneously in immunocompromised mice; this includes patient-derived xenograft (PDX) models. However, orthotopic implantation of intact tumour tissue can lead to metastasis that mimics that seen in patients. These patient-derived orthotopic xenograft (PDOX) models have a long history and might better recapitulate human tumours than PDX models.

  1. 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

  2. Marine collagen scaffolds for nasal cartilage repair: prevention of nasal septal perforations in a new orthotopic rat model using tissue engineering techniques.

    PubMed

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

    2013-10-01

    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.

  3. [Orthotopic liver transplant in rats. Surgical technique, complications and treatment].

    PubMed

    Lausada, Natalia R; Gondolesi, G E; Ortiz, E; Dreizzen, E; Raimondi, J C

    2002-01-01

    The orthotopic rat liver transplant model is a widely used technique in transplantation research. It has many advantages over other animal transplant models because of its availability and low cost. However, it must be emphasized that success with the rat model requires thorough training. The aim of this paper is to describe the microsurgical technique involved in 60 rat liver transplants and to discuss the complications and their treatments. Forty-nine liver transplants were performed at the Experimental Laboratory of the University Hospital, Ontario, Canada (ELUH) and 11 were performed at the Laboratorio de Trasplante de Organos de la Facultad de Ciencias Médicas de La Plata, Buenos Aires. Argentina (LTO). Among the transplants performed at the ELUH, the observed complications were haemorrhage (n = 4), pneumothorax (n = 1), anastomotic failure (n = 15), bile leak (n = 3), and bile duct necrosis (n = 9). The remaining 17 rats at the ELUH were healthy at day 7 after surgery. Animal survival immediately postop, at 24 hours postop and at 7 days postop was achieved with the 9th, 20th and 21st transplants respectively. At the LTO, 3 rats died as a result of anaesthetic complications. Seven-day animal survival was achieved with the 11th transplant. We beleive that the description of the orthotopic rat liver transplantation technique, as well as the discussion regarding complications and their management, can be useful for researchers interested in performing liver transplantation in rats.

  4. Post-transfusion acquired malaria complicating orthotopic liver transplantation.

    PubMed

    Talabiska, D G; Komar, M J; Wytock, D H; Rubin, R A

    1996-02-01

    Early infectious complications within the first 3 months of orthotopic liver transplantation are common and are associated with significant morbidity and mortality. Here we report the first case of transfusion-acquired malaria in an orthotopic liver transplantation recipient. The patient was found to have Plasmodium ovale malaria during evaluation of a severe febrile illness. The infection was traced to a platelet transfusion and responded to treatment with chloroquine. Risk factors associated with the development of malaria infection are identifiable and should be reviewed from the recipient and donor when possible. Routes of infection in the liver transplant patient would include blood products, the organ itself, and resurgence of latent infection. Theoretically, immunosuppression may have an impact on the disease process. Clinicians caring for these patients need to have a high index of suspicion in order to diagnose and treat malaria effectively in the post-transplant setting. Although rare, malaria should be added to the list of pathogens that can infect organ transplant recipients.

  5. Treatment Experience of Severe Abdominal Infection after Orthotopic Liver Transplantation.

    PubMed

    Wang, Y-G; Wu, J-S; Jiang, B; Wang, J-H; Liu, C-P; Peng, C; Tian, B-Z

    2015-06-01

    This study aims to investigate the causes and treatment experience of severe abdominal infection after orthotopic liver transplantation. Clinical data were retrospectively analysed in perioperative severe abdominal infection of 186 orthotopic liver transplantation cases from March 2004 to November 2011. Among the 186 patients, 16 cases had severe abdominal infection: five cases had bile duct anastomotic leakage-inducing massive hydrops and infection under liver interstice, 10 cases had extensive bleeding of surgical wound leading to massive haematocele and infection around the liver, and one case had postoperative lower oesophageal fistula leakage causing massive hydrops and infection under the left diaphragm. After definite diagnosis, 12 cases underwent surgery within three days, with no death. Among the four cases that underwent surgery three days after diagnosis, one case died of multiple-organ failure five days after abdominal cavity exploration, which was performed 21 days after liver transplantation. Severe abdominal infections after liver transplantation were the most common causes of death in perioperative liver transplantation. Comprehensive treatment with efficacious antibiotics, multiple-organ support, controlled surgical removal of the lesion, and adequate drainage establishment was the key to the entire treatment.

  6. Orthotopic liver transplantation for giant liver haemangioma: A case report.

    PubMed

    Lange, Undine G; Bucher, Julian N; Schoenberg, Markus B; Benzing, Christian; Schmelzle, Moritz; Gradistanac, Tanja; Strocka, Steffen; Hau, Hans-Michael; Bartels, Michael

    2015-12-24

    In liver haemangiomas, the risk of complication rises with increasing size, and treatment can be obligatory. Here we present a case of a 46-year-old female who suffered from a giant haemangioma causing severe portal hypertension and vena cava compression, leading to therapy refractory ascites, hyponatremia and venostasis-associated thrombosis with pulmonary embolism. The patients did not experience tumour rupture or consumptive coagulopathy. Surgical resection was impossible because of steatosis of the non-affected liver. Orthotopic liver transplantation was identified as the only treatment option. The patient's renal function remained stable even though progressive morbidity and organ allocation were improbable according to the patient's lab model for end-stage liver disease (labMELD) score. Therefore, non-standard exception status was approved by the European organ allocation network "Eurotransplant". The patient underwent successful orthotopic liver transplantation 16 mo after admission to our centre. Our case report indicates the underrepresentation of morbidity associated with refractory ascites in the labMELD-based transplant allocation system, and it indicates the necessity of promptly applying for non-standard exception status to enable transplantation in patients with a severe clinical condition but low labMELD score. Our case highlights the fact that liver transplantation should be considered early in patients with non-resectable, symptomatic benign liver tumours.

  7. Orthotopic liver transplantation for giant liver haemangioma: A case report

    PubMed Central

    Lange, Undine G; Bucher, Julian N; Schoenberg, Markus B; Benzing, Christian; Schmelzle, Moritz; Gradistanac, Tanja; Strocka, Steffen; Hau, Hans-Michael; Bartels, Michael

    2015-01-01

    In liver haemangiomas, the risk of complication rises with increasing size, and treatment can be obligatory. Here we present a case of a 46-year-old female who suffered from a giant haemangioma causing severe portal hypertension and vena cava compression, leading to therapy refractory ascites, hyponatremia and venostasis-associated thrombosis with pulmonary embolism. The patients did not experience tumour rupture or consumptive coagulopathy. Surgical resection was impossible because of steatosis of the non-affected liver. Orthotopic liver transplantation was identified as the only treatment option. The patient’s renal function remained stable even though progressive morbidity and organ allocation were improbable according to the patient’s lab model for end-stage liver disease (labMELD) score. Therefore, non-standard exception status was approved by the European organ allocation network “Eurotransplant”. The patient underwent successful orthotopic liver transplantation 16 mo after admission to our centre. Our case report indicates the underrepresentation of morbidity associated with refractory ascites in the labMELD-based transplant allocation system, and it indicates the necessity of promptly applying for non-standard exception status to enable transplantation in patients with a severe clinical condition but low labMELD score. Our case highlights the fact that liver transplantation should be considered early in patients with non-resectable, symptomatic benign liver tumours. PMID:26722664

  8. Multimodality imaging in an orthotopic mammary window chamber model

    NASA Astrophysics Data System (ADS)

    Schafer, Rachel; Leung, Hui Min; Gmitro, Arthur F.

    2013-02-01

    Window chamber models have been utilized for many years to investigate cancer development and the tumor microenvironment. Orthotopic mammary window chamber model have been developed for detailed study of breast cancer. Orthotopic window chamber models, due to the native environment, support more realistic growth and tumor behavior than ectopic models. The work by other groups thus far utilizing mammary window chamber models has focused solely on optical imaging techniques, limited to probing the first millimeter or less of tissue. These techniques do not take full advantage of the unrestricted, three-dimensional tumor growth the model supports. We have developed a custom plastic structure compatible with multimodality imaging. We present in this work the implementation of our custom window chamber in a mouse model and the successful imaging of the window chamber cancer model with MRI, nuclear imaging, and optical techniques. MRI provides a full three-dimensional view of the tumor growth and allows for additional, potentially clinically translatable, approaches to be utilized in investigating the cancer microenvironment. Nuclear imaging is accomplished using the Beta Imager, which is a novel approach to nuclear imaging of window chambers. The Beta Imager detects photons after the interaction of a single positron with a scintillator, instead of the coincidence detection of annihilation gamma ray pairs. We utilized the radioisotope glucose analog, 2-deoxy-2- (18F)fluoro-D-glucose or FDG, with the Beta Imager to obtain information on the glycolytic metabolism of the tumor and surrounding region.

  9. 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.

  10. Tissue Engineered Scaffolds for an Effective Healing and Regeneration: Reviewing Orthotopic Studies

    PubMed Central

    2014-01-01

    It is commonly stated that tissue engineering is the most promising approach to treat or replace failing tissues/organs. For this aim, a specific strategy should be planned including proper selection of biomaterials, fabrication techniques, cell lines, and signaling cues. A great effort has been pursued to develop suitable scaffolds for the restoration of a variety of tissues and a huge number of protocols ranging from in vitro to in vivo studies, the latter further differentiating into several procedures depending on the type of implantation (i.e., subcutaneous or orthotopic) and the model adopted (i.e., animal or human), have been developed. All together, the published reports demonstrate that the proposed tissue engineering approaches spread toward multiple directions. The critical review of this scenario might suggest, at the same time, that a limited number of studies gave a real improvement to the field, especially referring to in vivo investigations. In this regard, the present paper aims to review the results of in vivo tissue engineering experimentations, focusing on the role of the scaffold and its specificity with respect to the tissue to be regenerated, in order to verify whether an extracellular matrix-like device, as usually stated, could promote an expected positive outcome. PMID:25250319

  11. Tissue engineered scaffolds for an effective healing and regeneration: reviewing orthotopic studies.

    PubMed

    Baiguera, Silvia; Urbani, Luca; Del Gaudio, Costantino

    2014-01-01

    It is commonly stated that tissue engineering is the most promising approach to treat or replace failing tissues/organs. For this aim, a specific strategy should be planned including proper selection of biomaterials, fabrication techniques, cell lines, and signaling cues. A great effort has been pursued to develop suitable scaffolds for the restoration of a variety of tissues and a huge number of protocols ranging from in vitro to in vivo studies, the latter further differentiating into several procedures depending on the type of implantation (i.e., subcutaneous or orthotopic) and the model adopted (i.e., animal or human), have been developed. All together, the published reports demonstrate that the proposed tissue engineering approaches spread toward multiple directions. The critical review of this scenario might suggest, at the same time, that a limited number of studies gave a real improvement to the field, especially referring to in vivo investigations. In this regard, the present paper aims to review the results of in vivo tissue engineering experimentations, focusing on the role of the scaffold and its specificity with respect to the tissue to be regenerated, in order to verify whether an extracellular matrix-like device, as usually stated, could promote an expected positive outcome.

  12. Resting hemodynamics after total versus standard orthotopic heart transplantation.

    PubMed

    Aleksic, I; Czer, L S; Freimark, D; Takkenberg, J J; Dalichau, H; Valenza, M; Blanche, C; Queral, C A; Nessim, S; Trento, A

    1996-08-01

    Total orthotopic heart transplantation (TOHT) requires longer surgery than standard orthotopic heart transplantation (SOHT), but offers normal anatomy and synchronous atrial contraction. We endeavored to test whether TOHT improves resting hemodynamics. We analyzed 60 patients with SOHT and 66 with TOHT transplanted between 12/89 and 7/94. Age, preoperative NYHA class, ejection fraction, and donor characteristics were similar. After applying exclusion criteria at 2 weeks postoperatively, 53 SOHT and 58 TOHT patients were accepted for further study. Right-heart hemodynamics were examined at 2 weeks and 6 months posttransplant. Despite a longer ischemic time (161 +/- 36 vs. 142 +/- 37 min, p = 0.004), cardiac output and index were higher in the TOHT group at 2 weeks (6.1 +/- 1.4 vs. 5.4 +/- 1.0 L/min, TOHT vs. SOHT, p = 0.01; and 3.3 +/- 0.7 vs. 2.9 +/- 0.6 L/min/m2, p = 0.005) but similar at 6 months (5.9 +/- 1.2 vs. 5.6 +/- 1.4 L/min; and 3.0 +/- 0.6 vs. 2.9 +/- 0.7 L/min/m2). Right-atrial pressure was lower with TOHT at both time points (7 +/- 4 vs. 9 +/- 4 mmHg, p = 0.02: and 5 +/- 2 vs. 7 +/- 3, p = 0.0006). Wedge pressure was similar at 2 weeks (12 +/- 5 vs. 13 +/- 5, p = 0.045). Heart rate (bpm) was higher at both time points with TOHT (84 +/- 10 vs. 75 +/- 12, p = 0.0003: and 90 +/- 12 vs. 82 +/- 9, p = 0.0006). Pulmonary vascular resistance was similar at both time points. Despite a longer ischemic time, total orthotopic heart transplantation does not impair postoperative cardiac function. There is an early improvement in cardiac output, a sustained higher heart rate reflecting preservation of donor sinus node function, and a lower right-atrial pressure.

  13. Long-term survival after orthotopic and heterotopic cardiac transplantation.

    PubMed Central

    Cooper, D K; Charles, R G; Fraser, R C; Beck, W; Barnard, C N

    1980-01-01

    Five long-term survivors of heart transplantation were reinvestigated. Two patients had undergone orthotopic heart transplantation over 11 and 9 years earlier and constitute two of the world's longest-surviving patients after this procedure. Three patients had undergone heterotopic heart transplantation (one left heart bypass alone and two biventricular bypass) four to six years earlier. Four of the five patients had had only one or no documented acute rejection episodes. Three had been given blood transfusions. None had had particularly good tissue matching in relation to the donor on HLA typing. All five patients were leading full and active lives. At review two patients had significant coronary artery disease, one severe, presumably due to chronic immune-complex deposition. Heart transplantation remains a major undertaking, but it can offer the patient many years of good-quality life. Images p1095-a p1095-b PMID:7000291

  14. Delayed biliary duct obstruction after orthotopic liver transplantation

    PubMed Central

    Martineau, G.; Porter, K. A.; Gorman, J.; Launois, B.; Schroter, G. T.; Palmer, W.; Putnam, C. W.; Groth, C. G.; Halgrimson, C. G.; Penn, I.; Starzl, T. E.

    2010-01-01

    After orthotopic liver transplantation and biliary reconstruction by cholecystoduodenostomy, four of 40 patients developed delayed obstruction of the cystic duct. The recipients had the clinical syndrome of fulminating cholangitis with jaundice, fever, leukocytosis, toxemia, and bacteremia. All four patients died; of the four, two patients died despite late reoperation and re-establishment of bile drainage by choledochoenterostomy. In all four cases, a factor contributing to the biliary obstruction may have been infection of the extrahepatic biliary ducts with or without ulceration, and in three of the livers, there was evidence of infection of the ducts with CMV. If cholecystoduodenostomy is used in future cases, prompt re-exploration and conversion to choledochoenterostomy should be considered if the diagnosis of duct obstruction, cholangitis, and persistent bacteremia are made. PMID:4341571

  15. Orthotopic models of pediatric brain tumors in zebrafish

    PubMed Central

    Eden, Christopher J.; Ju, Bensheng; Murugesan, Mohankumar; Phoenix, Timothy; Nimmervoll, Birgit; Tong, Yiai; Ellison, David W.; Finkelstein, David; Wright, Karen; Boulos, Nidal; Dapper, Jason; Thiruvenkatam, Radhika; Lessman, Charles; Taylor, Michael R.; Gilbertson, Richard J.

    2014-01-01

    High-throughput screens (HTS) of compound toxicity against cancer cells can identify thousands of potential new drug-leads. But only limited numbers of these compounds can progress to expensive and labor intensive efficacy studies in mice, creating a ‘bottle-neck’ in the drug development pipeline. Approaches that triage drug-leads for further study are greatly needed. Here, we provide an intermediary platform between HTS and mice by adapting mouse models of pediatric brain tumors to grow as orthotopic xenografts in the brains of zebrafish. Freshly isolated mouse ependymoma, glioma and choroid plexus carcinoma cells expressing red fluorescence protein (RFP) were conditioned to grow at 34°C. Conditioned tumor cells were then transplanted orthotopically into the brains of zebrafish acclimatized to ambient temperatures of 34°C. Live in vivo fluorescence imaging identified robust, quantifiable and reproducible brain tumor growth as well as spinal metastasis in zebrafish. All tumor xenografts in zebrafish retained the histological characteristics of the corresponding parent mouse tumor and efficiently recruited fish endothelial cells to form a tumor vasculature. Finally, by treating zebrafish harboring ERBB2-driven gliomas with an appropriate cytotoxic chemotherapy (5-fluorouracil) or tyrosine kinase inhibitor (Erlotinib), we show that these models can effectively assess drug efficacy. Our data demonstrate, for the first time, that mouse brain tumors can grow orthtopically in fish and serve as a platform to study drug efficacy. Since large cohorts of brain tumor bearing zebrafish can be generated rapidly and inexpensively, these models may serve as a powerful tool to triage drug-leads from HTS for formal efficacy testing in mice. PMID:24747973

  16. [Cesarean section in an orthotopic liver transplantation patient].

    PubMed

    Guasch Arévalo, E; Alcantarilla Martín, C; López López, M A; Suárez Cobián, A; Gilsanz, F

    2002-01-01

    We describe the case of a woman with a functioning orthotopic liver transplant who was receiving cyclosporine treatment. An emergency cesarean section was performed, with epidural analgesia, for prolonged pregnancy and an unfavorable cervix. No complications were recorded either during or after surgery. She gave birth to a healthy boy and both were discharged on the fifth day after delivery. Organ transplantation is an increasingly common procedure, and Spain, which has a large number of organ donors, is the country where the largest number of transplants in Europe is performed. Immunosuppressive therapy has advanced greatly, allowing patients to survive longer and enjoy good quality of life. Many transplanted women in their childbearing years consider pregnancy, which can lead to medical problems, a worsened clinical picture or complications related to pregnancy, putting the lives of both mother and fetus at risk. Perioperative management by an anesthesiologist is necessary, whether delivery is vaginal or cesarean. Whenever immunosuppressive therapy is involved, the use of general or regional anesthetics carries risk, as do pregnancy and delivery themselves.

  17. Protective effect of immunosuppressive treatment before orthotopic kidney autotransplantation.

    PubMed

    Cicora, Federico; Lausada, Natalia; Vasquez, Daniela N; Cicora, Paola; Guerrieri, Diego; Gonzalez, Pedro; Zalazar, Gustavo; Stringa, Pablo; Raimondi, Clemente

    2011-01-15

    Ischemia reperfusion injury (IRI) is one of the risk factors for delayed graft function, acute rejection and long term allograft survival after kidney transplantation. IRI is an independent antigen inflammatory process that produces tissue damage. Our objective was to study the impact of immunosuppressive treatment (IS) on IRI applying only one dose of IS before orthotopic kidney autotransplantation. Twenty-four rats allocated in four groups were studied. One group served as control (G1: autotransplanted rats without IS) and the rest received IS 12 h before kidney autotransplantation (G2: Rapamycin, G3: Mycophenolate mofetil and G4: Tacrolimus). Improved renal function and systemic inflammatory response were found among IS groups compared to the control group (Delta Urea p<0.0001; Delta Creatinine p<0.0001; Delta C3 p<0.001). The number of apoptotic nuclei in renal medulla in G1 was higher than in IS groups (p<0.0001). Tubular damage was less severe in IS groups respecting G1 (p<0.001). C3, TNF-α and IL-6 expression in kidney samples was reduced when IS was used compared to the control group. No differences were observed among the different immunosuppressive drugs tested. However, Heme oxygenase-1(HO-1) was increased only in Rapamycin treatment. These data suggest that the use of IS administered before transplant attenuates the IRI process after kidney transplantation in an animal model. Copyright © 2010 Elsevier B.V. All rights reserved.

  18. Inorganic Nanovehicle Targets Tumor in an Orthotopic Breast Cancer Model

    NASA Astrophysics Data System (ADS)

    Choi, Goeun; Kwon, Oh-Joon; Oh, Yeonji; Yun, Chae-Ok; Choy, Jin-Ho

    2014-03-01

    The clinical efficacy of conventional chemotherapeutic agent, methotrexate (MTX), can be limited by its very short plasma half-life, the drug resistance, and the high dosage required for cancer cell suppression. In this study, a new drug delivery system is proposed to overcome such limitations. To realize such a system, MTX was intercalated into layered double hydroxides (LDHs), inorganic drug delivery vehicle, through a co-precipitation route to produce a MTX-LDH nanohybrid with an average particle size of approximately 130 nm. Biodistribution studies in mice bearing orthotopic human breast tumors revealed that the tumor-to-liver ratio of MTX in the MTX-LDH-treated-group was 6-fold higher than that of MTX-treated-one after drug treatment for 2 hr. Moreover, MTX-LDH exhibited superior targeting effect resulting in high antitumor efficacy inducing a 74.3% reduction in tumor volume compared to MTX alone, and as a consequence, significant survival benefits. Annexin-V and propidium iodine dual staining and TUNEL analysis showed that MTX-LDH induced a greater degree of apoptosis than free MTX. Taken together, our data demonstrate that a new MTX-LDH nanohybrid exhibits a superior efficacy profile and improved distribution compared to MTX alone and has the potential to enhance therapeutic efficacy via inhibition of tumor proliferation and induction of apoptosis.

  19. An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

    PubMed

    Paschall, Amy V; Liu, Kebin

    2016-08-14

    Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo.

  20. Changes in Resting Energy Expenditure Following Orthotopic Liver Transplantation.

    PubMed

    Chen, Yimin; Kintner, Jennifer; Rifkin, Sam K; Keim, Kathryn S; Tangney, Christy C

    2016-08-01

    There is no consensus whether resting energy expenditure (REE) following orthotopic liver transplantation (OLT) is altered. The objectives of this investigation were to describe changes in measured REE (mREE) using indirect calorimetry in 25 OLT patients on days 5, 10, and 15 after baseline (within 72 hours following OLT) and compare mREE changes with those calculated with 2 predicted equations for energy expenditure (pREE): the Harris-Benedict and Schofield equations. Patients were 57 ± 5.4 years of age, 44% were male, 36% were black, and 72% had liver disease of viral etiology. Measured REE (at baseline and days 5, 10, and 15, per kcal/d: 1832 ± 952, 1565 ± 383, 1538 ± 345, 1578 ± 418) and kcal per kilogram of body weight (22.7 ± 12.8, 18.4 ± 4, 18.7 ± 3.8, 21 ± 6.5) did not change over time. In contrast, changes in pREE based on either the Harris-Benedict (P < .001) or Schofield (P = .006) equation using measured weights at each corresponding time point and lowest body weight during the study to estimate dry weight were significant. Wide ranges in both mREE and mREE expressed per kilogram of body weight at each study time point were observed in contrast to pREE, which declined by day 15. The observed differences in mREE over time suggest indirect calorimetry is indicated if available following OLT. Additional research is warranted to determine the most appropriate predictive equation with suitable stress factors to use when indirect calorimetry is not available. © 2015 American Society for Parenteral and Enteral Nutrition.

  1. Catheter ablation of organized atrial arrhythmias in orthotopic heart transplantation.

    PubMed

    Mouhoub, Yamina; Laredo, Mikael; Varnous, Shaida; Leprince, Pascal; Waintraub, Xavier; Gandjbakhch, Estelle; Hébert, Jean-Louis; Frank, Robert; Maupain, Carole; Pavie, Alain; Hidden-Lucet, Françoise; Duthoit, Guillaume

    2017-07-21

    Organized atrial arrhythmias (OAAs) are common after orthotopic heart transplantation (OHT). Some controversies remain about their clinical presentation, relationship with atrial anastomosis and electrophysiologic features. The objectives of this retrospective study were to determine the mechanisms of OAAs after OHT and describe the outcomes of radiofrequency catheter ablation (RFCA). Thirty consecutive transplanted patients (mean age 48 ± 17 years, 86.6% male) underwent 3-dimensional electroanatomic mapping and RFCA of their OAA from 2004 to 2012 at our center. Twenty-two patients had biatrial anastomosis and 8 had bicaval anastomosis. Macro-reentry was the arrhythmia mechanism for 96% of patients. The electrophysiologic diagnoses were: cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) in 93% of patients (n = 28); perimitral AFL in 3% (n = 1); and focal atrial tachycardia (FAT) in 3% (n = 1). In 5 patients with biatrial anastomosis, a right FAT was inducible. Primary RFCA success was obtained in 93% of patients. Mean follow-up time was 39 ± 26.8 months. Electrical repermeation between recipient and donor atria, present in 20% of patients (n = 6), did not account for any of the OAAs observed. Survival without OAA relapse at 12, 24 and 60 months was 93%, 89% and 79%, respectively. CTI-dependent AFL accounted for most instances of OAA after OHT, regardless of anastomosis type. Time from transplantation to OAA was shorter with bicaval than with biatrial anastomosis. RFCA was safe and provided good long-term results. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  2. 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

  3. Vascular complications after orthotopic liver transplantation: hepatic artery thrombosis.

    PubMed

    Pareja, E; Cortes, M; Navarro, R; Sanjuan, F; López, R; Mir, J

    2010-10-01

    Hepatic artery thrombosis (HAT) is the second main cause of liver graft failure after primary nonfunction. It is the most frequent arterial complication in orthotopic liver transplantation (OLT). The consensus for early HAT definition consists of an arterial thrombosis detected during the first month after OLT. HAT is associated with markedly increased morbidity, being the leading cause of graft loss (53%) and mortality. However, improvements in postoperative care have resulted in a marked reduction of its incidence. We performed a review of all patients who underwent liver transplantations from January 1991 to December 2009, involving 1560 subjects who underwent 1674 OLT, excluding children. To analyze the impact of the study period on HAT, we defined 3 periods: the first between January 1991 and April 1993, the second from May 1993 to December 2003, and the last from January 2004 to December 2009. The total number of patients with HAT was 48 (2.8%) including 32 (1.9%) early HAT and 16 (0.9%) late HAT. The incidence of HAT diminished as the surgical team gained experience from 9.3% in the first period to 2.1% in the last. Most patients with early HAT presented acute fulminant hepatic failure (30%) and most were retransplantations (81%). In general, there are 3 modalities for HAT: revascularization, retransplantation, and observation. The choice of the treatment depended on the time of diagnosis although retransplantation was the treatment of choice for most groups. Minimizing risk factors, protocols for early detection, and good operative techniques should be the standard in all centers. Copyright © 2010 Elsevier Inc. All rights reserved.

  4. Genetically engineered pre-microRNA-34a prodrug suppresses orthotopic osteosarcoma xenograft tumor growth via the induction of apoptosis and cell cycle arrest

    PubMed Central

    Zhao, Yong; Tu, Mei-Juan; Wang, Wei-Peng; Qiu, Jing-Xin; Yu, Ai-Xi; Yu, Ai-Ming

    2016-01-01

    Osteosarcoma (OS) is the most common primary malignant bone tumor in children, and microRNA-34a (miR-34a) replacement therapy represents a new treatment strategy. This study was to define the effectiveness and safety profiles of a novel bioengineered miR-34a prodrug in orthotopic OS xenograft tumor mouse model. Highly purified pre-miR-34a prodrug significantly inhibited the proliferation of human 143B and MG-63 cells in a dose dependent manner and to much greater degrees than controls, which was attributed to induction of apoptosis and G2 cell cycle arrest. Inhibition of OS cell growth and invasion were associated with release of high levels of mature miR-34a from pre-miR-34a prodrug and consequently reduction of protein levels of many miR-34a target genes including SIRT1, BCL2, c-MET, and CDK6. Furthermore, intravenous administration of in vivo-jetPEI formulated miR-34a prodrug significantly reduced OS tumor growth in orthotopic xenograft mouse models. In addition, mouse blood chemistry profiles indicated that therapeutic doses of bioengineered miR-34a prodrug were well tolerated in these animals. The results demonstrated that bioengineered miR-34a prodrug was effective to control OS tumor growth which involved the induction of apoptosis and cell cycle arrest, supporting the development of bioengineered RNAs as a novel class of large molecule therapeutic agents. PMID:27216562

  5. Nicotine replacement therapy

    MedlinePlus

    ... nicotine replacement product, even for a short time. Alternative Names Smoking cessation - nicotine replacement; Tobacco - nicotine replacement therapy References American Cancer Society. Guide to quitting smoking. Last revised February ...

  6. Shoulder replacement - discharge

    MedlinePlus

    ... page: //medlineplus.gov/ency/patientinstructions/000178.htm Shoulder replacement - discharge To use the sharing features on this page, please enable JavaScript. You had shoulder replacement surgery to replace the bones of your shoulder ...

  7. Hip replacement - discharge

    MedlinePlus

    ... surgery to replace all or part of your hip joint with an artificial joint called a prosthesis. This ... You're in the Hospital You had a hip joint replacement surgery to replace all or part of ...

  8. Orthotopic heart transplant versus left ventricular assist device: A national comparison of cost and survival

    PubMed Central

    Mulloy, Daniel P.; Bhamidipati, Castigliano M.; Stone, Matthew L.; Ailawadi, Gorav; Kron, Irving L.; Kern, John A.

    2012-01-01

    Objectives Orthotopic heart transplantation is the standard of care for end-stage heart disease. Left ventricular assist device implantation offers an alternative treatment approach. Left ventricular assist device practice has changed dramatically since the 2008 Food and Drug Administration approval of the HeartMate II (Thoratec, Pleasanton, Calif), but at what societal cost? The present study examined the cost and efficacy of both treatments over time. Methods All patients who underwent either orthotopic heart transplantation (n = 9369) or placement of an implantable left ventricular assist device (n = 6414) from 2005 to 2009 in the Nationwide Inpatient Sample were selected. The trends in treatment use, mortality, and cost were analyzed. Results The incidence of orthotopic heart transplantation increased marginally within a 5-year period. In contrast, the annual left ventricular assist device implantation rates nearly tripled. In-hospital mortality from left ventricular assist device implantation decreased precipitously, from 42% to 17%. In-hospital mortality for orthotopic heart transplantation remained relatively stable (range, 3.8%–6.5%). The mean cost per patient increased for both orthotopic heart transplantation and left ventricular assist device placement (40% and 17%, respectively). With the observed increase in both device usage and cost per patient, the cumulative Left ventricular assist device cost increased 232% within 5 years (from $143 million to $479 million). By 2009, Medicare and Medicaid were the primary payers for nearly one half of all patients (orthotopic heart transplantation, 45%; left ventricular assist device, 51%). Conclusions Since Food and Drug Administration approval of the HeartMate II, mortality after left ventricular assist device implantation has decreased rapidly, yet has remained greater than that after orthotopic heart transplantation. The left ventricular assist device costs have continued to increase and have been

  9. Orthotopic heart transplantation in patients with univentricular physiology.

    PubMed

    Michielon, Guido; Carotti, Adriano; Pongiglione, Giacomo; Cogo, Paola; Parisi, Francesco

    2011-05-01

    Parallel advancements in surgical technique, preoperative and postoperative care, as well as a better understanding of physiology in patients with duct-dependent pulmonary or systemic circulation and a functional single ventricle, have led to superb results in staged palliation of most complex congenital heart disease (CHD) [1]. The Fontan procedure and its technical modifications have resulted in markedly improved outcomes of patients with single ventricle anatomy [2,3,4]. The improved early survival has led to an exponential increase of the proportion of Fontan patients surviving long into adolescence and young adulthood [5]. Improved early and late survival has not yet abolished late mortality secondary to myocardial failure, therefore increasing the referrals for cardiac transplantation [6]. Interstage attrition [7] is moreover expected in staged palliation towards completion of a Fontan-type circulation, while Fontan failure represents a growing indication for heart transplantation [8]. Heart transplantation has therefore become the potential "fourth stage" [9] or a possible alternative to a high-risk Fontan operation [10] in a strategy of staged palliation for single ventricle physiology. Heart transplant barely accounts for 16% of pediatric solid organ transplants [11]. The thirteenth official pediatric heart transplantation report- 2010 [11] indicates that pediatric recipients received only 12.5% of the total reported heart transplants worldwide. Congenital heart disease is not only the most common recipient diagnosis, but also the most powerful predictor of 1-year mortality after OHT. Results of orthotopic heart transplantations (OHT) for failing single ventricle physiology are mixed. Some authors advocate excellent early and mid-term survival after OHT for failing Fontan [9], while others suggest that rescue-OHT after failing Fontan seems unwarranted [10]. Moreover, OHT outcome appears to be different according to the surgical staging towards the Fontan

  10. Left ventricular noncompaction cardiomyopathy in end-stage heart failure patients undergoing orthotopic heart transplantation.

    PubMed

    Ottaviani, Giulia; Segura, Ana Maria; Rajapreyar, Indranee N; Zhao, Bihong; Radovancevic, Rajko; Loyalka, Pranav; Kar, Biswajit; Gregoric, Igor; Buja, L Maximilian

    2016-01-01

    Previous studies reported that left ventricular noncompaction (LVNC) is a cardiomyopathy, familial or sporadic, arising from arrest of the normal process of trabecular remodeling during embryonic development. The diagnosis is usually made by echocardiography, but to date, there has been little research on the occurrence and clinicopathological features of LVNC in the explanted hearts of orthotopic heart transplant (OHT) recipients. The clinical, echocardiographic, and pathologic findings were reviewed for evidence of LVNC, diagnosed by echocardiographic criteria, in 105 patients with end-stage heart failure (HF) undergoing OHT. Analyses of multiple sections of the explanted hearts were carried out. The hearts were evaluated for grades (0, negative; 1, mild/occasional foci; 2, moderate/multiple foci; 3, severe/extensive, diffuse) of fibrosis, reactive and replacement, hypertrophy, myocytolysis in left ventricle, right ventricle, interventricular septum, and atria. Absolute measurements of noncompacted and compacted portions of the left ventricle wall and noncompacted/compacted ratios were calculated. Isolated LVNC was observed in 0 of 54 ischemic cardiomyopathy and in 4 of 51 (7.8%) nonischemic cardiomyopathy patients - 2 men and 2 women, with a mean age±SEM of 34.2±6.9years. The echocardiogram disclosed marked left ventricular dilatation, prominent trabeculations, and left ventricle ejection fraction <20%. Mural thrombi were seen in 3 of 4 (75%) patients. The heart weight mean±SEM was 468±55.3 g (range, 340-600g); noncompacted myocardium was 22±5.8mm, compacted myocardium was 13.2±3.5mm, and noncompacted/compacted ratio was 1.7/1±0.2. The total scores of hypetrophy, myocytolysis, and fibrosis were as follows: left ventricle, 7.7±0.2; right ventricle, 6.2±0.5; interventricular septum, 6.7±0.2; and atria, 7.5±0.3. LVNC is an unusual form of nonischemic cardiomyopathy in patients suffering from end-stage HF undergoing OHT. The variability in the

  11. New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice.

    PubMed

    Sakamoto, Shuichi; Inoue, Hiroyuki; Ohba, Shunichi; Kohda, Yasuko; Usami, Ihomi; Masuda, Tohru; Kawada, Manabu; Nomoto, Akio

    2015-04-01

    Small-cell lung cancer (SCLC) is an aggressive cancer with high metastatic ability and novel strategies against the metastasis are urgently needed to improve SCLC treatment. However, the mechanism of metastasis of SCLC remains largely to be elucidated. For further studies of SCLC metastasis, we developed a new orthotopic transplantation model in mice. We established a GFP-labeled subline from the human SCLC cell line DMS273 and transplanted them orthotopically into the lung of nude mice with Matrigel. The GFP-labeled cells showed significant metastatic activity and formed metastatic foci in distant tissues such as bone, kidney, and brain, as observed in SCLC patients. From a bone metastasis focus of the mouse, we isolated another subline, termed G3H, with enhanced metastatic potential and higher hepatocyte growth factor (HGF) expression than the parental line. Further studies indicated that the HGF/MET signaling pathway was involved in in vitro motility and invasion activities of the G3H cells and treatments with MET inhibitors decreased formation of distant metastases in our orthotopic model using G3H cells. These data indicated that our model mimics the clinical aspect of SCLC such as metastatic tropism and autocrine of HGF/MET signaling. Compared with other orthotopic SCLC models, our model has a superior ability to form distant metastases. Therefore, our model will provide a valuable tool for the study of SCLC metastasis. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  12. Endoscopy-guided orthotopic implantation of colorectal cancer cells results in metastatic colorectal cancer in mice.

    PubMed

    Bettenworth, Dominik; Mücke, Marcus M; Schwegmann, Katrin; Faust, Andreas; Poremba, Christopher; Schäfers, Michael; Domagk, Dirk; Lenz, Philipp

    2016-08-01

    Advanced stage colorectal cancer (CRC) is still associated with limited prognosis. For preclinical evaluation of novel therapeutic approaches, murine models with orthotopic tumor growth and distant metastases are required. However, these models usually require surgical procedures possibly influencing tumor immunogenicity and development. The aim of this study was to establish a minimal-invasive endoscopy-based murine orthotopic model of metastatic CRC. During colonoscopy of CD-1 nude and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, implantation of Caco-2 and HT-29 CRC cells was performed subcutaneously (s.c.) or orthotopic into the colonic submucosa. White light endoscopy (WLE) and fluorescence endoscopy (FE) were applied for tumor detection in vivo. Ex vivo, resected tumors were examined by fluorescence reflectance imaging (FRI), histology, gelatin zymography and immunohistochemistry. In CD-1 nude mice, marked tumor growth was observed within 14 days after subcutaneous implantation while submucosal implantation failed to induce CRC after 17 weeks. In contrast, in NOD/SCID mice submucosal injection of HT-29 cells resulted in pronounced tumor growth 12 days post injectionem. Subsequently, rapid tumor expansion occurred, occupying the entire colonic circumference. Importantly, post mortem histological analyses confirmed liver metastases in 28.6 % and peritoneal metastases in 14.3 % of all mice. FRI and gelatin zymography did not detect a significantly increased matrix metalloproteinases (MMPs) expression in s.c. implanted tumors while MMP-tracer uptake was significantly enhanced in orthotopic implanted tumors. Neither s.c. nor orthotopic Caco-2 cell implantation resulted in tumor development. We successfully established an endoscopy-based model of metastatic CRC in immunodeficient mice.

  13. The influence of surgical technique on early posttransplant atrial fibrillation – comparison of biatrial, bicaval, and total orthotopic heart transplantation

    PubMed Central

    Rivinius, Rasmus; Helmschrott, Matthias; Ruhparwar, Arjang; Erbel, Christian; Gleissner, Christian A; Darche, Fabrice F; Thomas, Dierk; Bruckner, Tom; Katus, Hugo A; Doesch, Andreas O

    2017-01-01

    Purpose Early posttransplant atrial fibrillation (AF) has been associated with worse clinical outcomes after heart transplantation (HTX). The type of surgical technique may constitute a relevant risk factor for AF. Patients and methods This retrospective single-center study included 530 adult patients. Patients were stratified by surgical technique (biatrial, bicaval, or total orthotopic HTX) and early posttransplant heart rhythm (AF or sinus rhythm). Univariate and multivariate analyses were performed to evaluate risk factors for AF. Results A total of 161 patients received biatrial HTX (30.4%), 115 bicaval HTX (21.7%), and 254 total orthotopic HTX (47.9%). Sixty-one of 530 patients developed early posttransplant AF (11.5%). Patients with AF showed a statistically inferior 5-year survival compared to those with sinus rhythm (P<0.0001). Total orthotopic HTX had the lowest rate of AF (total orthotopic HTX [6.3%], bicaval HTX [14.8%], biatrial HTX [17.4%], P=0.0012). Multivariate analysis showed pretransplant valvular heart disease (P=0.0372), posttransplant enlarged left atrium (P=0.0066), posttransplant mitral regurgitation (P=0.0370), and non-total orthotopic HTX (P=0.0112) as risk factors for AF. Conclusion Early posttransplant AF was associated with increased mortality (P<0.0001). Total orthotopic HTX showed the lowest rate of AF compared to biatrial or bicaval HTX (P=0.0012). PMID:28331331

  14. Bioluminescent Orthotopic Mouse Models of Human Localized Non-Small Cell Lung Cancer: Feasibility and Identification of Circulating Tumour Cells

    PubMed Central

    Lahon, Benoit; Castier, Yves; Lesèche, Guy; Soria, Jean-Charles; Vozenin, Marie-Catherine; Decraene, Charles; Deutsch, Eric

    2011-01-01

    Background Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. Methods Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. Results Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. Conclusions Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model. PMID:22022511

  15. Multispectral optoacoustic and MRI coregistration for molecular imaging of orthotopic model of human glioblastoma.

    PubMed

    Attia, Amalina Binte Ebrahim; Ho, Chris Jun Hui; Chandrasekharan, Prashant; Balasundaram, Ghayathri; Tay, Hui Chien; Burton, Neal C; Chuang, Kai-Hsiang; Ntziachristos, Vasilis; Olivo, Malini

    2016-07-01

    Multi-modality imaging methods are of great importance in oncologic studies for acquiring complementary information, enhancing the efficacy in tumor detection and characterization. We hereby demonstrate a hybrid non-invasive in vivo imaging approach of utilizing magnetic resonance imaging (MRI) and Multispectral Optoacoustic Tomography (MSOT) for molecular imaging of glucose uptake in an orthotopic glioblastoma in mouse. The molecular and functional information from MSOT can be overlaid on MRI anatomy via image coregistration to provide insights into probe uptake in the brain, which is verified by ex vivo fluorescence imaging and histological validation. In vivo MSOT and MRI imaging of an orthotopic glioma mouse model injected with IRDye800-2DG. Image coregistration between MSOT and MRI enables multifaceted (anatomical, functional, molecular) information from MSOT to be overlaid on MRI anatomy images to derive tumor physiological parameters such as perfusion, haemoglobin and oxygenation.

  16. Generation of a syngeneic orthotopic transplant model of prostate cancer metastasis

    PubMed Central

    Ellis, Leigh; Lehet, Kristin; Ku, ShengYu; Azabdaftari, Gissou; Pili, Roberto

    2014-01-01

    Progression to metastatic disease is the primary cause of mortality in men with prostate cancer (PCa). Mouse models which progress with spontaneous metastasis are limited. Such models would allow for extensive studies of molecular mechanisms of metastasis, and more definite pre- clinical therapy trials. Orthotopic murine models have been described; however a limiting biology of these models is their lack of an intact immune system. Within, we describe the development of an androgen sensitive and castrate resistant tractable orthotopic murine syngeneic (immune competent) model of prostate cancer. Both models develop primary tumors which spontaneously progress to metastatic disease in lymph tissue. These models will allow for more complete mechanistic and therapeutic studies in a short time period. PMID:25485289

  17. Pediatric orthotopic heart transplant requiring perioperative exchange transfusion: a case report.

    PubMed

    McNeer, Brian; Dickason, Brent; Niles, Scott; Ploessl, Jay

    2004-12-01

    An 11-month-old patient with idiopathic cardiomyopathy was scheduled for orthotopic heart transplantation. A perioperative exchange transfusion was performed because of elevated panel reactive antibody levels. This process was accomplished in the operating room prior to instituting cardiopulmonary bypass using a modified cardiopulmonary bypass circuit. In preparation for the procedure, the cardiopulmonary bypass circuit was primed with washed leukocyte-filtered banked packed red blood cells, fresh-frozen plasma, albumin, and heparin. Pump prime laboratory values were normalized prior to beginning the exchange transfusion. The patient's blood was downloaded from the venous line just proximal to the venous reservoir while simultaneously transfusing the normalized prime at normothermia. Approximately 125% of the patients calculated blood volume was exchanged. This technique greatly reduces the likelihood of hyperacute rejection. The exchange transfusion process, in addition to the patient immature immune system, provides additional options in orthotopic heart transplantation for patients that may otherwise not be considered suitable candidates.

  18. Temporal characterization of lymphatic metastasis in an orthotopic mouse model of oral cancer.

    PubMed

    Szaniszlo, Peter; Fennewald, Susan M; Qiu, Suimin; Kantara, Carla; Shilagard, Tuya; Vargas, Gracie; Resto, Vicente A

    2014-11-01

    The overall mortality rate in cases of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years, mostly because of the high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiologic processes leading to lymphatic metastasis development, there is an urgent need for relevant animal models. HNSCC cell lines were implanted into the tongues of athymic nude mice. Histology, immunohistochemistry, and ex vivo 2-photon microscopy were used to evaluate tumor progress and spread. Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis. This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology. © 2014 Wiley Periodicals, Inc.

  19. Immunotherapy of HPV-associated cancer: DNA/plant-derived vaccines and new orthotopic mouse models.

    PubMed

    Venuti, Aldo; Curzio, Gianfranca; Mariani, Luciano; Paolini, Francesca

    2015-10-01

    Under the optimistic assumption of high-prophylactic HPV vaccine coverage, a significant reduction of cancer incidence can only be expected after decades. Thus, immune therapeutic strategies are needed for persistently infected individuals who do not benefit from the prophylactic vaccines. However, the therapeutic strategies inducing immunity to the E6 and/or E7 oncoprotein of HPV16 are more effective for curing HPV-expressing tumours in animal models than for treating human cancers. New strategies/technologies have been developed to improve these therapeutic vaccines. Our studies focussed on preparing therapeutic vaccines with low-cost technologies by DNA preparation fused to either plant-virus or plant-toxin genes, such as saporin, and by plant-produced antigens. In particular, plant-derived antigens possess an intrinsic adjuvant activity that makes these preparations especially attractive for future development. Additionally, discrepancy in vaccine effectiveness between animals and humans may be due to non-orthotopic localization of animal models. Orthotopic transplantation leads to tumours giving a more accurate representation of the parent tumour. Since HPV can cause cancer in two main localizations, anogenital and oropharynx area, we developed two orthotopic tumour mouse models in these two sites. Both models are bioluminescent in order to follow up the tumour growth by imaging and are induced by cell injection without the need to intervene surgically. These models were utilized for immunotherapies with genetic or plant-derived therapeutic vaccines. In particular, the head/neck orthotopic model appears to be very promising for studies combining chemo-radio-immune therapy that seems to be very effective in patients.

  20. Inferior Vena Cava Torsion and Stenosis Complicated by Compressive Pericaval Regional Ascites following Orthotopic Liver Transplantation

    PubMed Central

    Gilroy, Richard; Johnson, Philip

    2013-01-01

    Inferior vena cava (IVC) stenosis and torsion are well-described rare complications following orthotopic liver transplantation (OLT). We present a case of inferior vena cava intermittent torsion and stenosis complicated by compressive regional ascites. To the best of our knowledge, this is the second case of post-OLT regional ascites related compressive IVC stenosis reported and the first reported case of torsion complicated by regional ascites compression. PMID:24386585

  1. 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

  2. Matrine protects sinusoidal endothelial cells from cold ischemia and reperfusion injury in rat orthotopic liver transplantation.

    PubMed

    Zhu, Xinhua; Qiu, Yudong; Shi, Mingke; Ding, Yitao

    2003-01-01

    The effect of matrine on cold ischemia and reperfusion injury of sinusoidal endothelial cells (SEC) was investigated in rats using an orthotopic liver transplantation (OLT) model. Syngeneic Sprague-Dawley (SD) rats were randomly assigned to 4 groups of 32 rats: untreated group (controls), low-dose treated group, high-dose treated group, and sham operation group (normals). After 5 hr of preservation in Ringer's solution, orthotopic implantation of the donor liver was performed. At 1, 2, 4, and 24 hr after reperfusion, 6 rats from each group were killed to collect blood and to excise the median hepatic lobe; the other 8 rats were observed to assess the 1-wk survival rate post-transplantation. All transplant recipients in the untreated group (controls) died within 48 hr, mostly between 10 to 20 hr. Matrine treatment increased the 1-wk survival rate to 75% in both treated groups. Plasma levels of hyaluronic acid (HA) at 1, 2, and 4 hr post-implantation were decreased significantly by matrine treatment. The immunohistochemical expression of intercellular adhesion molecule-1 (ICAM-1) in rat liver decreased significantly in both treated groups, and the pathological changes of SEC were ameliorated. Matrine markedly inhibited the activation of Kupffer cells and their release of tumor necrosis factor (TNF). Hepatic malondialdehyde (MDA) levels and superoxide dismutase (SOD) activities were improved by matrine administration. In conclusion, matrine can protect SEC from cold ischemia and reperfusion injury after rat orthotopic liver transplantation.

  3. Reepithelialization of orthotopic tracheal allografts prevents rejection after withdrawal of immunosuppression.

    PubMed

    Genden, Eric M; Govindaraj, Satish; Chaboki, Houtan; Cleven, Heidi; Fedorova, Elena; Bromberg, Jonathan S; Mayer, Lloyd

    2005-04-01

    Prior work has demonstrated that immunosuppressed orthotopic tracheal allografts undergo progressive reepithelialization over a 48-day period with recipient-derived tracheal epithelium. We hypothesized that reepithelialization of tracheal allografts would prevent rejection after withdrawal of immunosuppression. BALB/c murine tracheal grafts were transplanted orthotopically into either syngeneic or allogeneic C57/BL6 recipients. The recipients were either not immunosuppressed, immunosuppressed with cyclosporine A (10 mg/kg per day) continuously, or immunosuppressed for 48 days and then withdrawn from immunosuppression. The grafts were assessed for acute and chronic rejection 10 days and 50 days after immunosuppression withdrawal. The immunosuppressed allograft recipients maintained a ciliated epithelium acutely and chronically after immunosuppression withdrawal. Ten days after immunosuppression withdrawal, there was a mild cellular infiltrate, which resolved 50 days after withdrawal. Electron microscopy, lymphocyte subpopulation assays, and lamina propria analysis demonstrated that immunosuppression withdrawal did not result in tracheal allograft rejection. In vitro and in vivo assessments did not demonstrate evidence of systemic or local immune tolerance. We conclude that reepithelialization of orthotopic tracheal allografts with recipient-derived mucosa prevents rejection of allograft segments. Tracheal transplantation may require only transient immunosuppression, which can be withdrawn after tracheal reepithelialization.

  4. Multimodal imaging of a humanized orthotopic model of hepatocellular carcinoma in immunodeficient mice

    PubMed Central

    Wu, Tao; Heuillard, Emilie; Lindner, Véronique; Bou About, Ghina; Ignat, Mihaela; Dillenseger, Jean-Philippe; Anton, Nicolas; Dalimier, Eugénie; Gossé, Francine; Fouré, Gael; Blindauer, Franck; Giraudeau, Céline; El-Saghire, Hussein; Bouhadjar, Mourad; Calligaro, Cynthia; Sorg, Tania; Choquet, Philippe; Vandamme, Thierry; Ferrand, Christophe; Marescaux, Jacques; Baumert, Thomas F.; Diana, Michele; Pessaux, Patrick; Robinet, Eric

    2016-01-01

    The development of multimodal strategies for the treatment of hepatocellular carcinoma requires tractable animal models allowing for advanced in vivo imaging. Here, we characterize an orthotopic hepatocellular carcinoma model based on the injection of luciferase-expressing human hepatoma Huh-7 (Huh-7-Luc) cells in immunodeficient mice. Luciferase allows for an easy repeated monitoring of tumor growth by in vivo bioluminescence. The intrahepatic injection was more efficient than intrasplenic or intraportal injection in terms of survival, rate of orthotopic engraftment, and easiness. A positive correlation between luciferase activity and tumor size, evaluated by Magnetic Resonance Imaging, allowed to define the endpoint value for animal experimentation with this model. Response to standard of care, sorafenib or doxorubicin, were similar to those previously reported in the literature, with however a strong toxicity of doxorubicin. Tumor vascularization was visible by histology seven days after Huh-7-Luc transplantation and robustly developed at day 14 and day 21. The model was used to explore different imaging modalities, including microtomography, probe-based confocal laser endomicroscopy, full-field optical coherence tomography, and ultrasound imaging. Tumor engraftment was similar after echo-guided intrahepatic injection as after laparotomy. Collectively, this orthotopic hepatocellular carcinoma model enables the in vivo evaluation of chemotherapeutic and surgical approaches using multimodal imaging. PMID:27739457

  5. Antitumor effects of exogenous ganglioside GM3 on bladder cancer in an orthotopic cancer model.

    PubMed

    Wang, Hua; Isaji, Tomoya; Satoh, Makoto; Li, Dechuan; Arai, Yoichi; Gu, Jianguo

    2013-01-01

    To investigate the therapeutic effects of exogenous gangliosides GM3 on human bladder cancer cell lines and the severe combined immunodeficiency mouse model of orthotopic bladder cancer. Human bladder cancer cell lines YTS-1, T24, 5637, and KK47 were used in the study. In vitro cytotoxicity of GM3 was assessed using the cell counting kit-8. Cell adhesion was determined using a spreading assay. Phosphorylation of epidermal growth factor receptor was determined by Western blotting. In vivo, the orthotopic bladder cancer model was established using severe combined immunodeficiency mice and GM3 was administered intravesically by way of a transurethral catheter. GM3 inhibited the proliferation of all the bladder cancer cell lines tested. The addition of GM3 decreased cell adhesion and epidermal growth factor-dependent phosphorylation of epidermal growth factor receptor. Direct instillation of GM3 into the bladder of the orthotopic model significantly inhibited tumor growth. Our results suggest exogenous GM3 as a potential therapeutic agent for treating bladder cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Improvements of surgical techniques in a rat model of an orthotopic single lung transplant

    PubMed Central

    2013-01-01

    Background Rats are widely used in modeling orthotopic lung transplantation. Recently the introduction of the cuff technique has greatly facilitated the anastomosing procedure used during the transplant. However, the procedure is still associated with several drawbacks including twisting of blood vessels, tissue injury and the extensive time required for the procedure. This study was performed to optimize the model of rat lung transplantation (LT) with the cuff technique. Methods A total of 42 adult Lewis rats received orthotopic LT with our newly modified procedures. The modified procedures were based on the traditional procedure and incorporated improvements involving orotracheal intubation; a cuff without a tail; conservative dissection in the hilum; preservation of the left lung during anastomosis; successive anatomizing of the bronchus, the pulmonary vein, and the pulmonary artery; and one operator. Results Transplants were performed in 42 rats with a successful rate of 95.23% (40/42). The mean duration for the complete procedure was 82.93 ± 14.56 minutes. All anastomoses were completed in one attempt without vessel laceration, twisting or angulation. In our study, two animals died within three days and one animal died ten days after the operation. All grafts were well inflated with robust blood perfusion and functioned normally as demonstrated by blood gas analysis. Conclusions We have developed a modified orthotopic LT technique that can be easily performed while overcoming major drawbacks. The modified technique has many advantages, such as easy graft implanting, shortened operation time, fewer complications and high reproducibility. PMID:23295132

  7. Necrotizing encephalitis caused by disseminated Aspergillus infection after orthotopic liver transplantation.

    PubMed

    Barrera-Herrera, Luis E; Vera, Alonso; Álvarez, Johanna; Lopez, Rocio

    2015-01-01

    Liver transplantation is the only available treatment for some patients with end-stage liver disease. Despite reduction in mortality rates due to advances related to surgical techniques, intensive medical management and immunosuppressive therapy, invasive fungal infections remain a serious complication in orthotopic liver transplantation. We report the case of an 18-year-old male diagnosed with autoimmune cirrhosis in 2009 who was assessed and listed for liver transplantation for massive variceal hemorrhage. One year after listing a successful orthotopic liver transplantation was performed. Uneventful early recovery was achieved; however, he developed pulmonary and neurological Aspergillus infection 23 and 40 days after surgery, respectively. Antibiotic therapy with voriconazole and amphotericin was started early, with no major response. Neuroimaging revealed multiple right frontal and right parietal lesions with perilesional edema; surgical management of the brain abscesses was performed. A biopsy with periodic acid-Schiff and Gomori stains revealed areas with mycotic microorganisms morphologically consistent with Aspergillus, later confirmed by culture. The patient developed necrotizing encephalitis secondary to aspergillosis and died. Necrotizing encephalitis as a clinical presentation of Aspergillus infection in an orthotopic liver transplant is not common, and even with adequate management, early diagnosis and prompt antifungal treatment, mortality rates remain high.

  8. Erection- and ejaculation-preserving cystectomy with orthotopic urinary diversion: is it feasible?

    PubMed

    Girgin, Cengiz; Oder, Mehmet; Sahin, M Oguz; Sezer, Akif; Berkmen, Serdar; Aydin, Rusen; Dincel, Cetin

    2006-01-01

    Nerve-sparing techniques to preserve sexual function in men undergoing cystoprostatectomy have been documented by different centers. We evaluated the results of the first 4 erection- and ejaculation-preserving cystectomies performed in our department. The ages of patients ranged between 36 and 43 years. In all cases, patients wished to maintain sexual function. Of the cases, 3 patients had pT1 G3 transitional cell carcinoma (TCC) refractory to treatment and one had pT2a adenocarcinoma of the bladder. Extirpation of the bladder and anterior proximal prostate en bloc with preservation of the vasa deferentia, seminal vesicles, posterior prostate, and neurovascular bundles was performed after pelvic lymphadenectomy. W-ileal neobladder was performed by using 40 cm of ileum. All patients had erections at the third month. Of the cases, 2 patients had antegrade ejaculation. The ejaculate volumes were 0.8 and 1.2 mL in patients with antegrade ejaculation. Patients in the other cases had retrograde ejaculation. All patients were continent day and night. We started clean intermittent catheterization in 1 case because of residual urine. There were no local recurrences. One patient with TCC died because of systemic disease in the postoperative 32nd month. The most important drawback of potent cases in cystectomy decision is erectile dysfunction after radical cystectomy. This drawback causes delay of the operation and sometimes mortality. As was the case in other reports, our limited number of cases in this study demonstrated that erection and ejaculation could be preserved in selected groups of patients.

  9. Radiation Source Replacement Workshop

    SciTech Connect

    Griffin, Jeffrey W.; Moran, Traci L.; Bond, Leonard J.

    2010-12-01

    This report summarizes a Radiation Source Replacement Workshop in Houston Texas on October 27-28, 2010, which provided a forum for industry and researchers to exchange information and to discuss the issues relating to replacement of AmBe, and potentially other isotope sources used in well logging.

  10. MDCA Needle 1 Replacement

    NASA Image and Video Library

    2013-04-22

    ISS035-E-025557(22 April 2013) ---Multi-user Droplet Combustion Apparatus (MDCA) Hardware Replacement: Cassidy accessed the Combustion Integration Rack (CIR) Combustion Chamber and removed the MDCA Chamber Insert Assembly (CIA). He then replaced the MDCA Needle 1 due to a fuel line that was damaged during previous activities when the MDCA CIA was being removed from the Combustion Chamber.

  11. 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

  12. 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

  13. The relationship between physical activity and heart rate variability in orthotopic heart transplant recipients.

    PubMed

    Lai, Fu-Chih; Chang, Wen-Lin; Jeng, Chii

    2012-11-01

    To investigate the relationship between physical activity and heart rate variability in orthotopic heart transplant recipients, to compare the difference in heart rate variability between patients one year after orthotopic heart transplant and healthy adults matched to the heart transplant recipients in terms of age, gender and physical activity levels. Although physical activity affects the heart rate variability in patients with heart disease, there is a paucity of literature discussing the correlation between physical activity and heart rate variability among heart transplant recipients. This was a descriptive and cross-sectional study. A total of 120 eligible subjects were divided into the orthotopic heart transplant recipient group (n = 60) and the healthy adult group (n = 60). The Seven-day Physical Activity Recall questionnaire was used to record the subjects' amount of physical activity per week. Heart rate variety parameters were determined by separate frequency domain components. Results indicated heart transplant recipients' heart rate variety was significantly lower than that of healthy adults in terms of mean, sdr, total power (ms(2)), low frequency (ms(2)), low frequency (nu), high frequency (ms(2)) and low frequency/high frequency. Heart transplant recipients' heart rate variety including total power (ms(2)), low frequency (ms(2)) and high frequency (ms(2)) was 18·2, 2 and 7·2% of healthy controls, respectively; the amount of absolutely and relatively moderate physical activity was positively related to high frequency (ms(2)) and high frequency (nu), but was negatively related to low frequency/high frequency. High frequency (nu) increases while the total amount of weekly physical activity increases. Results confirmed that the more the moderate physical activity performed, the better the patient's heart rate variability. We suggest that clinical care providers have to encourage heart transplant recipients to engage in moderate physical activity.

  14. In vivo echographic evidence of tumoral vascularization and microenvironment interactions in metastatic orthotopic human neuroblastoma xenografts.

    PubMed

    Joseph, Jean-Marc; Gross, Nicole; Lassau, Nathalie; Rouffiac, Valérie; Opolon, Paule; Laudani, Lysiane; Auderset, Katya; Geay, Jean-François; Mühlethaler-Mottet, Annick; Vassal, Gilles

    2005-03-01

    Human neuroblastoma (NB) is the second most frequent solid tumor of childhood and represents a highly heterogeneous disease at clinical and biologic levels. Little progress has been made to improve the poor prognosis of patients with high-stage NB. Tumor progression and metastatic dissemination still represent major obstacles to the successful treatment of advanced stage disease. In order to develop and evaluate new, targeted, therapeutic strategies, fully defined and biologically relevant in vivo models of NB are strongly needed. We have developed an orthotopic model of metastatic human NB in the nude mouse, using 2 well-characterized NB cell lines. Tumor growth, vascular properties and metastatic patterns were investigated using a sensitive and newly developed in vivo echographic technology in addition to immunohistochemistry and PCR analyses. Results show that implantation of low numbers of NB cells directly into the adrenal gland of nude mice resulted in rapid and homogeneous tumor growth without tumor morbidity. Nude mice were shown to rapidly develop highly vascularized adrenal tumors that selectively metastasized to the liver and bone marrow. In addition, the newly formed mouse vessels in orthotopic but not in heterotopic tumors, were found to express the highly angiogenic alphavbeta3 integrin marker, indicating the development of a truly malignant neovasculature in orthotopic conditions only. This observation confirms the impact of the regional microenvironment on tumor biology and suggests the existence of cross-talk with the tumor cells. In conclusion, such model faithfully reproduces the growth, vascular and metastatic patterns as observed in patients. It therefore represents a powerful and biologically relevant tool to improve our understanding of the biology of NB and to develop and assess new antiangiogenic and metastasis-targeted therapies. (c) 2004 Wiley-Liss, Inc.

  15. 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

  16. Establishment of a dual-color fluorescence tracing orthotopic transplantation model of hepatocellular carcinoma.

    PubMed

    Chen, Qian; Wang, Xiaoping; Wu, Hao; Wang, Hui; Zhu, Mingao; Wang, Roushu; Wu, Ying; Zhang, Luyao; Meng, Qiao; Song, Ranran; Zhuang, Zhixiang; Huang, Qiang

    2016-01-01

    Different experimental models of hepatocellular carcinoma (HCC) have been used to investigate the biological mechanisms of hepatocarcinogenesis and its progression. However, previous studies have highlighted the difficulty of distinguishing between the tumor cells and stroma in experimental models of HCC. Therefore the aim of the present study was to establish a red‑green dual‑color fluorescence tracing orthotopic transplantation model of HCC, and investigate its practical values. Stable high red fluorescent protein (RFP)‑expressing HepG2 human hepatoma cells and Hepa1‑6 mice hepatoma cells were injected into the right liver lobe of green fluorescent protein‑expressing nude mice. The growth and metastasis of the tumors were visualized using a whole‑body in vivo fluorescence imaging system in real time. HCC tissues were extracted from tumor‑bearing mice, and cut into 5‑µm serial frozen slices. The organizational structure of the transplanted tumors was observed under a microscope. A dual‑color fluorescence tracing orthotopic transplantation tumor model of HCC was successfully established with a success rate of 100%. The growth and metastasis of the tumors were visualized at each stage of development in the tumor‑bearing mice. Tumor cells with red fluorescence and host cells with green fluorescence were identified to merge in the reconstruction region of tumor tissue. The invasion, migration, and cell fusion between tumor and host cells was observed clearly. The dual‑color fluorescence tracing orthotopic transplantation model of HCC was determined to be a stable and reliable method for tracking tumor progression. Mutual interactions between hepatoma cells and host tissues may be observed directly using this model, further elucidating the development of the tumor microenvironment.

  17. Intrahepatic Tissue Implantation Represents a Favorable Approach for Establishing Orthotopic Transplantation Hepatocellular Carcinoma Mouse Models

    PubMed Central

    Zuo, Bingfeng; Gao, Xianjun; Zhang, Ti; Du, Zhi; Wu, Chenxuan; Yin, HaiFang

    2016-01-01

    Mouse models are commonly used for studying hepatocellular carcinoma (HCC) biology and exploring new therapeutic interventions. Currently three main modalities of HCC mouse models have been extensively employed in pre-clinical studies including chemically induced, transgenic and transplantation models. Among them, transplantation models are preferred for evaluating in vivo drug efficacy in pre-clinical settings given the short latency, uniformity in size and close resemblance to tumors in patients. However methods used for establishing orthotopic HCC transplantation mouse models are diverse and fragmentized without a comprehensive comparison. Here, we systemically evaluate four different approaches commonly used to establish HCC mice in preclinical studies, including intravenous, intrasplenic, intrahepatic inoculation of tumor cells and intrahepatic tissue implantation. Four parameters—the latency period, take rates, pathological features and metastatic rates—were evaluated side-by-side. 100% take rates were achieved in liver with intrahepatic, intrasplenic inoculation of tumor cells and intrahepatic tissue implantation. In contrast, no tumor in liver was observed with intravenous injection of tumor cells. Intrahepatic tissue implantation resulted in the shortest latency with 0.5cm (longitudinal diameter) tumors found in liver two weeks after implantation, compared to 0.1cm for intrahepatic inoculation of tumor cells. Approximately 0.1cm tumors were only visible at 4 weeks after intrasplenic inoculation. Uniform, focal and solitary tumors were formed with intrahepatic tissue implantation whereas multinodular, dispersed and non-uniform tumors produced with intrahepatic and intrasplenic inoculation of tumor cells. Notably, metastasis became visible in liver, peritoneum and mesenterium at 3 weeks post-implantation, and lung metastasis was visible after 7 weeks. T cell infiltration was evident in tumors, resembling the situation in HCC patients. Our study

  18. Effect of dual treatment with SDF-1 and BMP-2 on ectopic and orthotopic bone formation.

    PubMed

    Lee, Chang-Hwan; Jin, Myoung Uk; Jung, Hong-Moon; Lee, Jung-Tae; Kwon, Tae-Geon

    2015-01-01

    The potent stem cell homing factor stromal cell-derived factor-1 (SDF-1) actively recruits mesenchymal stem cells from circulation and from local bone marrow. It is well established that bone morphogenetic protein-2 (BMP-2) induces ectopic and orthotopic bone formation. However, the exact synergistic effects of BMP-2 and SDF-1 in ectopic and orthotopic bone regeneration models have not been fully investigated. The purpose of this study was to evaluate the potential effects of simultaneous SDF-1 and BMP-2 treatment on bone formation. Various doses of SDF-1 were loaded onto collagen sponges with or without BMP-2.These sponges were implanted into subcutaneous pockets and critical-size calvarial defects in C57BL/6 mice. The specimens were harvested 4 weeks post-surgery and the degree of bone formation in specimens was evaluated by histomorphometric and radiographic density analyses. Osteogenic potential and migration capacity of mesenchymal cells and capillary tube formation of endothelial cells following dual treatment with SDF-1 and BMP-2 were evaluated with in vitro assays. SDF-1-only-treated implants did not yield significant in vivo bone formation and SDF-1 treatment did not enhance BMP-2-induced ectopic and orthotopic bone regeneration. In vitro experiments showed that concomitant use of BMP-2 and SDF-1 had no additive effect on osteoblastic differentiation, cell migration or angiogenesis compared to BMP-2 or SDF-1 treatment alone. These findings imply that sequence-controlled application of SDF-1 and BMP-2 must be further investigated for the enhancement of robust osteogenesis in bone defects.

  19. Effect of Dual Treatment with SDF-1 and BMP-2 on Ectopic and Orthotopic Bone Formation

    PubMed Central

    Jung, Hong-Moon; Lee, Jung-Tae; Kwon, Tae-Geon

    2015-01-01

    Purposes The potent stem cell homing factor stromal cell-derived factor-1 (SDF-1) actively recruits mesenchymal stem cells from circulation and from local bone marrow. It is well established that bone morphogenetic protein-2 (BMP-2) induces ectopic and orthotopic bone formation. However, the exact synergistic effects of BMP-2 and SDF-1 in ectopic and orthotopic bone regeneration models have not been fully investigated. The purpose of this study was to evaluate the potential effects of simultaneous SDF-1 and BMP-2 treatment on bone formation. Materials and Methods Various doses of SDF-1 were loaded onto collagen sponges with or without BMP-2.These sponges were implanted into subcutaneous pockets and critical-size calvarial defects in C57BL/6 mice. The specimens were harvested 4 weeks post-surgery and the degree of bone formation in specimens was evaluated by histomorphometric and radiographic density analyses. Osteogenic potential and migration capacity of mesenchymal cells and capillary tube formation of endothelial cells following dual treatment with SDF-1 and BMP-2 were evaluated with in vitro assays. Results SDF-1-only-treated implants did not yield significant in vivo bone formation and SDF-1 treatment did not enhance BMP-2-induced ectopic and orthotopic bone regeneration. In vitro experiments showed that concomitant use of BMP-2 and SDF-1 had no additive effect on osteoblastic differentiation, cell migration or angiogenesis compared to BMP-2 or SDF-1 treatment alone. Conclusions These findings imply that sequence-controlled application of SDF-1 and BMP-2 must be further investigated for the enhancement of robust osteogenesis in bone defects. PMID:25781922

  20. Honokiol thwarts gastric tumor growth and peritoneal dissemination by inhibiting Tpl2 in an orthotopic model.

    PubMed

    Pan, Hung-Chuan; Lai, De-Wei; Lan, Keng-Hsin; Shen, Chin-Chang; Wu, Sheng-Mao; Chiu, Chien-Shan; Wang, Keh-Bin; Sheu, Meei-Ling

    2013-11-01

    Honokiol is known to suppress the growth of cancer cells; however, to date, its antiperitoneal dissemination effects have not been studied in an orthotopic mouse model. In the present study, we evaluated the antiperitoneal dissemination potential of Honokiol in an orthotopic mouse model and assessed associations with tumor growth factor-β1 (TGFβ1) and cells stimulated by a carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Our results demonstrate that tumor growth, peritoneal dissemination and peritoneum or organ metastasis of orthotopically implanted MKN45 cells were significantly decreased in Honokiol-treated mice and that endoplasmic reticulum (ER) stress was induced. Honokiol-treated tumors showed increased epithelial signatures such as E-cadherin, cytokeratin-18 and ER stress marker. In contrast, decreased expression of vimentin, Snail and tumor progression locus 2 (Tpl2) was also noted. TGFβ1 and MNNG-induced downregulation of E-cadherin and upregulation of Tpl2 were abrogated by Honokiol treatment. The effect of Tpl2 inhibition in cancer cells or endothelial cells was associated with inactivation of CCAAT/enhancer binding protein B, nuclear factor kappa-light-chain-enhancer of activated B cell and activator protein-1 and suppression of vascular endothelial growth factor. Inhibition of Tpl2 in gastric cancer cells by small interfering RNA or pharmacological inhibitor was found to effectively reduce growth ability and vessel density in vivo. Honokiol-induced reversal of epithelial-to-mesenchymal transition (EMT) and ER stress-induced apoptosis via Tp12 may involve the paralleling processes. Taken together, our results suggest that the therapeutic inhibition of Tpl2 by Honokiol thwarts both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

  1. 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

  2. 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.

  3. Detection of rejection of canine orthotopic cardiac allografts with indium-111 lymphocytes and gamma scintigraphy

    SciTech Connect

    Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.

    1988-07-01

    Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed.

  4. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.

    PubMed

    Jones, Lee W; Antonelli, Jodi; Masko, Elizabeth M; Broadwater, Gloria; Lascola, Christopher D; Fels, Diane; Dewhirst, Mark W; Dyck, Jason R B; Nagendran, Jeevan; Flores, Catherine T; Betof, Allison S; Nelson, Erik R; Pollak, Michael; Dash, Rajesh C; Young, Martin E; Freedland, Stephen J

    2012-07-01

    The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

  5. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer

    PubMed Central

    Antonelli, Jodi; Masko, Elizabeth M.; Broadwater, Gloria; Lascola, Christopher D.; Fels, Diane; Dewhirst, Mark W.; Dyck, Jason R. B.; Nagendran, Jeevan; Flores, Catherine T.; Betof, Allison S.; Nelson, Erik R.; Pollak, Michael; Dash, Rajesh C.; Young, Martin E.; Freedland, Stephen J.

    2012-01-01

    The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6–8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 105) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with “productive” tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer. PMID:22604887

  6. Simultaneous bilateral multipuncture tubeless percutaneous nephrolithotomy in patient with orthotopic bladder substitution.

    PubMed

    Al-Kohlany, Khaled M; Al-Badany, Tawfik H; El-Nono, Ibrahim H

    2007-06-01

    We report the successful treatment of a patient that presented with bladder tumor, bilateral multiple renal stones, right lower ureteral stone, and bilateral hydroureteronephrosis with progressively rising serum creatinine. Initially, he was managed by drainage of the upper tract by left percutaneous nephrostomy tube until serum creatinine dropped to normal value then he was managed by radical cystectomy and orthotopic bladder substitution. Three weeks later, he was subjected to simultaneous bilateral multi-puncture tubeless percutaneous nephrolithotomy. In addition, we report on the feasibility of opacification of the collecting system via ascending pouchogram by direct passage of the dye through the directly implanted ureters thus avoiding intravenous contrast injection.

  7. 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

  8. Orthotopic mouse models of tumor metastasis expressing fluorescent reporters produce imageable circulating tumor cells.

    PubMed

    Hoffman, Robert M

    2014-12-01

    Circulating tumor cells (CTC) are of high importance, since they are potential metastatic precursors and are readily available for prognostic analysis and treatment testing. In this review, we demonstrate the great power that green fluorescent protein (GFP) labeling and orthotopic mouse models of cancer confer to the study of CTCs for isolation and characterization, including metastatic testing in mice and the chick embryo as well as drug response testing in vitro. We also describe a facile method to label patient CTCs ex vivo using a telomerase-expressing GFP-containing adenovirus that will allow the CTC studies described in this review to be translated clinically.

  9. Ankle replacement - discharge

    MedlinePlus

    ... ankle replacement. Your surgeon removed and reshaped damaged bones, and put in an artificial ankle joint. You received pain medicine and were shown how to treat swelling around your new ankle joint.

  10. Carbohydrates as Fat Replacers.

    PubMed

    Peng, Xingyun; Yao, Yuan

    2017-02-28

    The overconsumption of dietary fat contributes to various chronic diseases, which encourages attempts to develop and consume low-fat foods. Simple fat reduction causes quality losses that impede the acceptance of foods. Fat replacers are utilized to minimize the quality deterioration after fat reduction or removal to achieve low-calorie, low-fat claims. In this review, the forms of fats and their functions in contributing to food textural and sensory qualities are discussed in various food systems. The connections between fat reduction and quality loss are described in order to clarify the rationales of fat replacement. Carbohydrate fat replacers usually have low calorie density and provide gelling, thickening, stabilizing, and other texture-modifying properties. In this review, carbohydrates, including starches, maltodextrins, polydextrose, gums, and fibers, are discussed with regard to their interactions with other components in foods as well as their performances as fat replacers in various systems.

  11. Knee joint replacement - slideshow

    MedlinePlus

    ... presentations/100088.htm Knee joint replacement - series—Normal anatomy To use the sharing features on this page, ... Bethesda, MD 20894 U.S. Department of Health and Human Services National Institutes of Health Page last updated: ...

  12. Replacing a Missing Tooth

    MedlinePlus

    ... vessels in the tooth pulps are rather large. Drilling down these teeth for crowns may expose the ... porcelain replacement tooth is held in place by metal extensions cemented to the backs of the adjacent ...

  13. Artificial Disc Replacement

    MedlinePlus

    ... treat this condition, alternatives to disc replacement include fusion, nonoperative care or no treatment. Typically, surgery is ... operative treatment for disc pain has been spinal fusion. This is a surgical procedure in which disc ...

  14. Hormone Replacement Therapy

    MedlinePlus

    ... before and during menopause, the levels of female hormones can go up and down. This can cause ... hot flashes and vaginal dryness. Some women take hormone replacement therapy (HRT), also called menopausal hormone therapy, ...

  15. Artificial Disc Replacement

    MedlinePlus

    ... also disc replacements designed for use in the cervical spine (the neck). These devices have only been used ... of your spine increases the risk of significant injury during this type of spinal surgery. Back pain ...

  16. Nonlinear Pixel Replacement Estimation.

    DTIC Science & Technology

    1986-04-01

    Systems Command _________ _______________________ _____ 6e ADDRESS IC,,, Sra,. and ZIP Co~ de , 10 SOURCE Of FUNDING NUMBERS% RORMELEMENT NO PROJECT NO... de - scribed, this method does not replace array elements with computed values, but rather replaces them with one of the nine original pixel values. The...8217, gmx . NOISE PStd dev=’. sd call exit end include ’mathfunc For/nolist’ C-9 c biweighted 3xZ3 filter compute weighted mean from input iara subroutine

  17. Androgen replacement for women.

    PubMed Central

    Basson, R.

    1999-01-01

    OBJECTIVES: To determine whether a postmenopausal syndrome comprising specific changes in sexual desire and response associated with low free testosterone exists. To determine whether this syndrome is ameliorated by testosterone replacement. QUALITY OF EVIDENCE: Literature documenting that replacement of physiological levels of testosterone is beneficial and safe is scant. Only one randomized prospective blinded study examines sexual outcome in detail. MAIN MESSAGE: Testosterone is an important metabolic and sex hormone produced by the ovary throughout life. The variable reduction in ovarian testosterone production coincident with menopause is sometimes associated with a syndrome of specific changes in sexual desire and sexual response. Estrogen deficiency also impairs sexual response, but its replacement will not improve and might exacerbate sexual symptoms from androgen loss. Diagnosis of androgen deficiency is clinical, based on accurate assessment of a woman's sexual status before and after menopause and only confirmed (rather than diagnosed) by a low level of free testosterone. Partial androgen replacement restores much of the sexual response and facilitates sexual desire that is triggered by external cues. Avoiding supraphysiological levels of testosterone lessens risk of masculinization. Avoiding alkylated testosterone lessens hepatic or lipid impairment. CONCLUSION: Further prospective randomized studies of replacement of physiological levels of testosterone in women with androgen deficiency syndrome are needed, using formulations of testosterone available in Canada. The consistency of sexual changes, the associated personal and relationship distress, together with our clinical experience of the gratifying response to physiological replacement, make further studies urgently needed. PMID:10509222

  18. Adenoviral targeting of malignant melanoma for fluorescence-guided surgery prevents recurrence in orthotopic nude-mouse models

    PubMed Central

    Yano, Shuya; Takehara, Kiyoto; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Bouvet, Michael; Fujiwara, Toshiyoshi; Hoffman, Robert M.

    2016-01-01

    Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. PMID:26701857

  19. Is severe pulmonary hypertension a contraindication for orthotopic heart transplantation? Not any more.

    PubMed

    Kettner, J; Dorazilová, Z; Netuka, I; Malý, J; Al-Hiti, H; Melenovský, V; Skalský, I; Říha, H; Málek, I; Kautzner, J; Pirk, J

    2011-01-01

    Pulmonary hypertension (PH) unresponsive to pharmacological intervention is considered a contraindication for orthotopic heart transplantation (OHTX) due to risk of postoperative right-heart failure. In this prospective study, we describe our experience with a treatment strategy of improving severe PH in heart transplant candidates by means of ventricular assist device (VAD) implantation and subsequent OHTX. In 11 heart transplantation candidates with severe PH unresponsive to pharmacological intervention we implanted VAD with the aim of achieving PH to values acceptable for OHTX. In all patients we observed significant drop in pulmonary pressures, PVR and TPG (p < 0.001 for all) 3 months after VAD implantation to values sufficient to allow OHTX. Seven patients underwent transplantation (mean duration of support 216 days) while none of patients suffered right-side heart failure in postoperative period. Two patients died after transplantation and five patients are living in very good condition with a mean duration of 286 days after OHTX. In our opinion, severe PH is not a contraindication for orthotopic heart transplantation any more.

  20. Longterm outcomes of auxiliary partial orthotopic liver transplantation in preadolescent children with fulminant hepatic failure.

    PubMed

    Weiner, Joshua; Griesemer, Adam; Island, Eddie; Lobritto, Steven; Martinez, Mercedes; Selvaggi, Gennaro; Lefkowitch, Jay; Velasco, Monica; Tryphonopoulos, Panagiotis; Emond, Jean; Tzakis, Andreas; Kato, Tomoaki

    2016-04-01

    By preserving part of the native liver, auxiliary partial orthotopic liver transplantation (APOLT) provides the advantage of potential immunosuppression (ISP) withdrawal if the native liver recovers but has had limited acceptance, especially in the United States, due to technical complications and low rates of native liver regeneration. No previous study has evaluated APOLT specifically for preadolescent children with fulminant hepatic failure (FHF). This population might benefit especially based on greater capacity for liver regeneration. Data from 13 preadolescent children who underwent APOLT were compared to 13 matched controls who underwent orthotopic liver transplantation (OLT) for FHF from 1996 to 2013. There were no significant differences in patient demographics or survival between the 2 groups. However, all surviving OLT recipients (10/13) remain on ISP, while all but 1 surviving APOLT recipient (12/13) showed native liver regeneration, and the first 10 recipients (76.9%) are currently off ISP with 2 additional patients currently weaning. In our experience, APOLT produced excellent survival and high rates of native liver regeneration in preadolescent children with FHF. This represents the largest series to date to report such outcomes. Liberating these children from lifelong ISP without the downside of increased surgical morbidity makes APOLT an attractive alternative. In conclusion, we therefore propose that, with the availability of technical expertise and with the technical modifications above, APOLT for FHF should be strongly considered for preteenage children with FHF.

  1. 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.

  2. Bioluminescence Imaging of Angiogenesis in a Murine Orthotopic Pancreatic Cancer Model

    PubMed Central

    Chen, Monica; Mojadidi, Michelle; Hines, O. Joe; Reber, Howard A.; Eibl, Guido

    2010-01-01

    Purpose Angiogenesis is essential for physiological processes as well as for carcinogenesis. New approaches to cancer therapy include targeting angiogenesis. One target is VEGF-A and its receptor VEGFR2. In this study, we sought to investigate pancreatic cancer angiogenesis in a genetically modified VEGFR2-luc-KI mouse. Procedures Live in vivo bioluminescence imaging of angiogenesis was performed continuously until sacrifice in subcutaneous tumors as well as in orthotopically transplanted tumors. Tumor tissue was immunostained for CD-31 and VEGFR2. Results Peritumoral angiogenesis measured by light emission was detected beginning at week 3 following subcutaneous injection. In the orthotopic model, light emission began at day 4, which likely corresponds to wound healing, and continued throughout the experimental period during tumor growth. Peritumoral CD-31 vessel- and VEGFR2-staining were positive. Conclusions The VEGFR2-luc-KI mouse is a valuable tool to demonstrate tumor angiogenesis and seems to be suitable to evaluate anti-angiogenic approaches in pancreatic cancer. PMID:20376570

  3. Orthotopic liver transplantation in fulminant and subfulminant hepatitis. The Paul Brousse experience.

    PubMed Central

    Bismuth, H; Samuel, D; Castaing, D; Adam, R; Saliba, F; Johann, M; Azoulay, D; Ducot, B; Chiche, L

    1995-01-01

    OBJECTIVE: The authors report on the experience of orthotopic liver transplantation in fulminant hepatitis at Paul Brousse Hospital. SUMMARY BACKGROUND DATA: Liver transplantation is a breakthrough in the treatment of patients with fulminant hepatitis. However, the indications, the timing for transplantation, the type of transplantation, and the use of ABO incompatible grafts in this setting still are debated. METHODS: Transplantation was indicated in patients with confusion or coma and factor V less than 20%, younger than 30 years of age, and confusion or coma and factor V less than 30% older than 30 years of age. RESULTS: Among 139 patients who met the aforementioned criteria for transplantation, 1 recovered, 22 died before transplantation, and 116 underwent transplants with a 1-year survival of 68%. Survival was 83% in patients with grade 1 and 2 comas at transplantation versus 56% (p < 0.001) in those with grade 3 comas; it was 51% versus 81% (p < 0.001) in those transplanted with high risk (ABO-incompatible, split, or steatotic) and low-risk grafts, respectively. In a multivariate analysis, steatotic and partial grafts were predictive of poorer patient survival, and ABO incompatibility was predictive of poorer graft survival. CONCLUSIONS: Orthotopic liver transplantation is an effective treatment in fulminant hepatitis. Use of high-risk grafts permitted transplantation of 83% of patients, but was responsible for higher mortality. PMID:7639578

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

    SciTech Connect

    Sochman, Jan; Peregrin, Jan H.; Pulda, Zdenek; Pavcnik, Dusan; Uchida, Barry T.; Timmermans, Hans A.; Roesch, Josef

    2010-04-15

    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 period 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.

  5. 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

  6. Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.

    PubMed

    Braekeveldt, Noémie; Wigerup, Caroline; Tadeo, Irene; Beckman, Siv; Sandén, Caroline; Jönsson, Jimmie; Erjefält, Jonas S; Berbegall, Ana P; Börjesson, Anna; Backman, Torbjörn; Øra, Ingrid; Navarro, Samuel; Noguera, Rosa; Gisselsson, David; Påhlman, Sven; Bexell, Daniel

    2016-06-01

    Treatment of high-risk childhood neuroblastoma is a clinical challenge which has been hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  7. Neuroblastoma patient-derived orthotopic xenografts retain metastatic patterns and geno- and phenotypes of patient tumours.

    PubMed

    Braekeveldt, Noémie; Wigerup, Caroline; Gisselsson, David; Mohlin, Sofie; Merselius, My; Beckman, Siv; Jonson, Tord; Börjesson, Anna; Backman, Torbjörn; Tadeo, Irene; Berbegall, Ana P; Ora, Ingrid; Navarro, Samuel; Noguera, Rosa; Påhlman, Sven; Bexell, Daniel

    2015-03-01

    Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers neural cell adhesion molecule, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  8. 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

  9. Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model.

    PubMed

    Chen, Xiaoyun; Wang, Jian; Cao, Ziquan; Hosaka, Kayoko; Jensen, Lasse; Yang, Huasheng; Sun, Yuping; Zhuang, Rujie; Liu, Yizhi; Cao, Yihai

    2015-07-14

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

  10. Establishment of a syngeneic orthotopic model of prostate cancer in immunocompetent rats

    PubMed Central

    Suzuki, Shugo; Naiki-Ito, Aya; Kuno, Toshiya; Punfa, Wanisa; Long, Ne; Kato, Hiroyuki; Inaguma, Shingo; Komiya, Masami; Shirai, Tomoyuki; Takahashi, Satoru

    2014-01-01

    We previously established 3 cell lines (PLS10, PLS20 and PLS30) from a chemically-induced prostate carcinoma in F344 rats, and demonstrated high potential for metastasis in nude mice. In the present study, we investigated the feasibility of establishing an orthotopic model using the 3 rat prostate cancer cell lines in immunocompetent rats with the aim of resolving species-mismatch problems and defects of immune systems. The PLS10, PLS20 and PLS30 cell lines were injected into the ventral prostates of 6-week-old rats, which were then sacrificed at experimental weeks 4 and 8. Tumor mass formation was found in rats with PLS10, but not in those with PLS20 or PLS30. Additionally, metastatic carcinomas could be detected in lymph nodes and lungs of PLS10-inoculated rats. Genetic analysis demonstrated K-ras gene mutations in PLS10 and PLS20, but not in PLS30 cells. There were no mutations in p53 and KLF6. In conclusion, we established a syngeneic orthotopic model for prostate cancer in immunocompetent rats simulating human castration-resistant prostate cancer (CRPC), which should prove useful for development and validation of therapeutic agents, especially with immunotherapy. PMID:26023257

  11. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus-Seropositive Patients.

    PubMed

    Conte, Antonio Hernandez; Kittleson, Michelle M; Dilibero, Deanna; Hardy, W David; Kobashigawa, Jon A; Esmailian, Fardad

    2016-02-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus-accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

  12. Successful Orthotopic Heart Transplantation and Immunosuppressive Management in 2 Human Immunodeficiency Virus–Seropositive Patients

    PubMed Central

    Kittleson, Michelle M.; Dilibero, Deanna; Hardy, W. David; Kobashigawa, Jon A.; Esmailian, Fardad

    2016-01-01

    Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation. PMID:27047290

  13. Navigated unicompartmental knee replacement.

    PubMed

    Jenny, Jean-Yves

    2008-06-01

    Computer-aided systems have been developed recently to improve the precision of implantation of unicompartmental knee replacement (UKR) or total knee replacement. Minimal invasive techniques have been developed to decrease the surgical trauma related to the prosthesis implantation. However, there might be a concern about the potential of minimal invasive techniques for a loss of accuracy. Navigation systems might address this issue. We are currently using routinely a nonimage-based navigation for total knee replacement. We developed a modified system for UKR, suitable for either a conventional or a mini-invasive approach. Navigated implantation of a UKR allowed improving the accuracy of the radiologic implantation. Mini-invasive implantation was effective, but the accuracy may not reach that of the conventional navigated technique and should be still improved. Minimal invasive techniques have to be validated because a loss of accuracy will negatively influence long-term outcomes.

  14. Toxicology of chlorofluorocarbon replacements.

    PubMed Central

    Dekant, W

    1996-01-01

    Chlorofluorocarbons (CFCs) are stable in the atmosphere and may reach the stratosphere. They are cleaved by UV-radiation in the stratosphere to yield chlorine radicals, which are thought to interfere with the catalytic cycle of ozone formation and destruction and deplete stratospheric ozone concentrations. Due to potential adverse health effects of ozone depletion, chlorofluorocarbon replacements with much lower or absent ozone depleting potential are developed. The toxicology of these compounds that represent chlorofluorohydrocarbons (HCFCs) or fluorohydrocarbons (HFCs) has been intensively studied. All compounds investigated (1, 1-dichloro-1-fluoroethane [HCFC-141b], 1,1,1,2-tetrafluoroethane [HFC-134a], pentafluoroethane [HFC-125], 1-chloro- 1,2,2,2-tetrafluoroethane [HCFC-124], and 1,1-dichloro-2,2,2-trifluoroethane [HCFC-123]) show only a low potential for skin and eye irritation. Chronic adverse effects on the liver (HCFC-123) and the testes (HCFC-141b and HCFC-134a), including tumor formation, were observed in long-term inhalation studies in rodents using very high concentrations of these CFC replacements. All CFC replacements are, to varying extents, biotransformed in the organism, mainly by cytochrome P450-catalyzed oxidation of C-H bonds. The formed acyl halides are hydrolyzed to give excretable carboxylic acids; halogenated aldehydes that are formed may be further oxidized to halogenated carboxylic acids or reduced to halogenated alcohols, which are excretory metabolites in urine from rodents exposed experimentally to CFC replacements. The chronic toxicity of the CFC replacements studied is unlikely to be of relevance for humans exposed during production and application of CFC replacements. PMID:8722112

  15. Toxicology of chlorofluorocarbon replacements.

    PubMed

    Dekant, W

    1996-03-01

    Chlorofluorocarbons (CFCs) are stable in the atmosphere and may reach the stratosphere. They are cleaved by UV-radiation in the stratosphere to yield chlorine radicals, which are thought to interfere with the catalytic cycle of ozone formation and destruction and deplete stratospheric ozone concentrations. Due to potential adverse health effects of ozone depletion, chlorofluorocarbon replacements with much lower or absent ozone depleting potential are developed. The toxicology of these compounds that represent chlorofluorohydrocarbons (HCFCs) or fluorohydrocarbons (HFCs) has been intensively studied. All compounds investigated (1, 1-dichloro-1-fluoroethane [HCFC-141b], 1,1,1,2-tetrafluoroethane [HFC-134a], pentafluoroethane [HFC-125], 1-chloro- 1,2,2,2-tetrafluoroethane [HCFC-124], and 1,1-dichloro-2,2,2-trifluoroethane [HCFC-123]) show only a low potential for skin and eye irritation. Chronic adverse effects on the liver (HCFC-123) and the testes (HCFC-141b and HCFC-134a), including tumor formation, were observed in long-term inhalation studies in rodents using very high concentrations of these CFC replacements. All CFC replacements are, to varying extents, biotransformed in the organism, mainly by cytochrome P450-catalyzed oxidation of C-H bonds. The formed acyl halides are hydrolyzed to give excretable carboxylic acids; halogenated aldehydes that are formed may be further oxidized to halogenated carboxylic acids or reduced to halogenated alcohols, which are excretory metabolites in urine from rodents exposed experimentally to CFC replacements. The chronic toxicity of the CFC replacements studied is unlikely to be of relevance for humans exposed during production and application of CFC replacements.

  16. Biological tooth replacement

    PubMed Central

    Sartaj, Rachel; Sharpe, Paul

    2006-01-01

    Teeth develop from a series of reciprocal interactions that take place between epithelium and mesenchyme during development of the mouth that begin early in mammalian embryogenesis. The molecular control of key processes in tooth development such as initiation, morphogenesis and cytodifferentiation are being increasingly better understood, to the point where this information can be used as the basis for approaches to produce biological replacement teeth (BioTeeth). This review outlines the current approaches, ideas and progress towards the production of BioTeeth that could form an alternative method for replacing lost or damaged teeth. PMID:17005022

  17. Patient-derived mouse models of cancer need to be orthotopic in order to evaluate targeted anti-metastatic therapy.

    PubMed

    Hiroshima, Yukihiko; Maawy, Ali; Zhang, Yong; Zhang, Nan; Murakami, Takashi; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2016-11-01

    Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients have their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We demonstrate in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models. A subcutaneous nude mouse model of HER-2 expressing cervical carcinoma was not sensitive to entinostat (a benzamide histone deactylase inhibitor), which also did not inhibit primary tumor growth in a PDOX model of the same tumor. However, in the PDOX model, entinostat alone significantly reduced the metastatic tumor burden, compared to the control. Thus, only the PDOX model could be used to discover the anti-metastatic activity of entinostat for this patient. The results of the present report indicate the importance of using mouse models that can recapitulate metastatic cancer for precisely individualizing cancer therapy.

  18. Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors in Human Colon Cancer Surgical Specimens and Orthotopic Tumors

    PubMed Central

    Kuwai, Toshio; Nakamura, Toru; Kim, Sun-Jin; Sasaki, Takamitsu; Kitadai, Yasuhiko; Langley, Robert R.; Fan, Dominic; Hamilton, Stanley R.; Fidler, Isaiah J.

    2008-01-01

    The design of targeted therapy, particularly patient-specific targeted therapy, requires knowledge of the presence and intratumoral distribution of tyrosine kinase receptors. To determine whether the expression of such receptors is constant or varies between and within individual colon cancer neoplasms, we examined the pattern of expression of the ligands, epidermal growth factor, vascular endothelial growth factor, and platelet-derived growth factor-B as well as their respective receptors in human colon cancer surgical specimens and orthotopic human colon cancers growing in the cecal wall of nude mice. The expression of the epidermal growth factor receptor and the vascular endothelial growth factor receptor on tumor cells and stromal cells, including tumor-associated endothelial cells, was heterogeneous in surgical specimens and orthotopic tumors. In some tumors, the receptor was expressed on both tumor cells and stromal cells, and in other tumors the receptor was expressed only on tumor cells or only on stromal cells. In contrast, the platelet-derived growth factor receptor was expressed only on stromal cells in both surgical specimens and orthotopic tumors. Examination of receptor expression in both individual surgical specimens and orthotopic tumors revealed that the platelet-derived growth factor receptor was expressed only on stromal cells and that the patterns of epidermal growth factor receptor and vascular endothelial growth factor receptor 2 expression differed between tumor cells. This heterogeneity in receptor expression among different tumor cells suggests that targeting a single tyrosine kinase may not yield eradication of the disease. PMID:18202197

  19. Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor

    PubMed Central

    2014-01-01

    Background Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease. Methods Fresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed. Results Herein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473±695-mm3 (median 199-mm3, range 12.6-2682.5-mm3) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also

  20. Window Replacement Tips.

    ERIC Educational Resources Information Center

    Wiens, Janet

    2001-01-01

    Explores ways to replace facility windows more easily and efficiently by evaluating long-term needs and window options. Recommends obtaining references from window manufacturer and installer, scheduling the work during times the facility is unoccupied, and ensuring that historic and life-safety issues be considered. (GR)

  1. Prioritizing equipment for replacement.

    PubMed

    Capuano, Mike

    2010-01-01

    It is suggested that clinical engineers take the lead in formulating evaluation processes to recommend equipment replacement. Their skill, knowledge, and experience, combined with access to equipment databases, make them a logical choice. Based on ideas from Fennigkoh's scheme, elements such as age, vendor support, accumulated maintenance cost, and function/risk were used.6 Other more subjective criteria such as cost benefits and efficacy of newer technology were not used. The element of downtime was also omitted due to the data element not being available. The resulting Periop Master Equipment List and its rationale was presented to the Perioperative Services Program Council. They deemed the criteria to be robust and provided overwhelming acceptance of the list. It was quickly put to use to estimate required capital funding, justify items already thought to need replacement, and identify high-priority ranked items for replacement. Incorporating prioritization criteria into an existing equipment database would be ideal. Some commercially available systems do have the basic elements of this. Maintaining replacement data can be labor-intensive regardless of the method used. There is usually little time to perform the tasks necessary for prioritizing equipment. However, where appropriate, a clinical engineering department might be able to conduct such an exercise as shown in the following case study.

  2. Python import replacement

    SciTech Connect

    2011-10-01

    SmartImport.py is a Python source-code file that implements a replacement for the standard Python module importer. The code is derived from knee.py, a file in the standard Python diestribution , and adds functionality to improve the performance of Python module imports in massively parallel contexts.

  3. Hexachloroethane Obscurant Replacement

    DTIC Science & Technology

    2012-01-01

    suggest that neither the alkali metal hydroxides nor chlorides are extremely toxic (11). Oral rat LD50 values are indeed lower for hydroxide salts...analyze for toxicity of combustion gases and particulates. Compositions containing boron potassium nitrate igniter blended with halide salts...variants were identified which should have improved performance. 15. SUBJECT TERMS Non- toxic obscurant, hexachloroethane smoke replacement 16

  4. Python import replacement

    SciTech Connect

    2011-10-01

    SmartImport.py is a Python source-code file that implements a replacement for the standard Python module importer. The code is derived from knee.py, a file in the standard Python diestribution , and adds functionality to improve the performance of Python module imports in massively parallel contexts.

  5. Replacing America's Job Bank

    ERIC Educational Resources Information Center

    Vollman, Jim

    2009-01-01

    The Job Central National Labor Exchange (www.jobcentral.com) has become the effective replacement for America's Job Bank with state workforce agencies and, increasingly, with community colleges throughout the country. The American Association of Community Colleges (AACC) has formed a partnership with Job Central to promote its use throughout the…

  6. Replacing America's Job Bank

    ERIC Educational Resources Information Center

    Vollman, Jim

    2009-01-01

    The Job Central National Labor Exchange (www.jobcentral.com) has become the effective replacement for America's Job Bank with state workforce agencies and, increasingly, with community colleges throughout the country. The American Association of Community Colleges (AACC) has formed a partnership with Job Central to promote its use throughout the…

  7. Life-Threatening Cardiac Tamponade Secondary to Chylopericardium Following Orthotopic Heart Transplantation-A Case Report.

    PubMed

    Wierzbicki, Karol; Mazur, Piotr; Węgrzyn, Piotr; Kapelak, Bogusław

    2016-08-23

    Chylopericardium is a rare complication in cardiac surgery, and an extremely rare occurrence in patients following orthotopic heart transplantation (OHT), which, however, can lead to cardiac tamponade. Here we present a case of a 59-year-old man who underwent OHT and suffered from chylopericardium resulting in cardiac tamponade late in the postoperative course, despite the initially uneventful early postoperative period (decreasing blood drainage was observed directly after the procedure, and the drains were safely removed). After the diagnosis of chylopericardium was made, the conservative treatment was initiated, which turned out to be insufficient, and eventually invasive approach for the recurrence of tamponade secondary to chylopericardium was required. We discuss the available therapeutic options for chylopericardium and demonstrate the successful invasive therapeutic approach with use of the absorbable fibrin sealant patch.

  8. Follicular variant of papillary carcinoma in submandibular ectopic thyroid with no orthotopic thyroid gland.

    PubMed

    Guerrissi, Jorge O

    2012-01-01

    Ectopic thyroid tissue with no orthotopic gland is extremely rare; malign transformation of ectopic thyroid is also an uncommon event, and rarer is the follicular variant of papillary carcinoma. In this clinical report, a case with submandibular ectopic thyroid without orthotropic thyroid gland is presented. Treatment was a complete resection of tumor, and histologic findings reveal follicular variant of papillary carcinoma. The patient had an uneventful postoperative recovery, and a substitution treatment with thyroxine was maintained. Physicians should be aware of the possibility that a lingual, submandibular, or lateral neck swelling could be an ectopic thyroid gland. This entity poses specific diagnostic and therapeutic difficulties, and definitive diagnosis is histologic. Computed tomographic scan, radioactive scan, and ultrasonography are necessary in revealing the presence of normal thyroid gland. Recommended treatment is primarily surgical, sometimes associated with radioiodine I 131 therapy and a substitution treatment with thyroxine.

  9. [Esophagectomy and colonic orthotopic transposition by video-assisted thoracoscopy (VATS)].

    PubMed

    Lau Torres, Víctor Eduardo; Salazar Tantaleán, Víctor Augusto

    2009-01-01

    The esophagectomy and colonic transposition by video-assisted thoracoscopy (VATS), still not recommended as a technique of choice for the treatment of benign and malignant esophagus despite good results in hospitalization, morbidity and mortality. This case describes a 24 year old male patient who swallowed muriatic acid, causing severe injuries to the esophagus and stomach. Initially, he performed jejunal transposition which subsequently are causing progressive dysphagia, readmitted 2 years later. This time surgery is performed in 2 stages: (1) rise of the ascending colon and jejunum distal to oesophageal vasculature itself, by open surgery (2) esophagectomy and colonic orthotopic transposition by VATS and posterior hypopharyngeal anastomosis in colon anterior cervical region. Patient was discharged without complications and shorter hospital stay. Currently no evidence of dysphagia, improved nutritional status and ultimately better quality of life.

  10. Fulminant hepatic failure from primary hepatic lymphoma: successful treatment with orthotopic liver transplantation and chemotherapy.

    PubMed

    Cameron, Andrew M; Truty, Jadwiga; Truell, Jeff; Lassman, Charles; Zimmerman, Michael A; Kelly, Burnett S; Farmer, Douglas G; Hiatt, Jonathan R; Ghobrial, Rafik; Busuttil, Ronald W

    2005-10-15

    Systemic lymphomas may involve the liver but rarely cause fulminant hepatic failure (FHF). Acute liver failure from primary hepatic lymphoma (PHL) is even less common with most patients succumbing to the sequelae of FHF before the correct diagnosis is made. We report a patient who underwent successful orthotopic liver transplant (OLT) and chemotherapy for FHF secondary to PHL. This previously-well male developed profound coagulopathy and encephalopathy 6 weeks after the onset of jaundice and fatigue. Workup failed to reveal the underlying cause of his liver failure and the patient soon required urgent OLT. Pathologic evaluation of his explanted liver revealed a malignant T-cell rich, large B-cell non-Hodgkin's lymphoma with widespread hepatocellular necrosis. The patient made an excellent clinical recovery and is undergoing CHOP-Rituxan chemotherapy. This scenario demonstrates that lymphoma should be considered in the differential diagnosis of FHF without clear etiology because of the potential for intervention with transplant and chemotherapy.

  11. Endoscopic diagnosis and management of biliary complications following orthotopic liver transplantation.

    PubMed

    Gholson, C F; Zibari, G; McDonald, J C

    1996-06-01

    Nonoperative management of biliary complications (BC) with endoscopic retrograde cholangiopancreatography (ERCP) is a natural sequel to the emergence of choledochocholedochostomy as the preferred biliary reconstruction for orthotopic liver transplantation (OLT). Overall, therapeutic ERCP's efficacy for posttransplant BC is difficult to assess because most published data are retrospective, anecdotal, or in abstract form, and there are no prospective, randomized studies. Thus, endoscopic management of posttransplant BC must be individualized. While T-tube-related late bile leaks and ductal calculi are amenable to endoscopic therapy, its efficacy for strictures is more difficult to define. Refined surgical technique has prevented many unifocal anastomotic lesions, while multifocal strictures (for which endoscopic therapeutic experience is minimal) are increasingly prevalent. Whether endoscopic sphincterotomy is appropriate for posttransplant sphincter of Oddi dysfunction is controversial, because the disorder may be transient and the risk significant. Multicenter, prospective studies are needed to determine more accurately the optimal role of endoscopic therapy after OLT.

  12. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids

    PubMed Central

    Fumagalli, Arianna; Drost, Jarno; Suijkerbuijk, Saskia J. E.; van Boxtel, Ruben; de Ligt, Joep; Offerhaus, G. Johan; Begthel, Harry; Beerling, Evelyne; Tan, Ee Hong; Sansom, Owen J.; Clevers, Hans; van Rheenen, Jacco

    2017-01-01

    In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize—i.e., to colonize distant sites—is the direct consequence of the loss of dependency on specific niche signals. PMID:28270604

  13. Management of pulmonary hypertension from left heart disease in candidates for orthotopic heart transplantation.

    PubMed

    Koulova, Anna; Gass, Alan L; Patibandla, Saikrishna; Gupta, Chhaya Aggarwal; Aronow, Wilbert S; Lanier, Gregg M

    2017-08-01

    Pulmonary hypertension in left heart disease (PH-LHD) commonly complicates prolonged heart failure (HF). When advanced, the PH becomes fixed or out of proportion and is associated with increased morbidity and mortality in patients undergoing orthotopic heart transplant (OHT). To date, the only recommended treatment of out of proportion PH is the treatment of the underlying HF by reducing the pulmonary capillary wedge pressure (PCWP) with medications and often along with use of mechanical circulatory support. Medical therapies typically used in the treatment of World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH) have been employed off-label in the setting of PH-LHD with varying efficacy and often negative outcomes. We will discuss the current standard of care including treating HF and use of mechanical circulatory support. In addition, we will review the studies published to date assessing the efficacy and safety of PAH medications in patients with PH-LHD being considered for OHT.

  14. Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer.

    PubMed

    Mauri, Giorgio; Chiodoni, Claudia; Parenza, Mariella; Arioli, Ivano; Tripodo, Claudio; Colombo, Mario Paolo

    2013-12-01

    Intra-tumor injection of immunotherapeutic agents is often the most effective, likely because of concomitant modification of tumor microenvironment. We tested an immunotherapeutic regimen consisting of CpG oligonucleotides and of adenovirus-mediated gene delivery of CCL16 chemokine directly into orthotopically implanted prostate tumors by ultrasound-guided injection, followed by systemic administration of an anti-IL-10R antibody. This combination treatment induced rapid stromal rearrangement, characterized by massive leukocyte infiltration and large areas of necrosis, a scenario that eventually led to complete tumor rejection and systemic immunity in 75 % of the treated mice. In vivo T lymphocyte depletion experiments demonstrated that the efficacy of CCL16/CpG/anti-IL-10R combination treatment relies upon CD8 T lymphocytes whereas CD4 T cells are dispensable. The results underlie the feasibility of echo-guided local immunotherapy of tumors located in visceral organs that are not easily accessible.

  15. Cellular rejection of the conduction system after orthotopic heart transplantation for congenital atrioventricular block.

    PubMed

    Chan, Jessica B; Levi, Daniel S; Lai, Chi K; Alejos, Juan C; Fishbein, Michael C

    2006-11-01

    We report a case of severe acute cellular rejection of the cardiac allograft conduction system in a 15-month-old girl who received orthotopic heart transplantation (OHT) for congestive heart failure from a congenital heart block. Post-operatively, the patient was treated for clinical evidence of rejection, but did not have electrocardiographic findings of heart block. Six weeks after transplantation, the patient developed sudden-onset bradycardia and died. Autopsy showed severe acute cellular rejection involving primarily the conduction system. Cellular rejection of the cardiac conduction system is a potentially lethal complication of OHT. Although diagnostic modalities to predict or detect ongoing cellular rejection in the conduction system are limited, recognizing the early signs, such as post-operative heart block, may prevent devastating consequences.

  16. Sodium bicarbonate infusion in patients undergoing orthotopic liver transplantation: a single center randomized controlled pilot trial.

    PubMed

    Weinberg, Laurence; Broad, Jeremy; Pillai, Param; Chen, Guangjun; Nguyen, Micheline; Eastwood, Glenn M; Scurrah, Nick; Nikfarjam, Mehrdad; Story, David; McNicol, Larry; Bellomo, Rinaldo

    2016-05-01

    Liver transplantation-associated acute kidney injury (AKI) carries significant morbidity and mortality. We hypothesized that sodium bicarbonate would reduce the incidence and/or severity of liver transplantation-associated AKI. In this double-blinded pilot RCT, adult patients undergoing orthotopic liver transplantation were randomized to an infusion of either 8.4% sodium bicarbonate (0.5 mEq/kg/h for the first hour; 0.15 mEq/kg/h until completion of surgery); (n = 30) or 0.9% sodium chloride (n = 30). AKI within the first 48 h post-operatively. There were no significant differences between the two treatment groups with regard to baseline characteristics, model for end-stage liver disease and acute physiology and chronic health evaluation (APACHE) II scores, and pre-transplantation renal function. Intra-operative factors were similar for duration of surgery, blood product requirements, crystalloid and colloid volumes infused and requirements for vasoactive therapy. Eleven patients (37%) in the bicarbonate group and 10 patients (33%) in the sodium chloride group developed a post-operative AKI (p = 0.79). Bicarbonate infusion attenuated the degree of immediate post-operative metabolic acidosis; however, this effect dissipated by 48 h. There were no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. The intra-operative infusion of sodium bicarbonate did not decrease the incidence of AKI in patients following orthotopic liver transplantation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. 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

  18. Orthotopic model of canine osteosarcoma in athymic rats for evaluation of stereotactic radiotherapy.

    PubMed

    Schwartz, Anthony L; Custis, James T; Harmon, Joseph F; Powers, Barbara E; Chubb, Laura S; LaRue, Susan M; Ehrhart, Nicole P; Ryan, Stewart D

    2013-03-01

    To develop an orthotopic model of canine osteosarcoma in athymic rats as a model for evaluating the effects of stereotactic radiotherapy (SRT) on osteosarcoma cells. 26 athymic nude rats. 3 experiments were performed. In the first 2 experiments, rats were injected with 1 × 10(6) Abrams canine osteosarcoma cells into the proximal aspect of the tibia (n = 12) or distal aspect of the femur (6). Tumor engraftment and progression were monitored weekly via radiography, luciferase imaging, and measurement of urine pyridinoline concentration for 5 weeks and histologic evaluation after euthanasia. In the third experiment, 8 rats underwent canine osteosarcoma cell injection into the distal aspect of the femur and SRT was administered to the affected area in three 12-Gy fractions delivered on consecutive days (total radiation dose, 36 Gy). Percentage tumor necrosis and urinary pyridinoline concentrations were used to assess local tumor control. The short-term effect of SRT on skin was also evaluated. Tumors developed in 10 of 12 tibial sites and all 14 femoral sites. Administration of SRT to rats with femoral osteosarcoma was feasible and successful. Mean tumor necrosis of 95% was achieved histologically, and minimal adverse skin effects were observed. The orthotopic model of canine osteosarcoma in rats developed in this study was suitable for evaluating the effects of local tumor control and can be used in future studies to evaluate optimization of SRT duration, dose, and fractionation schemes. The model could also allow evaluation of other treatments in combination with SRT, such as chemotherapy or bisphosphonate, radioprotectant, or parathyroid hormone treatment.

  19. Lactate blood levels in the perioperative period of orthotopic liver transplantation.

    PubMed

    De Gasperi, A; Mazza, E; Corti, A; Zoppi, F; Prosperi, M; Fantini, G; Scaiola, A; Colella, G; Amici, O; Notaro, P; Rocchini, A; Ceresa, F; Roselli, E; Grugni, M C

    1997-01-01

    To investigate whether early postoperative changes in blood lactate concentration indicate the functional recovery of the newly grafted liver, changes in oxygen supply, oxygen consumption, acid-base equilibrium, and blood lactate concentrations were prospectively studied in a group of 53 postnecrotic cirrhotic patients during the various phases of orthotopic liver transplantation (preanhepatic, anhepatic, neohepatic) and for the first 48 h following reperfusion. The patients were divided into two groups according to the quality of the early graft function, as indicated by alanine aminotransferase, bile flow, and prothrombin activity: group A (49 patients), good immediate graft function and group B (4 patients), immediate graft non-function. Lactate levels rose in the same manner during the preanhepatic and anhepatic stages and peaked after revascularization of the graft. Following reperfusion, however, distinctly different blood lactate profiles were recorded in the two groups of patients. A fall in lactate concentration was recorded in group A patients, whereas a continuous rise occurred in group B patients: the difference becoming significant by the end of surgery (P < or = 0.05). During the first 48 h following revascularization of the graft, opposite trends in lactate concentration, bile flow, alanine aminotransferase, and prothrombin activity were evident in the two groups of patients: 24 h after reperfusion, lactate levels were below 2 mmol/l in 47 of 49 patients from group A, while they plateaued above 4 mmol/l in all patients from group B. Group A patients had lower alanine aminotransferase levels (P < or = 0.001), higher prothrombin activity, (P < or = 0.01), and greater bile flow (P < or = 0.02). If validated in larger series, the blood lactate profile, probably more than the absolute level, appears to be a useful indicator of the early recovery of liver metabolic capacities in the immediate postoperative period of orthotopic liver transplantation.

  20. 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.

  1. 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

  2. Development of an orthotopic model of invasive pancreatic cancer in an immunocompetent murine host

    PubMed Central

    Tseng, William W.; Winer, Daniel; Kenkel, Justin A.; Choi, Okmi; Shain, Alan H.; Pollack, Jonathan R.; French, Randy; Lowy, Andrew M.; Engleman, Edgar G.

    2010-01-01

    Purpose The most common preclinical models of pancreatic adenocarcinoma utilize human cells or tissues that are xenografted into immunodeficient hosts. Several immunocompetent, genetically engineered mouse models of pancreatic cancer exist; however, tumor latency and disease progression in these models are highly variable. We sought to develop an immunocompetent, orthotopic mouse model of pancreatic cancer with rapid and predictable growth kinetics. Experimental Design Cell lines with epithelial morphology were derived from liver metastases obtained from KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice. Tumor cells were implanted in the pancreas of immunocompetent, histocompatible B6/129 mice, and the mice were monitored for disease progression. Relevant tissues were harvested for histological, genomic and immunophenotypic analysis. Results All mice developed pancreatic tumors by 2 weeks. Invasive disease and liver metastases were noted by 6-8 weeks. Histological examination of tumors demonstrated cytokeratin-19-positive adenocarcinoma with regions of desmoplasia. Genomic analysis revealed broad chromosomal changes along with focal gains and losses. Pancreatic tumors were infiltrated with dendritic cells, myeloid-derived suppressor cells, macrophages and T lymphocytes. Survival was decreased in RAG-/- mice, which are deficient in T cells, suggesting that an adaptive immune response alters the course of disease in wild-type mice. Conclusions We have developed a rapid, predictable orthotopic model of pancreatic adenocarcinoma in immunocompetent mice that mimics human pancreatic cancer with regard to genetic mutations, histological appearance and pattern of disease progression. This model highlights both the complexity and relevance of the immune response to invasive pancreatic cancer and may be useful for the preclinical evaluation of new therapeutic agents. PMID:20534740

  3. 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.

  4. Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy.

    PubMed Central

    Turner, J. H.; Rose, A. H.; Glancy, R. J.; Penhale, W. J.

    1998-01-01

    Extrapolation to humans from experimental radioimmunotherapy in nude mouse xenograft models is confounded by large relative tumour size and small volume of distribution in mice allowing tumour uptake of radiolabelled antibodies unattainable in patients. Our large animal model of human tumours in cyclosporin-immunosuppressed sheep demonstrated tumour uptake of targeted radiolabelled monoclonal antibodies comparable with uptakes reported in clinical trials. Sheep immunosuppression with daily intravenous cyclosporin augmented by oral ketoconazole maintained trough blood levels of cyclosporin within the range 1000-1500 ng ml(-1). Human tumour cells were transplanted orthotopically by inoculation of 10(7) cells: SKMEL melanoma subcutaneously; LS174T and HT29 colon carcinoma into bowel, peritoneum and liver; and JAM ovarian carcinoma into ovary and peritoneum. Tumour xenografts grew at all sites within 3 weeks of inoculation, preserving characteristic morphology without evidence of necrosis or host rejection. Lymphatic metastasis was demonstrated in regional nodes draining xenografts of melanoma and ovarian carcinoma. Colonic LS1 74T xenografts produced mucin and carcinoembryonic antigen (CEA). The anti-CEA IgG1 monoclonal antibody A5B7 was radiolabelled with iodine-131 and administered intravenously to sheep. Peak uptake at 5 days in orthotopic human tumour transplants in gut was 0.027% DI g(-1) (percentage of injected dose per gram) and 0.034% DI g(-1) in hepatic metastases with tumour to blood ratios of 2-2.5. Non-specific tumour uptake in melanoma was 0.003% DI g(-1). Uptake of radiolabelled monoclonal antibody in human tumours in our large animal model is comparable with that observed in patients and may be more realistic than nude mice xenografts for prediction of clinical efficacy of radioimmunotherapy. Images Figure 1 Figure 2 Figure 3 PMID:9716032

  5. Multimodality imaging methods for assessing retinoblastoma orthotopic xenograft growth and development.

    PubMed

    Corson, Timothy W; Samuels, Brian C; Wenzel, Andrea A; Geary, Anna J; Riley, Amanda A; McCarthy, Brian P; Hanenberg, Helmut; Bailey, Barbara J; Rogers, Pamela I; Pollok, Karen E; Rajashekhar, Gangaraju; Territo, Paul R

    2014-01-01

    Genomic studies of the pediatric ocular tumor retinoblastoma are paving the way for development of targeted therapies. Robust model systems such as orthotopic xenografts are necessary for testing such therapeutics. One system involves bioluminescence imaging of luciferase-expressing human retinoblastoma cells injected into the vitreous of newborn rat eyes. Although used for several drug studies, the spatial and temporal development of tumors in this model has not been documented. Here, we present a new model to allow analysis of average luciferin flux ([Formula: see text]) through the tumor, a more biologically relevant parameter than peak bioluminescence as traditionally measured. Moreover, we monitored the spatial development of xenografts in the living eye. We engineered Y79 retinoblastoma cells to express a lentivirally-delivered enhanced green fluorescent protein-luciferase fusion protein. In intravitreal xenografts, we assayed bioluminescence and computed [Formula: see text], as well as documented tumor growth by intraocular optical coherence tomography (OCT), brightfield, and fluorescence imaging. In vivo bioluminescence, ex vivo tumor size, and ex vivo fluorescent signal were all highly correlated in orthotopic xenografts. By OCT, xenografts were dense and highly vascularized, with well-defined edges. Small tumors preferentially sat atop the optic nerve head; this morphology was confirmed on histological examination. In vivo, [Formula: see text] in xenografts showed a plateau effect as tumors became bounded by the dimensions of the eye. The combination of [Formula: see text] modeling and in vivo intraocular imaging allows both quantitative and high-resolution, non-invasive spatial analysis of this retinoblastoma model. This technique will be applied to other cell lines and experimental therapeutic trials in the future.

  6. Fluorescence laparoscopy imaging of pancreatic tumor progression in an orthotopic mouse model

    PubMed Central

    Tran Cao, Hop S.; Kaushal, Sharmeela; Lee, Claudia; Snyder, Cynthia S.; Thompson, Kari J.; Horgan, Santiago; Talamini, Mark A.; Hoffman, Robert M.

    2010-01-01

    Background The use of fluorescent proteins to label tumors is revolutionizing cancer research, enabling imaging of both primary and metastatic lesions, which is important for diagnosis, staging, and therapy. This report describes the use of fluorescence laparoscopy to image green fluorescent protein (GFP)-expressing tumors in an orthotopic mouse model of human pancreatic cancer. Methods The orthotopic mouse model of human pancreatic cancer was established by injecting GFP-expressing MiaPaCa-2 human pancreatic cancer cells into the pancreas of 6-week-old female athymic mice. On postoperative day 14, diagnostic laparoscopy using both white and fluorescent light was performed. A standard laparoscopic system was modified by placing a 480-nm short-pass excitation filter between the light cable and the laparoscope in addition to using a 2-mm-thick emission filter. A camera was used that allowed variable exposure time and gain setting. For mouse laparoscopy, a 3-mm 0° laparoscope was used. The mouse’s abdomen was gently insufflated to 2 mm Hg via a 22-gauge angiocatheter. After laparoscopy, the animals were sacrificed, and the tumors were collected and processed for histologic review. The experiments were performed in triplicate. Results Fluorescence laparoscopy enabled rapid imaging of the brightly fluorescent tumor in the pancreatic body. Use of the proper filters enabled simultaneous visualization of the tumor and the surrounding structures with minimal autofluorescence. Fluorescence laparoscopy thus allowed exact localization of the tumor, eliminating the need to switch back and forth between white and fluorescence lighting, under which the background usually is so darkened that it is difficult to maintain spatial orientation. Conclusion The use of fluorescence laparoscopy permits the facile, real-time imaging and localization of tumors labeled with fluorescent proteins. The results described in this report should have important clinical potential. PMID:20533064

  7. Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.

    PubMed

    Szpunar, Mercedes J; Belcher, Elizabeth K; Dawes, Ryan P; Madden, Kelley S

    2016-03-01

    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.

  8. 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.

  9. Intravenously Administered Alphavirus Vector VA7 Eradicates Orthotopic Human Glioma Xenografts in Nude Mice

    PubMed Central

    Ruotsalainen, Janne J.; Martikainen, Miika W.; Stanford, Marianne M.; McCart, J. Andrea; Bell, John C.; Hinkkanen, Ari E.

    2010-01-01

    Background VA7 is a neurotropic alphavirus vector based on an attenuated strain of Semliki Forest virus. We have previously shown that VA7 exhibits oncolytic activity against human melanoma xenografts in immunodeficient mice. The purpose of this study was to determine if intravenously administered VA7 would be effective against human glioma. Methodology/Principal Findings In vitro, U87, U251, and A172 human glioma cells were infected and killed by VA7-EGFP. In vivo, antiglioma activity of VA7 was tested in Balb/c nude mice using U87 cells stably expressing firefly luciferase in subcutaneous and orthotopic tumor models. Intravenously administered VA7-EGFP completely eradicated 100% of small and 50% of large subcutaneous U87Fluc tumors. A single intravenous injection of either VA7-EGFP or VA7 expressing Renilla luciferase (VA7-Rluc) into mice bearing orthotopic U87Fluc tumors caused a complete quenching of intracranial firefly bioluminescence and long-term survival in total 16 of 17 animals. In tumor-bearing mice injected with VA7-Rluc, transient intracranial and peripheral Renilla bioluminescence was observed. Virus was well tolerated and no damage to heart, liver, spleen, or brain was observed upon pathological assessment at three and ninety days post injection, despite detectable virus titers in these organs during the earlier time point. Conclusion VA7 vector is apathogenic and can enter and destroy brain tumors in nude mice when administered systemically. This study warrants further elucidation of the mechanism of tumor destruction and attenuation of the VA7 virus. PMID:20066051

  10. Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice.

    PubMed

    Yezhelyev, Maksim V; Koehl, Gudrun; Guba, Markus; Brabletz, Thomas; Jauch, Karl-Walter; Ryan, Anderson; Barge, Alan; Green, Tim; Fennell, Michael; Bruns, Christiane J

    2004-12-01

    The Src family comprises a family of nonreceptor intracellular tyrosine kinases that mediate a variety of cellular pathways. Src kinases are overexpressed in a variety of human tumors, including cancer of the colon, breast, and pancreas, and they are an integral part of tumor cell signaling pathways associated with migration, proliferation, adhesion, and angiogenesis. We investigated whether the blockade of Src kinase by daily oral administration of the novel Src tyrosine kinase inhibitor AZM475271 [kindly provided by AstraZeneca (Macclesfield, United Kingdom)], alone or in combination with intraperitoneal gemcitabine, can inhibit growth and metastasis of orthotopically implanted human pancreatic carcinoma cells in nude mice. Treatment with AZM475271 alone reduced the primary pancreatic tumor volume by approximately 40%, whereas AZM475271 plus gemcitabine reduced tumor volume by 90%. Furthermore, treatment with AZM475271 and gemcitabine significantly reduced metastasis: none of eight animals who received the combination treatment had lymph node or liver metastases, compared with five of five and three of five animals, respectively, in the control group (P = 0.001). Src inhibition by AZM475271 (alone or with gemcitabine) was associated with significantly reduced tumor cell proliferation, decreased tumor microvessel density, and increased apoptosis in vivo. Moreover, these effects were all significantly increased when gemcitabine was combined with AZM475271 compared with gemcitabine alone. Src inhibition by AZM475271, either alone or in combination with gemcitabine, demonstrated significant antitumor and antimetastatic activity in an orthotopic nude mouse model for human pancreatic cancer. The combination of AZM475271 with gemcitabine sensitized tumor cells to the cytotoxic effect of gemcitabine.

  11. Multimodality Imaging Methods for Assessing Retinoblastoma Orthotopic Xenograft Growth and Development

    PubMed Central

    Corson, Timothy W.; Samuels, Brian C.; Wenzel, Andrea A.; Geary, Anna J.; Riley, Amanda A.; McCarthy, Brian P.; Hanenberg, Helmut; Bailey, Barbara J.; Rogers, Pamela I.; Pollok, Karen E.; Rajashekhar, Gangaraju; Territo, Paul R.

    2014-01-01

    Genomic studies of the pediatric ocular tumor retinoblastoma are paving the way for development of targeted therapies. Robust model systems such as orthotopic xenografts are necessary for testing such therapeutics. One system involves bioluminescence imaging of luciferase-expressing human retinoblastoma cells injected into the vitreous of newborn rat eyes. Although used for several drug studies, the spatial and temporal development of tumors in this model has not been documented. Here, we present a new model to allow analysis of average luciferin flux () through the tumor, a more biologically relevant parameter than peak bioluminescence as traditionally measured. Moreover, we monitored the spatial development of xenografts in the living eye. We engineered Y79 retinoblastoma cells to express a lentivirally-delivered enhanced green fluorescent protein-luciferase fusion protein. In intravitreal xenografts, we assayed bioluminescence and computed , as well as documented tumor growth by intraocular optical coherence tomography (OCT), brightfield, and fluorescence imaging. In vivo bioluminescence, ex vivo tumor size, and ex vivo fluorescent signal were all highly correlated in orthotopic xenografts. By OCT, xenografts were dense and highly vascularized, with well-defined edges. Small tumors preferentially sat atop the optic nerve head; this morphology was confirmed on histological examination. In vivo, in xenografts showed a plateau effect as tumors became bounded by the dimensions of the eye. The combination of modeling and in vivo intraocular imaging allows both quantitative and high-resolution, non-invasive spatial analysis of this retinoblastoma model. This technique will be applied to other cell lines and experimental therapeutic trials in the future. PMID:24901248

  12. 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

  13. Novel syngeneic pseudo-orthotopic prostate cancer model: vascular, mitotic and apoptotic responses to castration.

    PubMed

    Frost, Gregory I; Lustgarten, Joseph; Dudouet, Brigitte; Nyberg, Linda; Hartley-Asp, Beryl; Borgström, Per

    2005-01-01

    We describe a novel syngeneic "pseudo-orthotopic" in vivo model of prostate cancer progression. Our model uses the dorsal skinfold chamber technique with fluorescence video microscopy and TRAMP-C2 tumor cells. The cells were transfected with a histone H2B-GFP fusion protein, permitting real-time measurement of tumor size, as well as mitotic and apoptotic indices. To generate a "pseudo-orthotopic" milieu, pieces of prostate tissue (10-15 mm2) from donor mice were implanted into the chambers of C57BL/6 mice. The prostate tissue grafted into the chambers retained its native vasculature, as determined by transplantation of prostate tissue from GFP transgenic mice. TRAMP-C2 prostate cancer tumor spheroids (25,000 cells) were implanted in the chamber. Without prostate tissue, TRAMP-C2 prostate tumors were poorly angiogenic, displayed low mitotic and apoptotic indices (0.7 x 10(-4)), and no significant tumor growth could be detected. TRAMP-C2 tumors growing on transplanted prostate tissue in the chamber on the other hand had mitotic indices in the order of 1.6 x 10(-4) and apoptotic indices in the order of 0.8 x 10(-4). Furthermore, tumors with stroma were highly angiogenic, and were fully vascularized within 7-10 days. During a 4-week observation period, the number of tumor cells increased by nearly 300%. We used the model to study the effects of surgical castration. The most profound response was a rapid vascular regression of the tumor vasculature. Castration also increased apoptotic indices within the tumor without significant changes in mitosis. This model may be utilized for the rapid analysis of new therapeutic candidates against prostate cancer.

  14. BDNF signaling contributes to oral cancer pain in a preclinical orthotopic rodent model

    PubMed Central

    Chodroff, Leah; Bendele, Michelle; Valenzuela, Vanessa; Henry, Michael

    2016-01-01

    The majority of patients with oral cancer report intense pain that is only partially managed by current analgesics. Thus, there is a strong need to study mechanisms as well as develop novel analgesics for oral cancer pain. Current study employed an orthotopic tongue cancer model with molecular and non-reflexive behavioral assays to determine possible mechanisms of oral cancer pain. Human oral squamous cell carcinoma cells line, HSC2, was injected into the tongue of male athymic mice and tumor growth was observed by day 6. Immunohistological analyses revealed a well-differentiated tumor with a localized immune response and pronounced sensory and sympathetic innervation and vascularization. The tumor expressed TMPRSS2, a protein previously reported with oral squamous cell carcinoma. ATF3 expression in trigeminal ganglia was not altered by tumor growth. Molecular characterization of the model demonstrated altered expression of several pain-related genes, out of which up-regulation of BDNF was most striking. Moreover, BDNF protein expression in trigeminal ganglia neurons was increased and inhibition of BDNF signaling with a tyrosine kinase B antagonist, ANA-12, reversed pain-like behaviors induced by the oral tumor. Oral squamous cell carcinoma tumor growth was also associated with a reduction in feeding, mechanical hypersensitivity in the face, as well as spontaneous pain behaviors as measured by the conditioned place preference test, all of which were reversed by analgesics. Interestingly, injection of HSC2 into the hindpaw did not reproduce this spectrum of pain behaviors; nor did injection of a colonic cancer cell line into the tongue. Taken together, this orthotopic oral cancer pain model reproduces the spectrum of pain reported by oral cancer patients, including higher order cognitive changes, and demonstrates that BDNF signaling constitutes a novel mechanism by which oral squamous cell carcinoma induces pain. Identification of the key role of tyrosine kinase B

  15. ARRANGEMENT FOR REPLACING FILTERS

    DOEpatents

    Blomgren, R.A.; Bohlin, N.J.C.

    1957-08-27

    An improved filtered air exhaust system which may be continually operated during the replacement of the filters without the escape of unfiltered air is described. This is accomplished by hermetically sealing the box like filter containers in a rectangular tunnel with neoprene covered sponge rubber sealing rings coated with a silicone impregnated pneumatic grease. The tunnel through which the filters are pushed is normal to the exhaust air duct. A number of unused filters are in line behind the filters in use, and are moved by a hydraulic ram so that a fresh filter is positioned in the air duct. The used filter is pushed into a waiting receptacle and is suitably disposed. This device permits a rapid and safe replacement of a radiation contaminated filter without interruption to the normal flow of exhaust air.

  16. Celotex (Registered) Replacement Study

    SciTech Connect

    Couture, S; Hafner, R

    2002-10-01

    The AL-R8 is the pit storage container in most widespread use at Pantex. The AL-R8 container family consists of standard 20-in.-diameter steel drums, 30 to 60 in. in height, with insulation inserts made of Celotex{reg_sign}--a fiberboard product made from processed sugar cane. Celotex is an acceptable material for inserts in many radioactive material shipping and storage containers. It is a good shock mitigator/insulator, does a fair job in fire protection (when oxygen is excluded), shielding, and criticality, and is inexpensive and easily available. However, the fiberboard absorbs water in humid environments which, when combined with chemical residues in the fiberboard, forms corrosive compounds that can shorten the life of the container and affect container contents. To protect the contents from this potentially damaging environment, the AL-R8 SI was developed to isolate the contents within a sealed stainless steel vessel inside the AL-R8. Although the SI protected the contents, corrosion studies indicated the SI lid bolts might corrode over time and surveillance showed that areas of the outer drum were still subject to corrosion. To address this potential problem, DOE/Albuquerque sponsored bolt and Celotex replacement studies. The bolt replacement study was assigned to Mason and Hanger's Pantex Facility and this Celotex Replacement Study to Lawrence Livermore National Laboratory. The Celotex Replacement Study evaluated options for replacing Celotex with a material that is chemically compatible with the AL-R8 SI container. The evaluation was limited to materials either used previously in nuclear materials shipping and storage containers or materials with known properties in a low-radiation environment. This limitation was set to ensure that the long-term aging effect on the new material is known a priori. Initial material evaluations narrowed the material choices to foam and cork. Although cork performed better than foam in some tests, cork was considered a less

  17. NARC Rayon Replacement Program

    NASA Technical Reports Server (NTRS)

    Wilson, Kenneth P.; McCool, Alex (Technical Monitor)

    2002-01-01

    This viewgraph presentation provides information on the search for a replacement product for the aerospace grade rayon formerly used in the reusable solid rocket motor (RSRM). The rayon used in RSRMs is no longer produced by the North American Rayon Corporation (NARC), though NASA has stockpiled rayon to be used until a suitable replacement is found to be used in the RSRM nozzle carbon cloth phenolic (CCP). The primary considerations are performance, process ability, variability, long term availability, and cost. The preference will be given to commercial off-the-shelf products as opposed to those which are custom made. The candidate materials have been tested in previous phases of this selection process, and Enka Textile Rayon has emerged as a possible fabric, though its availability is still in question.

  18. Ulnar head replacement.

    PubMed

    Herbert, Timothy J; van Schoonhoven, Joerg

    2007-03-01

    Recent years have seen an increasing awareness of the anatomical and biomechanical significance of the distal radioulnar joint (DRUJ). With this has come a more critical approach to surgical management of DRUJ disorders and a realization that all forms of "excision arthroplasty" can only restore forearm rotation at the expense of forearm stability. This, in turn, has led to renewed interest in prosthetic replacement of the ulnar head, a procedure that had previously fallen into disrepute because of material failures with early implants, in particular, the Swanson silicone ulnar head replacement. In response to these early failures, a new prosthesis was developed in the early 1990s, using materials designed to withstand the loads across the DRUJ associated with normal functional use of the upper limb. Released onto the market in 1995 (Herbert ulnar head prosthesis), clinical experience during the last 10 years has shown that this prosthesis is able to restore forearm function after ulnar head excision and that the materials (ceramic head and noncemented titanium stem), even with normal use of the limb, are showing no signs of failure in the medium to long term. As experience with the use of an ulnar head prosthesis grows, so does its acceptance as a viable and attractive alternative to more traditional operations, such as the Darrach and Sauve-Kapandji procedures. This article discusses the current indications and contraindications for ulnar head replacement and details the surgical procedure, rehabilitation, and likely outcomes.

  19. Renal Replacement Therapy

    PubMed Central

    Ricci, Zaccaria; Romagnoli, Stefano; Ronco, Claudio

    2016-01-01

    During the last few years, due to medical and surgical evolution, patients with increasingly severe diseases causing multiorgan dysfunction are frequently admitted to intensive care units. Therapeutic options, when organ failure occurs, are frequently nonspecific and mostly directed towards supporting vital function. In these scenarios, the kidneys are almost always involved and, therefore, renal replacement therapies have become a common routine practice in critically ill patients with acute kidney injury. Recent technological improvement has led to the production of safe, versatile and efficient dialysis machines. In addition, emerging evidence may allow better individualization of treatment with tailored prescription depending on the patients’ clinical picture (e.g. sepsis, fluid overload, pediatric). The aim of the present review is to give a general overview of current practice in renal replacement therapies for critically ill patients. The main clinical aspects, including dose prescription, modality of dialysis delivery, anticoagulation strategies and timing will be addressed. In addition, some technical issues on physical principles governing blood purification, filters characteristics, and vascular access, will be covered. Finally, a section on current standard nomenclature of renal replacement therapy is devoted to clarify the “Tower of Babel” of critical care nephrology. PMID:26918174

  20. Replacement steel windows

    SciTech Connect

    Brown, M.A.; Condren, S.J.

    1999-07-01

    This paper presents the authors experiences in the investigation, design, and installation of replacement steel windows for two renovation projects at a major university in the northeast: a student residential complex and the law school. The authors review the construction of the existing walls (cast-in-place concrete barrier wall at the student residential complex and brick and stone masonry barrier wall at the law school), and the construction and performance of the original steel windows. To maintain the appearance of these architecturally significant buildings, the university elected to install replacement steel windows. The authors discuss special design consideration for steel windows (versus the more prevalent aluminum replacement window), including available window section profiles, corrosion protection, frame fabrication, and glazing design. The authors also review window flashing concepts they employed for the barrier wall construction, which has no drainage cavity. The authors summarize lessons learned during the window selection, design, fabrication, testing, and installation phases of the projects, and present recommendations for improved durability and water penetration resistance of steel windows.

  1. In Vivo Selection of Intermediately- and Highly-Malignant Variants of Triple-negative Breast Cancer in Orthotopic Nude Mouse Models.

    PubMed

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

    2016-12-01

    Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2 (HER2), is a recalcitrant disease in need of effective therapy. We previously isolated very-highly metastatic variants of the TNBC cell line MDA-MB-231 using serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. MDA-MB-231 cells expressing red fluorescent protein (MDA-MB-231-RFP) (1×10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation into the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for three or seven cycles in order to isolate intermediately, or highly-metastatic variants, respectively. The degree of malignancy of isolated variants of MDA-MB-231 depends on the extent of orthotopic transplantation. Serial transplantation resulted in MDA-MB-231-RFP which significantly produced larger tumors compared with the parental MDA-MB-231-RFP. Serial orthotopic implantation for three cycles resulted in intermediately-metastatic variants of MDA-MB-231-RFP. MDA-MB-231-RFP serially orthotopically transplanted seven times significantly metastasized more to lymph nodes compared with parental MDA-MB-231-RFP cells and the intermediately-metastatic variant. The highly-metastatic variant MDA-MB-231-RFP cells

  2. Total ankle joint replacement.

    PubMed

    2016-02-01

    Ankle arthritis results in a stiff and painful ankle and can be a major cause of disability. For people with end-stage ankle arthritis, arthrodesis (ankle fusion) is effective at reducing pain in the shorter term, but results in a fixed joint, and over time the loss of mobility places stress on other joints in the foot that may lead to arthritis, pain and dysfunction. Another option is to perform a total ankle joint replacement, with the aim of giving the patient a mobile and pain-free ankle. In this article we review the efficacy of this procedure, including how it compares to ankle arthrodesis, and consider the indications and complications.

  3. Immediate total tooth replacement.

    PubMed

    Garber, D A; Salama, M A; Salama, H

    2001-03-01

    Successful implant placement at the time of extraction has been documented. Implant placement at the time of extraction was initially performed as a two-stage procedure often with barrier membranes and sophisticated second-stage surgical uncoverings. The authors describe the next generation of this technique, including atraumatic tooth removal with simultaneous root form, implant placement, and temporization at one appointment. This technique of "Immediate Total Tooth Replacement" allows for the maintenance of the bony housing and soft-tissue form that existed before extraction, while at the same time establishing a root form anchor in the bone for an esthetic restoration.

  4. [Hormone replacement therapy].

    PubMed

    Nozue, E

    1994-03-01

    Hormone replacement therapy after menopause has shown so many advantages, such as reduction in risk of coronary artery disease and osteoporotic fracture besides treatment for climacteric symptoms, yet disadvantage such as a probability of an increase in the risk of breast cancer with long-term use still remains. In Japan HRT is now at the starting point. We must try to make more effort to accumulate data on the safety of HRT during-and-after menopause. It is our hope that doctors, not only gynecologists, but also doctors of other specialties will join our program for the health and happiness of women after menopause.

  5. A bioluminescent orthotopic mouse model of human osteosarcoma that allows sensitive and rapid evaluation of new therapeutic agents In vivo.

    PubMed

    Comstock, Kenine E; Hall, Christopher L; Daignault, Stephanie; Mandlebaum, Sarah A; Yu, Chunyan; Keller, Evan T

    2009-01-01

    Osteosarcoma (OSA) is the most common primary malignant bone tumor in children, 30% of whom develop lung metastases despite aggressive treatment. Our objective was to develop a mouse model of OSA for preclinical studies that (i) incorporates the natural history of OSA including tumor growth in bone and development of lung metastasis and (ii) is amenable to non-invasive detection methods. A human OSA cell line that expresses high levels of luciferase was created. Following subcutaneous injection, nine out of ten mice showed tumor growth. Eight out of ten mice showed tumor growth following orthotopic injection into the proximal tibia. Thirty percent of mice showed pulmonary metastasis by bioluminescent imaging eight to 10 weeks following orthotopic injection. Animals receiving cisplatin treatment showed reduced tumor volume compared to animals treated with vehicle alone. This model allows real-time detection of tumors and can be used to study mechanisms of OSA metastasis and test new therapeutic agents.

  6. Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models.

    PubMed

    Suetsugu, Atsushi; Honma, Kimi; Saji, Shigetoyo; Moriwaki, Hisataka; Ochiya, Takahiro; Hoffman, Robert M

    2013-03-01

    Exosomes play an important role in cell-to-cell communication to promote tumor metastasis. In order to image the fate of cancer-cell-derived exosomes in orthotopic nude mouse models of breast cancer, we used green fluorescent protein (GFP)-tagged CD63, which is a general marker of exosomes. Breast cancer cells transferred their own exosomes to other cancer cells and normal lung tissue cells in culture. In orthotopic nude-mouse models, breast cancer cells secreted exosomes into the tumor microenvironment. Tumor-derived exosomes were incorporated into tumor-associated cells as well as circulating in the blood of mice with breast cancer metastases. These results suggest that tumor-derived exosomes may contribute to forming a niche to promote tumor growth and metastasis. Our results demonstrate the usefulness of GFP imaging to investigate the role of exosomes in cancer metastasis.

  7. Cadmium plating replacements

    NASA Technical Reports Server (NTRS)

    Nelson, Mary J.; Groshart, Earl C.

    1995-01-01

    The Boeing Company has been searching for replacements to cadmium plate. Two alloy plating systems seem close to meeting the needs of a cadmium replacement. The two alloys, zinc-nickel and tin-zinc are from alloy plating baths; both baths are neutral pH. The alloys meet the requirements for salt fog corrosion resistance, and both alloys excel as a paint base. Currently, tests are being performed on standard fasteners to compare zinc-nickel and tin-zinc on threaded hardware where cadmium is heavily used. The Hydrogen embrittlement propensity of the zinc-nickel bath has been tested, and just beginning for the tin-zinc bath. Another area of interest is the electrical properties on aluminum for tin-zinc and will be discussed. The zinc-nickel alloy plating bath is in production in Boeing Commercial Airplane Group for non-critical low strength steels. The outlook is promising that these two coatings will help The Boeing Company significantly reduce its dependence on cadmium plating.

  8. Sutureless aortic valve replacement

    PubMed Central

    Phan, Kevin

    2015-01-01

    The increasing incidence of aortic stenosis and greater co-morbidities and risk profiles of the contemporary patient population has driven the development of minimally invasive aortic valve surgery and percutaneous transcatheter aortic valve implantation (TAVI) techniques to reduce surgical trauma. Recent technological developments have led to an alternative minimally invasive option which avoids the placement and tying of sutures, known as “sutureless” or rapid deployment aortic valves. Potential advantages for sutureless aortic prostheses include reducing cross-clamp and cardiopulmonary bypass (CPB) duration, facilitating minimally invasive surgery and complex cardiac interventions, whilst maintaining satisfactory hemodynamic outcomes and low paravalvular leak rates. However, given its recent developments, the majority of evidence regarding sutureless aortic valve replacement (SU-AVR) is limited to observational studies and there is a paucity of adequately-powered randomized studies. Recently, the International Valvular Surgery Study Group (IVSSG) has formulated to conduct the Sutureless Projects, set to be the largest international collaborative group to investigate this technology. This keynote lecture will overview the use, the potential advantages, the caveats, and current evidence of sutureless and rapid deployment aortic valve replacement (AVR). PMID:25870807

  9. Power Plant Replacement Study

    SciTech Connect

    Reed, Gary

    2010-09-30

    This report represents the final report for the Eastern Illinois University power plant replacement study. It contains all related documentation from consideration of possible solutions to the final recommended option. Included are the economic justifications associated with the chosen solution along with application for environmental permitting for the selected project for construction. This final report will summarize the results of execution of an EPC (energy performance contract) investment grade audit (IGA) which lead to an energy services agreement (ESA). The project includes scope of work to design and install energy conservation measures which are guaranteed by the contractor to be self-funding over its twenty year contract duration. The cost recovery is derived from systems performance improvements leading to energy savings. The prime focus of this EPC effort is to provide a replacement solution for Eastern Illinois University's aging and failing circa 1925 central steam production plant. Twenty-three ECMs were considered viable whose net impact will provide sufficient savings to successfully support the overall project objectives.

  10. Power Plant Replacement Study

    SciTech Connect

    Reed, Gary

    2010-09-30

    This report represents the final report for the Eastern Illinois University power plant replacement study. It contains all related documentation from consideration of possible solutions to the final recommended option. Included are the economic justifications associated with the chosen solution along with application for environmental permitting for the selected project for construction. This final report will summarize the results of execution of an EPC (energy performance contract) investment grade audit (IGA) which lead to an energy services agreement (ESA). The project includes scope of work to design and install energy conservation measures which are guaranteed by the contractor to be self-funding over its twenty year contract duration. The cost recovery is derived from systems performance improvements leading to energy savings. The prime focus of this EPC effort is to provide a replacement solution for Eastern Illinois University’s aging and failing circa 1925 central steam production plant. Twenty-three ECMs were considered viable whose net impact will provide sufficient savings to successfully support the overall project objectives.

  11. Cadmium plating replacements

    SciTech Connect

    Nelson, M.J.; Groshart, E.C.

    1995-03-01

    The Boeing Company has been searching for replacements to cadmium plate. Two alloy plating systems seem close to meeting the needs of a cadmium replacement. The two alloys, zinc-nickel and tin-zinc are from alloy plating baths; both baths are neutral pH. The alloys meet the requirements for salt fog corrosion resistance, and both alloys excel as a paint base. Currently, tests are being performed on standard fasteners to compare zinc-nickel and tin-zinc on threaded hardware where cadmium is heavily used. The Hydrogen embrittlement propensity of the zinc-nickel bath has been tested, and just beginning for the tin-zinc bath. Another area of interest is the electrical properties on aluminum for tin-zinc and will be discussed. The zinc-nickel alloy plating bath is in production in Boeing Commercial Airplane Group for non-critical low strength steels. The outlook is promising that these two coatings will help The Boeing Company significantly reduce its dependence on cadmium plating.

  12. Power Plant Replacement Study

    SciTech Connect

    Reed, Gary

    2010-09-30

    This report represents the final report for the Eastern Illinois University power plant replacement study. It contains all related documentation from consideration of possible solutions to the final recommended option. Included are the economic justifications associated with the chosen solution along with application for environmental permitting for the selected project for construction. This final report will summarize the results of execution of an EPC (energy performance contract) investment grade audit (IGA) which lead to an energy services agreement (ESA). The project includes scope of work to design and install energy conservation measures which are guaranteed by the contractor to be self-funding over its twenty year contract duration. The cost recovery is derived from systems performance improvements leading to energy savings. The prime focus of this EPC effort is to provide a replacement solution for Eastern Illinois University’s aging and failing circa 1925 central steam production plant. Twenty-three ECMs were considered viable whose net impact will provide sufficient savings to successfully support the overall project objectives.

  13. Power Plant Replacement Study

    SciTech Connect

    Reed, Gary

    2010-09-30

    This report represents the final report for the Eastern Illinois University power plant replacement study. It contains all related documentation from consideration of possible solutions to the final recommended option. Included are the economic justifications associated with the chosen solution along with application for environmental permitting for the selected project for construction. This final report will summarize the results of execution of an EPC (energy performance contract) investment grade audit (IGA) which lead to an energy services agreement (ESA). The project includes scope of work to design and install energy conservation measures which are guaranteed by the contractor to be self‐funding over its twenty year contract duration. The cost recovery is derived from systems performance improvements leading to energy savings. The prime focus of this EPC effort is to provide a replacement solution for Eastern Illinois University’s aging and failing circa 1925 central steam production plant. Twenty‐three ECMs were considered viable whose net impact will provide sufficient savings to successfully support the overall project objectives.

  14. Total disc replacement.

    PubMed

    Vital, J-M; Boissière, L

    2014-02-01

    Total disc replacement (TDR) (partial disc replacement will not be described) has been used in the lumbar spine since the 1980s, and more recently in the cervical spine. Although the biomechanical concepts are the same and both are inserted through an anterior approach, lumbar TDR is conventionally indicated for chronic low back pain, whereas cervical TDR is used for soft discal hernia resulting in cervicobrachial neuralgia. The insertion technique must be rigorous, with precise centering in the disc space, taking account of vascular anatomy, which is more complex in the lumbar region, particularly proximally to L5-S1. All of the numerous studies, including prospective randomized comparative trials, have demonstrated non-inferiority to fusion, or even short-term superiority regarding speed of improvement. The main implant-related complication is bridging heterotopic ossification with resulting loss of range of motion and increased rates of adjacent segment degeneration, although with an incidence lower than after arthrodesis. A sufficiently long follow-up, which has not yet been reached, will be necessary to establish definitively an advantage for TDR, particularly in the cervical spine. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Effects of epidermal growth factor receptor blockade on ependymoma stem cells in vitro and in orthotopic mouse models.

    PubMed

    Servidei, Tiziana; Meco, Daniela; Trivieri, Nadia; Patriarca, Valentina; Vellone, Valerio Gaetano; Zannoni, Gian Franco; Lamorte, Giuseppe; Pallini, Roberto; Riccardi, Riccardo

    2012-09-01

    Some lines of evidence suggest that tumors, including ependymoma, might arise from a subpopulation of cells, termed cancer stem cells (CSCs), with self-renewal and tumor-initiation properties. Given the strict dependence of CSCs on epidermal growth factor (EGF) through EGF receptor (EGFR), we investigated the effects of EGFR inhibitors in ependymoma-stem cells (SCs) in vitro and in orthotopic mouse models. We established two ependymoma-SC lines from two recurrent pediatric ependymoma. Both lines expressed markers of radial glia--the candidate SCs of ependymoma--and showed renewal ability, multipotency, and tumorigenicity after orthotopic implantation, despite markedly different expression of CD133 (94 vs. 6%). High phosphorylated-EGFR/EGFR ratio was detected, which decreased after differentiation. EGFR inhibitors (gefitinib and AEE788) reduced clonogenicity, proliferation and survival of ependymoma-SC lines dose-dependently, and blocked EGF-induced activation of EGFR, Akt and extracellular signal-regulated kinase 1/2. Overall, AEE788 was more effective than gefitinib. EGFR blockade as well as differentiation strongly reduced CD133 expression. However, ex vivo treatment with AEE788 did not impair orthotopic tumor engraftment, whereas ex vivo differentiation did, suggesting that CD133 does not absolutely segregate for tumorigenicity in ependymoma-SCs. Orally administered AEE788 prolonged survival of mice bearing ependymoma-SC-driven orthotopic xenografts from 56 to 63 days, close to statistical significance (log-rank p=0.06). Our study describes for the first time EGFR signaling in ependymoma-SCs and the effects of EGFR blockade in complementary in vitro and in vivo systems. The experimental models we developed can be used to further investigate the activity of EGFR inhibitors or other antineoplastic agents in this tumor.

  16. Photoimmunotherapy lowers recurrence after pancreatic cancer surgery in orthotopic nude mouse models

    PubMed Central

    Maawy, Ali A.; Hiroshima, Yukihiko; Zhang, Yong; Garcia-Guzman, Miguel; Luiken, George A.; Kobayashi, Hisataka; Hoffman, Robert M.; Bouvet, Michael

    2015-01-01

    Introduction Photoimmunotherapy (PIT) is based on the use of a monoclonal antibody specific to cancer epitopes conjugated to a photosensitizer near-infrared (NIR) phthalocyanine dye (IR700). In this study, PIT with IR700 conjugated to anti-carcinoembryonic antigen (CEA) was used as an adjunct to surgery in orthotopically-implanted human pancreatic cancer in a nude mouse model in order to eliminate microscopic disease in the tumor bed and prevent local as well as metastatic recurrence. Materials & Methods Athymic nude mice were orthotopically implanted with the human pancreatic cancer cell line BxPC3 expressing green fluorescent protein (GFP). After tumor engraftment, the mice were divided into two groups: bright light surgery (BLS) + anti-CEA-IR700 + 690 nm laser (PIT) and BLS only. Anti-CEA-IR700 (100 μg) was administered to the treatment group via tail vein injection 24 hours prior to therapy. Tumors were resected and the surgical bed was treated with intraoperative phototherapy at an intensity of 150 mW/cm2 for 30 minutes. Mice were imaged non-invasively for 8 weeks using an OV-100 small animal fluorescence imager. Results BLS+PIT reduced local recurrence to 1/7 mice to 7/7 mice with BLS-only (p=0.001) and metastatic recurrence to 2/7 mice compared to 6/7 mice with BLS-only (p=0.03). Local tumor growth continued at a rapid rate after BLS only compared to BLS+PIT where almost no local growth occurred. There was a significant difference in tumor size between mice in the BLS+PIT (2.14 mm2, 95% CI [6.34, −2.06] and BLS-only groups (115.2 mm2, 95% CI [141.6, 88.8]) (p<0.001) at 6 weeks after surgery. There was also a significant difference in tumor weight between the BLS+PIT group (6.65 mg, 95% CI [19.65, −6.35] and BLS-only group (1100 mg, 95% CI [1406, 794] at 8 weeks (p<0.001) after surgery. Conclusions PIT holds promise in the treatment of pancreatic cancer and may serve as a useful adjunct to surgery in the eradication of microscopic residual disease that

  17. Orthotopic liver transplantation without venovenous bypass using the conventional and piggyback techniques.

    PubMed

    Vieira de Melo, P S; Miranda, L E C; Batista, L L; Neto, O C L F; Amorim, A G; Sabat, B D; Cândido, H L L; Adeodato, L C L; Lemos, R S; Carvalho, G L; Lacerda, C M

    2011-05-01

    Orthotopic liver transplantation is a widely used procedure for the treatment of irreversible liver diseases for which there is no possibility of medical treatment. When this procedure is performed by the conventional technique, the retrohepatic vena cava is removed along with the native liver. The inferior vena cava (IVC) remains clamped until the revascularization of the graft, and in this period there is a reduction in the venous return, which may induce a fall by up to 50% in the cardiac output with hemodynamic instability and a fall in renal perfusion pressure. The use of a portal-femoral-axillary venovenous bypass system, in which the blood from the femoral and portal veins returns to the heart via the axillary vein propelled by a centrifugal pump, is intended to minimize the effects of the IVC clamping. In the piggyback (PB) technique, the native liver is removed and the IVC of the recipient is preserved and only partially clamped. We have employed both techniques without the use of venovenous bypass for 10 years. The objective of this study was to compare the results obtained from the use of the two techniques. A retrospective analysis was performed of 195 patients transplanted between 1999 and 2008: 125 by the conventional technique and 70, the PB technique. The intraoperative parameters were analyzed (surgical time, ischemia time, use of blood products, and diuresis), as well as intensive care support (duration of stay in intensive care unit and use of vasoactive drugs), period of intubation, length of hospital stay, renal function, graft function, postoperative complications, retransplantation, and patient survival. The PB group showed a reduction in surgical time, warm ischemia time, the use of packed red blood cells concentrates, and fresh frozen plasma, as well as mortality at 30 days (P<.05). There were no differences in relation to cold ischemia time, intraoperative diuresis; length of stay and use of vasoactive drugs in the intensive care unit; the

  18. Incidence and treatment of hepatic artery complications after orthotopic liver transplantation

    PubMed Central

    Zhao, Ji-Chun; Lu, Shi-Chun; Yan, Lu-Nan; Li, Bo; Wen, Tian-Fu; Zeng, Yong; Cheng, Nan-Sheng; Wang, Jing; Luo, Yan; Pen, Yu-Lan

    2003-01-01

    AIM: To investigate the incidence and treatment of hepatic artery complications after orthotopic liver transplantation. METHODS: From February 1999 to May 2002, orthotopic liver transplantations (OLT) were performed in 72 patients with end-stage liver diseases with an average age of 40.2 ± 13.6 years (ranged from 11 to 68 years), 56 were males and 16 females. The preoperative evaluation for the 72 patients was performed using duplexsonography, abdominal CT scan, and angiography of the hepatic artery. All donor grafts were perfused and preserved in University of Wisconsin solution at 4 °C. OLT was performed with standard techniques with or without a veno-venous bypass. Reconstructions of hepatic artery were performed between the branch patches of gastroduodenal/hepatic or splenic/common hepatic artery confluence of the donors and recipients, and an end-to-end anastomosis between other arterial vessels of the donors and recipients was done. Arterial anastomosis was performed with interrupted 7-0/8-0 monofilament polypropylene suture under 3.5 x loupe magnification. Diagnosis of the complications of hepatic artery after OLT was based on the clinical presentations, ultrasound findings and arterial angiography. All patients were followed up regularly for duplex ultrasound scan after discharge. RESULTS: The overall incidence of arterial complications in 72 patients after OLTs was 1.4% (1/72). One 3 cm pseudoaneurysm at the side of anastomotic site of hepatic artery was found by urgent arteriogram due to hemoperitoneum secondary to bile leakage after OLT. Subsequently the pseudoaneurysm was successfully embolized and the blood flow toward the donor liver in hepatic artery remained. The overall postoperative 30-day mortality rate was 8.33%. The one-year survival rate was 83.72% in 50 patients with benign diseases and was 71.43% in 22 patients with malignant diseases following OLT. No death associated with complications of hepatic artery occurred. CONCLUSION: Careful

  19. Targeted contrast-enhanced ultrasound imaging of angiogenesis in an orthotopic mouse tumor model of renal carcinoma.

    PubMed

    Wei, Shuping; Fu, Ninghua; Sun, Yu; Yang, Zhijian; Lei, Li; Huang, Pengfei; Yang, Bin

    2014-06-01

    Previous studies have reported that microbubbles bearing targeting ligands to molecular markers of angiogenesis can be successfully detected by ultrasound imaging in various animal models of solid cancer. In the present study, we sought to investigate the activity of microbubbles targeted to vascular endothelial growth factor receptor 2 (VEGFR2) in an orthotopic model of renal cell carcinoma (RCC). Microbubbles conjugated to an anti-VEGFR2 antibody (MBV) were compared with microbubbles conjugated to an isotype control antibody (MBC) or naked microbubbles (MBN). An orthotopic mouse model of human RCC was established by surgically implanting an established tumor within the renal capsule in mice. Tumor growth and blood flow were verified by B-mode and color Doppler ultrasound imaging. VEGFR2 expression within the tumor and renal parenchyma was detected by immunohistochemistry. The duration of contrast enhancement of MBV was much longer than those of MBN and MBC when assessed over 10 min. The baseline-subtracted contrast intensity within the tumor was higher for MBV than for MBC and MBN (p < 0.01). Additionally, the contrast intensity for MBV was significantly higher in the tumor region than in normal parenchyma (p < 0.01). Microbubbles targeting VEGFR2 exhibit suitable properties for imaging angiogenesis in orthotopic models of renal cell carcinoma, with potential applications in life science research and clinical medicine. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  20. Disruptive TP53 Mutation is Associated with Aggressive Disease Characteristics in an Orthotopic Murine Model of Oral Tongue Cancer

    PubMed Central

    Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J.; Zhao, Mei; Pickering, Curtis R.; Zhou, Ge; Sandulache, Vlad C.; Wheeler, David A.; Gibbs, Richard A.; Caulin, Carlos; Myers, Jeffrey N.

    2011-01-01

    Purpose To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer, and to correlate TP53 mutation status with these findings. Experimental Design Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and western blot analysis for the p53 protein after induction with 5-fluorouracil was performed. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or non-disruptive), and level of p53 protein expression. The behavior of tumors in these different groups was compared. Results The 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations. Conclusions HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. PMID:21903770

  1. Disruptive TP53 mutation is associated with aggressive disease characteristics in an orthotopic murine model of oral tongue cancer.

    PubMed

    Sano, Daisuke; Xie, Tong-Xin; Ow, Thomas J; Zhao, Mei; Pickering, Curtis R; Zhou, Ge; Sandulache, Vlad C; Wheeler, David A; Gibbs, Richard A; Caulin, Carlos; Myers, Jeffrey N

    2011-11-01

    To characterize tumor growth and metastatic potential in head and neck squamous cell carcinoma (HNSCC) cell lines in an orthotopic murine model of oral tongue cancer and to correlate TP53 mutation status with these findings. Cells from each of 48 HNSCC cell lines were orthotopically injected into the oral tongues of nude mice. Tumor volume, cervical lymph node metastasis, and mouse survival were recorded. Direct sequencing of the TP53 gene and Western blot analysis for the p53 protein after induction with 5-fluorouracil was conducted. Cell lines were categorized as either mutant TP53 or wild-type TP53, and lines with TP53 mutation were further categorized on the basis of type of mutation (disruptive or nondisruptive) and level of p53 protein expression. The behavior of tumors in these different groups was compared. These 48 HNSCC cell lines showed a wide range of behavior from highly aggressive and metastatic to no tumor formation. Mice injected with cells harboring disruptive TP53 mutations had faster tumor growth, greater incidence of cervical lymph node metastasis, and shorter survival than mice injected with cells lacking these mutations. HNSCC cell lines display a wide spectrum of behavior in an orthotopic model of oral cancer. Cell lines with disruptive TP53 mutations are more aggressive in this system, corroborating clinical reports that have linked these mutations to poor patient outcome. ©2011 AACR

  2. Endovascular treatment with primary stenting of inferior cava vein torsion following orthotopic liver transplantation with modified piggyback technique.

    PubMed

    Ferro, Carlo; Andorno, Enzo; Guastavino, Andrea; Rossi, Umberto G; Seitun, Sara; Bovio, Giulio; Valente, Umberto

    2014-03-01

    This study was undertaken to evaluate primary stenting in patients with inferior vena cava torsion after orthotopic liver transplantation performed with modified piggyback technique. From November 2003 to October 2010, six patients developed clinical, laboratory and imaging findings suggestive of caval stenosis, after a mean period of 21 days from an orthotopic liver transplantation performed with modified piggyback technique. Vena cavography showed stenosis due to torsion of the inferior vena cava at the anastomoses and a significant caval venous pressure gradient. All patients were treated with primary stenting followed by in-stent angioplasty in three cases. In all patients, the stents were successfully positioned at the caval anastomosis and the venous gradient pressure fell from a mean value of 10 to 2 mmHg. Signs and symptoms resolved in all six patients. One patient died 3 months after stent placement due to biliary complications. No evidence of recurrence or complications was noted during the follow-up (mean 49 months). Primary stenting of inferior vena cava stenosis due to torsion of the anastomoses in patients receiving orthotopic liver transplantation with modified piggyback technique is a safe, effective and durable treatment.

  3. Overexpression of normal and mutated forms of HRAS induces orthotopic bladder invasion in a human transitional cell carcinoma.

    PubMed

    Theodorescu, D; Cornil, I; Fernandez, B J; Kerbel, R S

    1990-11-01

    Recent studies have shown that orthotopic (transurethral) transplantation of human bladder cancer cell lines into nude mice permits tumor growth that accurately reflects their clinical malignant status in the original host. Thus, such a system allows a unique opportunity to analyze the genetic events involved in the conversion of low-grade bladder cancer, the vast majority of which are curable, to the high-grade life-threatening form of the disease. Since 5-10% of transitional cell carcinomas (TCCs) have been shown to contain a mutated HRAS gene, and protein expression levels of all forms of HRAS have been correlated with TCC progression, we chose to study the contribution of the HRAS oncogene in bladder tumor progression. We evaluated the effects of transfection of normal or mutated HRAS genes into a human TCC, called RT-4, that behaves as a superficial noninvasive papillary tumor after transurethral orthotopic inoculation into athymic nude mice. We found that overexpression of either transfected normal or mutated HRAS genes converted RT-4 cells to express an invasive phenotype remarkably similar in nature to the clinical behavior of high-grade bladder carcinomas. These results suggest a role for overexpressed normal or mutated RAS genes in human bladder carcinoma progression, and highlight the importance of using orthotopic inoculation systems for evaluation of the contribution of oncogenes to malignant tumor progression.

  4. Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours

    PubMed Central

    Steen, Stig; Paskevicius, Audrius; Liao, Qiuming; Sjöberg, Trygve

    2016-01-01

    Abstract Objectives. The aim of this study was to demonstrate safe orthotopic transplantation of porcine donor hearts harvested 24 hours after brain death and preserved for 24 hours before transplantation. Design. Circulatory normalization of brain dead (decapitated) pigs was obtained using a new pharmacological regimen (n = 10). The donor hearts were perfused at 8 °C in cycles of 15 min perfusion followed by 60 min without perfusion. The perfusate consisted of an albumin-containing hyperoncotic cardioplegic nutrition solution with hormones and erythrocytes. Orthotopic transplantation was done in 10 recipient pigs after 24 hours’ preservation. Transplanted pigs were monitored for 24 hours, then an adrenaline stress test was done. Results. All transplanted pigs were stable throughout the 24-hour observation period with mean aortic pressure around 80 mmHg and normal urine production. Mean right and left atrial pressures were in the range of 3–6 and 5–10 mmHg, respectively. Blood gases at 24 hours did not differ from baseline values. The adrenaline test showed a dose dependent response, with aortic pressure increasing from 98/70 to 220/150 mmHg and heart rate from 110 to 185 beats/min. Conclusion. Orthotopic transplantation of porcine hearts harvested 24 hours after brain death and preserved for 24 hours can be done safely. PMID:26882241

  5. Non-invasive fluorescent-protein imaging of orthotopic pancreatic-cancer-patient tumorgraft progression in nude mice.

    PubMed

    Suetsugu, Atsushi; Katz, Matthew; Fleming, Jason; Truty, Mark; Thomas, Ryan; Saji, Shigetoyo; Moriwaki, Hisataka; Bouvet, Michael; Hoffman, Robert M

    2012-08-01

    In order to individualize and therefore have more effective treatment for pancreatic cancer, we have developed a multicolor, imageable, orthotopic mouse model for individual patients with pancreatic cancer by passaging their tumors through transgenic nude mice expressing green fluorescent protein (GFP) and red fluorescent protein (RFP). The tumors acquired brightly fluorescent stroma from the transgenic host mice, which was stably associated with the tumors through multiple passages. In the present study, pancreatic cancer patient tumor specimens were initially established in NOD.CB17-Prkdc(scid)/NcrCrl (NOD/SCID) mice. The tumors were then passaged orthotopically into transgenic nude mice ubiquitously expressing GFP and subsequently to nude mice ubiquitously expressing RFP. The tumors, with very bright GFP and RFP stroma, were then orthotopically passaged to non-transgenic nude mice. It was possible to image the brightly fluorescent tumors non-invasively longitudinally as they progressed in the non-transgenic nude mice. This non-invasive imageable tumorgraft model will be valuable to screen for effective treatment options for individual patients with pancreatic cancer, as well as for the discovery of improved agents for this treatment-resistant disease.

  6. Tumor-Specific Fluorescent Antibody Imaging Enables Accurate Staging Laparoscopy in an Orthotopic Model of Pancreatic Cancer

    PubMed Central

    Cao, Hop S Tran; Kaushal, Sharmeela; Metildi, Cristina A; Menen, Rhiana S; Lee, Claudia; Snyder, Cynthia S; Messer, Karen; Pu, Minya; Luiken, George A; Talamini, Mark A; Hoffman, Robert M; Bouvet, Michael

    2014-01-01

    Background/Aims Laparoscopy is important in staging pancreatic cancer, but false negatives remain problematic. Making tumors fluorescent has the potential to improve the accuracy of staging laparoscopy. Methodology Orthotopic and carcinomatosis models of pancreatic cancer were established with BxPC-3 human pancreatic cancer cells in nude mice. Alexa488-anti-CEA conjugates were injected via tail vein 24 hours prior to laparoscopy. Mice were examined under bright field laparoscopic (BL) and fluorescence laparoscopic (FL) modes. Outcomes measured included time to identification of primary tumor for the orthotopic model and number of metastases identified within 2 minutes for the carcinomatosis model. Results FL enabled more rapid and accurate identification and localization of primary tumors and metastases than BL. Using BL took statistically significantly longer time than FL. More metastatic lesions were detected and localized under FL compared to BL and with greater accuracy, with sensitivities of 96% vs. 40%, respectively, when compared to control. FL was sensitive enough to detect metastatic lesions <1mm. Conclusions The use of fluorescence laparoscopy with tumors labeled with fluorophore-conjugated anti-CEA antibody permits rapid detection and accurate localization of primary and metastatic pancreatic cancer in an orthotopic model. The results of the present report demonstrate the future clinical potential of fluorescence laparoscopy. PMID:22369743

  7. About recent developments of synthetic polymers for a suitable cell adhesion/growth support in tissue engineering-based either augmentation cystoplasty or neobladder.

    PubMed

    Alberti, Contardo

    2014-01-01

    Among the regenerative medicine technologies, the tissue engineering has emerged, in recent years, as a prominent tool, particularly given the tremendous developments in the field of synthetic polymer-based scaffolds. Scaffold surface coatings with either extracellular matrix (ECM) proteins or integrin-binding bioactive peptide sequences, such as RDG, proved to be extremely useful to enhance cell adhesion and growth. Nevertheless, about it, excellent effects may be reached by electrospinning-obtained nanofiber-structured synthetic polymer scaffold – such as polyurethane or polyethylene-terephthalate electrospun nanofibers – without resorting to surface- coated adhesion proteins. As for bladder tissue engineering, properly cell-seeded synthetic biomaterial-based scaffolds allow today timely chances to obtain constructs provided with specific bladder native tissue-like both histological-immunohistochemical and functional-dynamic features. Recent bright advances in the tissue engineering research, particularly in the area of materials science – together with increasing availability of suitable bioreactors – and stem cell biology, make foreseeable, in the near future, further technological improvements that might widen the clinical applications of bladder tissue engineering up to whole bladder replacement in radical tumor surgery.

  8. Hormone replacement therapy and longevity.

    PubMed

    Comhaire, F

    2016-02-01

    To assess whether hormone replacement therapy influences longevity, an analysis was made of published life tables allowing for the calculation of the relative benefit of hormone replacement therapy on longevity in men with late onset hypogonadism and in post-menopausal women. It was found that testosterone replacement therapy of men suffering from late onset hypogonadism increased survival rate by 9-10% in 5 years, similar to that of eugonadal, non-LOH men with normal endogenous testosterone secretion. Oestrogen replacement therapy resulted in increased survival by 2.6% in 5 years. It is concluded that hormone replacement therapy increases longevity.

  9. Restricted Crystalloid Fluid Therapy during Orthotopic Liver Transplant Surgery and its Effect on Respiratory and Renal Insufficiency in the Early Post-operative Period: A Randomized Clinical Trial.

    PubMed

    Sahmeddini, M A; Janatmakan, F; Khosravi, M B; Ghaffaripour, S; Eghbal, M H; Nickeghbalian, S; Malek-Hosseini, S A

    2014-01-01

    Respiratory and renal insufficiencies are common dysfunctions during post-liver transplantation period that increase post-operative mortality and morbidity rates. Intra-operative fluid therapy is an important factor associated with pulmonary and renal insufficiency. To evaluate the relation between intra-operative fluid therapy and early renal and respiratory insufficiency after liver transplantation. In this randomized clinical study, 67 adult patients with end-stage liver disease who underwent orthotopic deceased donor liver transplantation were randomly allocated into two groups. The restricted fluid group, which received a controlled fluid administration of normal saline, 5 mL/kg/hr during anesthesia, and non-restricted fluid group received a controlled infusion of normal saline 10 mL/kg/hr during anesthesia. Early post-operative respiratory and renal insufficiency in both groups were assessed. The patients were monitored during the three stages of liver transplantation for their hemodynamic indices. The trial is registered with the Iranian Randomized Clinical Trial Registry, number IRCT2013101811662N4. The baseline demographic and clinical characteristics were similar in both studied groups. The prevalence of respiratory insufficiency in the non-restricted fluid group (15%) significantly (p=0.01) higher than that in the restricted fluid group (0%). The post-operative mean±SD serum creatinine was 1.0±0.1 mg/dL in the non-restricted fluid group and 1.1±0.2 in the restricted fluid group (p=0.43). No patients in the studied groups required post-operative continuous renal replacement therapy. Restricted crystalloid fluid administration during orthotropic liver transplantation though decreased post-operative chance of pulmonary insufficiency, did not increase renal dysfunction.

  10. Restricted Crystalloid Fluid Therapy during Orthotopic Liver Transplant Surgery and its Effect on Respiratory and Renal Insufficiency in the Early Post-operative Period: A Randomized Clinical Trial

    PubMed Central

    Sahmeddini, M. A.; Janatmakan, F.; Khosravi, M. B.; Ghaffaripour, S.; Eghbal, M. H.; Nickeghbalian, S.; Malek-Hosseini, S. A.

    2014-01-01

    Background: Respiratory and renal insufficiencies are common dysfunctions during post-liver transplantation period that increase post-operative mortality and morbidity rates. Intra-operative fluid therapy is an important factor associated with pulmonary and renal insufficiency. Objective: To evaluate the relation between intra-operative fluid therapy and early renal and respiratory insufficiency after liver transplantation. Methods: In this randomized clinical study, 67 adult patients with end-stage liver disease who underwent orthotopic deceased donor liver transplantation were randomly allocated into two groups. The restricted fluid group, which received a controlled fluid administration of normal saline, 5 mL/kg/hr during anesthesia, and non-restricted fluid group received a controlled infusion of normal saline 10 mL/kg/hr during anesthesia. Early post-operative respiratory and renal insufficiency in both groups were assessed. The patients were monitored during the three stages of liver transplantation for their hemodynamic indices. The trial is registered with the Iranian Randomized Clinical Trial Registry, number IRCT2013101811662N4. Results: The baseline demographic and clinical characteristics were similar in both studied groups. The prevalence of respiratory insufficiency in the non-restricted fluid group (15%) significantly (p=0.01) higher than that in the restricted fluid group (0%). The post-operative mean±SD serum creatinine was 1.0±0.1 mg/dL in the non-restricted fluid group and 1.1±0.2 in the restricted fluid group (p=0.43). No patients in the studied groups required post-operative continuous renal replacement therapy. Conclusions: Restricted crystalloid fluid administration during orthotropic liver transplantation though decreased post-operative chance of pulmonary insufficiency, did not increase renal dysfunction. PMID:25184031

  11. Functional replacements for gluten.

    PubMed

    Zannini, Emanuele; Jones, Julie Miller; Renzetti, Stefano; Arendt, Elke K

    2012-01-01

    Celiac disease (CD) is an immune-mediated disease triggered in genetically susceptible individuals by ingested gluten from wheat, rye, barley, and other closely related cereal grains. Currently, the only therapy able to normalize the clinical and histological manifestation of the disease is a strict and life-long gluten-free (GF) diet. The replacement of gluten presents a significant technological challenge, as it is an essential structure-building protein, which is necessary for formulating high-quality baked goods. The objective of this paper is to review some basics about CD, its current prevalence, and the recent advances in the preparation of high-quality GF breads using GF flours, starches, hydrocolloids, gums, and novel functional ingredients and technologies.

  12. Antenna grout replacement system

    NASA Technical Reports Server (NTRS)

    Mcclung, C. E. (Inventor)

    1983-01-01

    An epoxy grout suitable for use in mounting and positioning bearing runner plates used in hydrostatic bearing assemblies for rotatably mounting large radio telescope structures to stationary support pedestals is described. The epoxy grout may be used in original mountings or may be used as part of a replacement system for repairing cavities in existing grout resulting from grout deterioration. The epoxy grout has a relatively short work life and cure time even in the presence of hydraulic oil. The epoxy grout cures without shrinking or sagging to form a grout which is sufficiently strong and durable to provide a grout especially well suited for use under the high pressure loading and close tolerance requirements of large hydrostatic bearing assemblies.

  13. Aerocoat 7 Replacement Coatings

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Kennedy Space Center has used Aerocoat 7 (AR-7) to protect stainless-steel flex hoses at Launch Complex (LC-39) and hydraulic lines of the Mobile Launcher Platform (MLP) because it provides excellent corrosion protection in low-temperature applications. The Sovereign Company produced AR-7 exclusively for NASA but discontinued production because the coating released high levels of volatile organic compounds (VOCs) and had a significant environmental impact. The purpose of this project was to select and evaluate potential replacement coatings for AR-7 that would be more environmentally sound. The physical and mechanical properties of commercially available coatings were investigated through the Internet. The ideal coating would be fluid enough to penetrate the outer mesh of a stainless-steel flex hose and coat the inner hose, and flexible enough to withstand the movement of the hose, as well as the expansion and contraction of its metal caused by changes in temperature.

  14. Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients.

    PubMed

    Nwaba, A; MacQuillan, G; Adams, L A; Garas, G; Delriviere, L; Augustson, B; DeBoer, B; Moody, H; Jeffrey, G P

    2013-03-01

    Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  15. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation

    PubMed Central

    Sosa, Rebecca A.; Zarrinpar, Ali; Lassman, Charles R.; Naini, Bita V.; Datta, Nakul; Rao, Ping; Harre, Nicholas; Zheng, Ying; Hoffmann, Alexander; Busuttil, Ronald W.; Gjertson, David W.; Zhai, Yuan; Kupiec-Weglinski, Jerzy W.; Reed, Elaine F.

    2016-01-01

    BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant. METHODS. We measured the expression of 38 cytokines, chemokines, and growth factors in preoperative and postoperative recipient circulating systemic blood (before transplant and 1 day, 1 week, and 1 month after transplant) and intraoperative portal blood (before and after reperfusion) of 53 OLT patients and analyzed this expression in relation to biopsy-proven IRI (n = 26 IRI+; 27 IRI–), clinical liver function tests early (days 1–7) after transplant, and expression of genes encoding cytokine receptors in biopsies of donor allograft taken before and after reperfusion. RESULTS. Bilirubin and arginine transaminase levels early after transplant correlated with IRI. Fourteen cytokines were significantly increased in the systemic and/or portal blood of IRI+ recipients that shifted from innate to adaptive-immune responses over time. Additionally, expression of cognate receptors for 10 of these cytokines was detected in donor organ biopsies by RNAseq. CONCLUSION. These results provide a mechanistic roadmap of the early immunological events both before and after IRI and suggest several candidates for patient stratification, monitoring, and treatment. FUNDING. Ruth L. Kirschstein National Research Service Award T32CA009120, Keck Foundation award 986722, and a Quantitative & Computational Biosciences Collaboratory Postdoctoral Fellowship. PMID:27942590

  16. Role of Interventional Radiology in the Treatment of Biliary Strictures Following Orthotopic Liver Transplantation

    SciTech Connect

    Righi, Dorico; Cesarani, Federico; Muraro, Emanuele; Gazzera, Carlo; Salizzoni, Mauro; Gandini, Giovanni

    2002-01-15

    Purpose: To evaluate the efficacy and safety of percutaneous treatment of biliary strictures complicating orthotopic liver transplantation (OLT). Methods: Between October 1990 and May 2000, 619 patients underwent 678 liver transplants. Seventy of the 619 (11%) patients were found to be affected by biliary strictures by July 2000. Bilioplasty was performed in 51 of these 70 (73%) patients. A cohort of 33 of 51 (65%) patients were clinically followed for more than 12 months after the last percutaneous treatment and included in the survey results. Results: After one to three treatments 24 of 33 (73%)patients were stricture-free on ultrasound and MR cholangiography follow-up. A delayed stricture recurrence required a fourth percutaneous bilioplasty in two of 33 (6%) patients. A surgical bilioenteric anastomosis was performed in six of 33 (18%) patients.Retransplantation was performed due to ischemic damage in one of 33(3%) patients. Conclusion: Interventional radiology is an effective therapeutic alternative for the treatment of most biliary strictures complicating OLT. It has a high success rate and should be considered before surgical interventions. Elective surgery may be necessary in a few failed cases or those with more severe and extensive biliary strictures.

  17. Vascular steal of the portal vein after orthotopic liver transplant: intraoperative sonographic diagnosis.

    PubMed

    Horrow, Mindy M; Phares, Matthew A; Viswanadhan, Narayan; Zaki, Radi; Araya, Victor; Ortiz, Jorge

    2010-01-01

    Spontaneous splenorenal shunts (SSRSs) are portosystemic connections between the splenic vein and the left renal vein (LRV) that develop commonly in patients with portal hypertension. (1) They reportedly occur in 18% to 19% of patients evaluated for a liver transplant. (2),(3) As the liver become more cirrhotic, a major steal phenomenon may occur, whereby blood is shunted from the high-resistance venous bed of the liver to the lower systemic pressure of the LRV. (4) Not infrequently, an SSRS will go undetected during orthotopic liver transplantation because dissection is limited to the right upper quadrant. The importance of these shunts may be underappreciated preoperatively by the radiologist. Usually, if small, these shunts will involute without incident when the lower-resistance allograft is implanted. (5),(6) Larger varices, those greater than 10 mm at the level of transition into the LRV, are more likely to steal blood from the liver, causing allograft failure and possibly death. (4),(7),(8) It is therefore important to document on preoperative imaging the size and location of portosystemic varices in any patient being evaluated for liver transplantation. We present a case in which intraoperative sonography showed a large SSRS that impaired hepatic portal inflow after transplantation, ultimately resulting in the patient's death.

  18. GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

    PubMed Central

    Zaouali, Mohamed Amine; Panisello, Arnau; Lopez, Alexandre; Castro, Carlos; Folch, Emma; Carbonell, Teresa; Rolo, Anabela; Palmeira, Carlos Marques; Garcia-Gil, Agustin; Adam, René; Roselló-Catafau, Joan

    2017-01-01

    We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia–reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention. PMID:28282906

  19. Uptake of verteporfin by orthotopic xenograft pancreas models with different levels of aggression

    NASA Astrophysics Data System (ADS)

    O'Hara, Julia; Samkoe, Kimberley S.; Chen, Alina; Hoopes, P. Jack; Rizvi, Imran; Hasan, Tayyaba; Pogue, Brian W.

    2009-06-01

    Pancreatic cancer is an aggressive disease with a poor prognosis, usually treated with chemoradiation therapy. Interstitial photodynamic therapy is a potentially effective adjuvant treatment that is under development. In the current study, two orthotopic pancreatic cancer models (AsPC-1 and Panc-1), have been characterized with respect to growth rates, morphology and liposomal drug (Verteporfin) uptake and distribution in SCID mice. Fluorescence of Verteporfin was measured in liver and tumor in vivo using a PDT fluorescence dosimeter with measurements taken before and up to one hour after tail vein injection. Fluorescence reached a plateau by about 15 minutes and did not decrease over the first hour. At time points from 15 minutes to 24 hrs, the internal organs (kidney, spleen, pancreas, tumor, muscle, lung, liver, and skin were excised and scanned on a Typhoon imager. The ratio of fluorescence in tumor versus normal tissues was analyzed with image processing, calculated at each time point and compared to in vivo results. Tissue distribution of Verteporfin in relation to functional vasculature marked by DiOc7 was carried out on frozen sections. Final analysis will result in determination of the ideal time point to administer light to achieve maximum tumor destruction while preserving normal tissue.

  20. Liver Transplantation in Man—II, a Report of two Orthotopic Liver Transplants in Adult Recipients

    PubMed Central

    Calne, R. Y.; Williams, Roger; Dawson, J. L.; Ansell, I. D.; Evans, D. B.; Flute, P. T.; Herbertson, P. M.; Joysey, V.; Keates, G. H. W.; Knill-Jones, R. P.; Mason, S. A.; Millard, P. R.; Pena, J. R.; Pentlow, B. D.; Salaman, J. R.; Sells, R. A.; Cullum, P. A.

    1968-01-01

    Two patients with primary hepatic malignancy were treated by hepatectomy and orthotopic liver transplantation. In both cases the donor liver was infused with cold solutions and kept chilled without continuous perfusion. There was immediate satisfactory hepatic function in both transplants. The first patient died after 11 weeks from overwhelming bacterial and fungal infections probably secondary to hepatic infarction due to thrombosis of the recipient hepatic artery. The thrombus occurred at the site of the arterial clamp. In an attempt to control the growth before transplantation, the patient had been treated with large doses of chlorambucil, which resulted in extreme marrow depression and septicaemia. The second patient developed cholestatic jaundice during the second and third weeks after transplantation, with histological evidence of mild rejection, which was controlled by increasing the dose of immunosuppressive agents. He is now well, having returned to work six weeks after the operation. Though the first patient showed no evidence of rejection, it is concluded that patients receiving liver allografts should receive immunosuppressive therapy. ImagesFig. 2Fig. 8Fig. 2Fig. 3A and BFig. 4Fig. 6Fig. 1Fig. 5Fig. 7 PMID:4881064

  1. Positively charged polypeptide nanogel enhances mucoadhesion and penetrability of 10-hydroxycamptothecin in orthotopic bladder carcinoma.

    PubMed

    Guo, Hui; Xu, Weiguo; Chen, Jinjin; Yan, Lesan; Ding, Jianxun; Hou, Yuchuan; Chen, Xuesi

    2017-01-03

    Bladder cancer (BC) has become a serious public health problem due to its continuously rising incidence, high recurrence rate, and poor quality of life. Intravesical instillation of chemotherapy, one of common and important treatment strategy for BC, is restricted partially due to the short residence time and the low penetration ability of current antineoplastic agent formulations in clinic. Herein, a positively charged disulfide-core-crosslinked polypeptide nanogel of poly(l-lysine)-poly(l-phenylalanine-co-l-cystine) (PLL-P(LP-co-LC)) was synthesized. 10-Hydroxycamptothecin (HCPT) was loaded into the core via a facile diffusion to obtain loading nanogel (i.e., NG/HCPT). The reduction-responsive cationic polypeptide nanogel not only showed a high drug-loading efficiency, a prolonged residence time, and an improved tissue penetration capability, but also demonstrated an ability to accurately and rapidly release HCPT in bladder cancer cells. NG/HCPT exhibited superior cytotoxicity against human T24 bladder cancer cells compared to that of free HCPT in vitro. Moreover, the positively charged loading nanogel exhibited significantly enhanced antitumor efficacy and reduced side effects toward orthotopic bladder cancer model in vivo. Overall, the smart polypeptide nanogel with enhanced residence and permeability provides a promising drug delivery platform for local chemotherapy of BC.

  2. Effect of antibiotic prophylaxis on the risk of surgical site infection in orthotopic liver transplant.

    PubMed

    Asensio, Angel; Ramos, Antonio; Cuervas-Mons, Valentin; Cordero, Elisa; Sánchez-Turrión, Victor; Blanes, Marino; Cervera, Carlos; Gavalda, Joan; Aguado, Jose M; Torre-Cisneros, Julian

    2008-06-01

    Surgical site infections are common bacterial infections in orthotopic liver transplantation. The purpose of this study was to determine the incidence, timing, location, and risk factors, specifically antibiotic prophylaxis, for surgical site infections. A prospective study was performed that included a population of 1222 consecutive patients (73.0% males) who underwent liver transplantation in Spanish hospitals belonging to the Red de Estudio de la Infección en el Trasplante research network. One hundred seven patients developed surgical site infections. The predominant infection sites were incisional wound (53 episodes) and peritonitis (40 episodes). The timing of the organ/space surgical site infections was slightly delayed in comparison with incisional surgical site infections. Enterococcus spp., Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii were the predominant pathogens. Choledochojejunal or hepaticojejunal reconstruction (odds ratio, 4.2; 95% confidence interval, 1.6-10.7), previous liver or kidney transplant (odds ratio, 2.6; 95% confidence interval, 1.1-6.3), and more than 4 red blood cell units transfused (odds ratio, 2.0; 95% confidence interval, 1.1-3.4) were independently associated with the development of surgical site infections. Biliary reconstruction by choledochojejunostomy or hepaticojejunostomy increases the risk of surgical site infections.

  3. EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model.

    PubMed

    Singh, Amit; Xu, Jing; Mattheolabakis, George; Amiji, Mansoor

    2016-04-01

    In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Ionized hypomagnesemia in patients undergoing orthotopic liver transplantation: a complication of citrate intoxication.

    PubMed

    Scott, V L; De Wolf, A M; Kang, Y; Altura, B T; Virji, M A; Cook, D R; Altura, B M

    1996-09-01

    Using a new ion-selective electrode, plasma concentration of ionized magnesium was measured in nine adult patients undergoing orthotopic liver transplantation. Baseline plasma ionized magnesium (IMg2+) concentration (0.49 +/- 0.07 mmol/L) was slightly below normal values (0.55-0.66 mmol/L, 95% CI): Six patients had ionized hypomagnesemia and two of these had total hypomagnesemia. Ionized IMg2+ concentration progressively decreased during the dissection (0.45 +/- 0.07 mmol/L, p < 0.05) and anhepatic stage (0.38 +/- 0.07 mmol/L, p < 0.05) and returned toward baseline values by 2 hours after graft reperfusion. Plasma ionized calcium levels and acid-base status were maintained within normal limits during surgery. Serum citrate concentration increased during the dissection (0.58 +/- 0.60 mmol/L) and anhepatic stages (1.18 +/- 0.78 mmol/L), the result of transfusion of citrate-rich blood products in the absence of adequate hepatic function, and gradually returned toward baseline values after graft reperfusion. IMg2+ concentration inversely correlated with the plasma citrate concentration (r2 = 0.54). The results of this study demonstrate that ionized hypomagnesemia invariably occurs during liver transplantation and suggest that this derangement may be a clinical concern, because magnesium is an important cofactor for the maintenance of cardiovascular homeostasis. The data further suggest the clinical importance of supplementation with magnesium based on the monitoring of plasma IMg2+ concentration.

  5. Recurrence of hepatitis C virus infection after orthotopic liver transplantation: role of genotypes.

    PubMed

    Casino, C; Lilli, D; Rivanera, D; Sabrina, C; Rossi, M; Casciaro, G; Alfani, D; Mancini, C

    1999-01-01

    In this study, we evaluated the correlation between alanine aminotrasferase levels and hepatitis C virus genotypes in liver transplant patients. We studied 18 patients who had undergone orthotopic liver transplantation because of end-stage cirrhosis (n = 9) or hepatocellular carcinoma (n = 9) hepatitis C virus related. Serum HCV-RNA testing was performed monthly on all the 18 series of serum samples from the first week after liver transplant until the end of the follow up, this period ranging from 1 to 39 months. After liver transplantation, serum HCV-RNA was detected in 14 patients (78%). Of the 8 patients infected with subtype 1b. 1 remained asymptomatic, 2 developed acute liver failure and 5 developed chronic hepatitis. In patients infected with types 1a (Choo et al., 1989), 2a (Choo et al., 1989), with a mixed infection 1b/3 (Kuo et al., 1989) or with an undetermined genotype, significant laboratory abnormalities were not observed. Recurrence of hepatitis C virus infection after liver transplantation is common, and recurrent hepatitis occurs in 50% of cases. Genotype 1b appears to be associated with a higher rate of recurrent hepatitis, compared to other genotypes.

  6. Orthotopic liver transplantation: reversible Doppler US findings in the immediate postoperative period.

    PubMed

    Sanyal, Rupan; Lall, Chandana G; Lamba, Ramit; Verma, Sadhna; Shah, Shetal N; Tirkes, Temel; Berry, William A; Sandrasegaran, Kumaresan

    2012-01-01

    Orthotopic liver transplantation (OLT) is the only definitive treatment for irreversible acute liver failure and chronic liver disease. In the immediate postoperative period after OLT, patients are closely monitored with Doppler ultrasonography (US) to detect treatable vascular complications and ensure graft survival. The first postoperative Doppler US examination is performed fairly early on the first postoperative day, before surgical wound closure has been performed. The immediate postoperative images, obtained when the effects of surgery are very recent, often reveal an array of findings that may appear alarming but that tend to normalize within a few days and are compatible with changes related to the surgery itself. These findings include a starry-sky appearance of reperfusion hepatic edema, transient foci of increased echogenicity, pneumobilia, small fluid collections, perihepatic hematomas, pleural effusion, temporary elevation of hepatic arterial velocity, transient elevation of resistive index (RI), decreased RI with tardus parvus waveform, increased portal venous flow and mono- or biphasic waveforms of the hepatic veins. Most of these changes revert to normal in the first postoperative week; deterioration atypical of transient changes requires further evaluation.

  7. Survival of primates following orthotopic cardiac transplantation treated with total lymphoid irradiation and chemical immune suppression

    SciTech Connect

    Pennock, J.L.; Reitz, B.A.; Bieber, C.P.; Aziz, S.; Oyer, P.E.; Strober, S.; Hoppe, R.; Kaplan, H.S.; Stinson, E.B.; Shumway, N.E.

    1981-12-01

    Fractionated total lymphoid irradiation (TLI) has been used for attempts at induction of a donor-specific tolerant-like state in allograft recipients and for immunosuppressive effects. Cyclosporin A (Cy A) has been shown to suppress rejection of organ grafts in many species including man. The present study was designed to test the effectiveness of TLI in combination with either CY A or rabbit anticynomolgus thymocyte globulin (ATG) and azathioprine. Thirty-one orthotopic cardiac allografts were performed using surface cooling and total circulatory arrest in outbred cynomolgus monkeys. TLI was administered preoperatively in fractions of 100 rad until a total of 600 or 1800 rad was achieved. Cy A was administered 17 mg/kg/day. All treatment groups demonstrated extended survival. Myocardial biopsies as early as 4 weeks were consistent with mild rejection in all treatment groups. No significant synergistic effect upon survival could be demonstrated utilizing TLI plus Cy A when compared with using Cy A alone. TLI (1800 rad) plus ATG and azathioprine was associated with a high incidence of early death attributable to leukopenia and infection. Cy A alone or in combination with TLI was associated with the development of lymphoid malignancy.

  8. Survival of primates following orthotopic cardiac transplantation treated with total lymphoid irradiation and chemical immune suppression

    SciTech Connect

    Pennock, J.L.; Reitz, B.A.; Beiber, C.P.; Aziz, S.; Oyer, P.E.; Strober, S.; Hoppe, R.; Kaplan, H.S.; Stinson, E.B.; Shumway, N.E.

    1981-12-01

    Fractionated total lymphoid irradiation (TLI) has been used for attempts at induction of a donor-specific tolerant-like state in allograft recipients and for immunosuppressive effects. Cyclosporin A (Cy A) has been shown to suppress rejection of organ grafts in many species including man. The present study was designed to test the effectiveness of TLI in combination with either Cy A or rabbit anticynomolgus thymocyte globulin (ATG) and azathioprine. Thirty-one orthotopic cardiac allografts were performed using surface cooling and total circulatory arrest in outbred cynomolgus monkeys. TLI was administered preoperatively in fractions of 100 rad until a total of 600 or 1800 rad was achieved. Cy A was administered 17 mg/kg/day. All treatment groups demonstrated extended survival. Myocardial biopsies as early as 4 weeks were consistent with mild rejection in all treatment groups. No significant synergistic effect upon survival could be demonstrated utilizing TLI (1800 rad) plus ATG and azathioprine was associated with a high incidence of early death attributable to leukopenia and infection. Cy A alone or in combination with TLI was associated with the development of lymphoid malignancy.

  9. Orthotopic Liver Transplantation in Children: Two-Year Experience with 47 Patients

    PubMed Central

    Gartner, J. Carlton; Zitelli, Basil J.; Malatack, J. Jeffrey; Shaw, Byers W.; Iwatsuki, Shunzaburo; Starzl, Thomas E.

    2010-01-01

    During a 24-month period (May 1981 to May 1983), 47 pediatric patients (ranging in age from 7 months to 18 years) underwent orthotopic liver transplantation using cyclosporine and prednisone. Major indications were biliary atresia/hypoplasia, and metabolic liver disease. Thirty-two of 138 patients evaluated for the procedure died prior to transplantation. Thirty patients are alive from 6 to 29 months later including 7/15 patients who required retransplantation. Twenty-one of 32 patients are alive at 1 year following initial transplantation. All 30 survivors are clinically well and living at home; only one has an abnormal bilirubin level. Serious, life-threatening medical and surgical complications were common during the early months following transplantation. With one exception, deaths and major rejection episodes occurred early (before 120 days). All survivors are relieved of the stigmata of chronic liver disease, and many have demonstrated catch-up growth. Liver transplantation is an effective treatment for end-stage pediatric liver disease. PMID:6377219

  10. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models

    PubMed Central

    Liu, Huiping; Patel, Manishkumar R.; Prescher, Jennifer A.; Patsialou, Antonia; Qian, Dalong; Lin, Jiahui; Wen, Susanna; Chang, Ya-Fang; Bachmann, Michael H.; Shimono, Yohei; Dalerba, Piero; Adorno, Maddalena; Lobo, Neethan; Bueno, Janet; Dirbas, Frederick M.; Goswami, Sumanta; Somlo, George; Condeelis, John; Contag, Christopher H.; Gambhir, Sanjiv Sam; Clarke, Michael F.

    2010-01-01

    To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44+ cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy. PMID:20921380

  11. Preliminary results of orthotopic en bloc uterus and ovary transplantation in the laboratory rat.

    PubMed

    Motoc, A; Jiga, L; Ionac, M; Raica, M; Motoc, M; Chiovschi, S

    2003-01-01

    A new experimental model of whole uterus and ovary transplantation in the laboratory rat was achieved. The main goals of this study were concerned with developing and standardizing the microsurgical technique of uterus transplantation in rats and observing the particular cellular patterns of acute allograft rejection at the level of the transplanted graft. Thirty-five orthotopic uterus transplantations were performed. An additional 20 female rats were used for dissection training sessions. Recipients were euthanasied at 24 hours, 48 hours and 72 hours. Immediate postoperative survival was 100%. Patency of the microsurgical anastomoses, checked at 24 hours, was 100%. At 72 hours thrombosis occurred in all anastomoses. The explanted uterine grafts were fixed in formaline and analyzed under light microscopy and specific imunohistochemical analysis. The acute allograft rejection has a particular cellular reaction pattern, probably due to the unique diversity of the tissues that compose it. Inflammatory cells like LTCD8+, LBCD20+ and mastocytes tend to agglomerate in the vicinity of nervous and vascular structures, showing no signs of lymphoid tissue disposition like in typical acute rejection. Uterus transplantation in rats has proven to be a valid experiment that allows us to express hope that by further research on transplantation of the uterus gynecologists will be able to introduce an adapted technique in the treatment of specific cases of human female infertility.

  12. Orthotopic Liver Transplantation in Human-Immunodeficiency-Virus-Positive Patients in Germany

    PubMed Central

    Anadol, E.; Beckebaum, S.; Radecke, K.; Paul, A.; Zoufaly, A.; Bickel, M.; Hitzenbichler, F.; Ganten, T.; Kittner, J.; Stoll, M.; Berg, C.; Manekeller, S.; Kalff, J. C.; Sauerbruch, T.; Rockstroh, J. K.; Spengler, U.

    2012-01-01

    Objectives. This summary evaluates the outcomes of orthotopic liver transplantation (OLT) of HIV-positive patients in Germany. Methods. Retrospective chart analysis of HIV-positive patients, who had been liver-transplanted in Germany between July 1997 and July 2011. Results. 38 transplantations were performed in 32 patients at 9 German transplant centres. The reasons for OLT were end-stage liver disease (ESLD) and/or liver failure due to hepatitis C (HCV) (n = 19), hepatitis B (HBV) (n = 10), multiple viral infections of the liver (n = 2) and Budd-Chiari-Syndrome. In July 2011 19/32 (60%) of the transplanted patients were still alive with a median survival of 61 months (IQR (interquartile range): 41–86 months). 6 patients had died in the early post-transplantation period from septicaemia (n = 4), primary graft dysfunction (n = 1), and intrathoracal hemorrhage (n = 1). Later on 7 patients had died from septicaemia (n = 2), delayed graft failure (n = 2), recurrent HCC (n = 2), and renal failure (n = 1). Recurrent HBV infection was efficiently prevented in 11/12 patients; HCV reinfection occurred in all patients and contributed considerably to the overall mortality. Conclusions. Overall OLT is a feasible approach in HIV-infected patients with acceptable survival rates in Germany. Reinfection with HCV still remains a major clinical challenge in HIV/HCV coinfection after OLT. PMID:22900154

  13. Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease

    PubMed Central

    Paris, Daniel; Ganey, Nowel; Banasiak, Magdalena; Laporte, Vincent; Patel, Nikunj; Mullan, Myles; Murphy, Susan F.; Yee, Gi-Taek; Bachmeier, Corbin; Ganey, Christopher; Beaulieu-Abdelahad, David; Mathura, Venkatarajan S; Brem, Steven; Mullan, Michael

    2010-01-01

    Alzheimer's disease (AD) is the most common form of dementia among the aging population and is characterized pathologically by the progressive intracerebral accumulation of Aβ peptides and neurofibrillary tangles. The level of proangiogenic growth factors and inflammatory mediators with proangiogenic activity is known to be elevated in AD brains which has led to the supposition that the cerebrovasculature of AD patients is in a proangiogenic state. However, angiogenesis depends on the balance between proangiogenic and antiangiogenic factors and the brains of AD patients also show an accumulation of endostatin and Aβ peptides which have been shown to be antiangiogenic. In order to determine whether angiogenesis is compromised in the brains of two transgenic mouse models of AD overproducing Aβ peptides (Tg APPsw and Tg PS1/APPsw mice), we assessed the growth and vascularization of orthotopically implanted murine gliomas since they require a high degree of angiogenesis to sustain their growth. Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared to their wild-type littermates. In addition, we show that Aβ inhibits the angiogenesis stimulated by glioma cells when co-cultured with human brain microvascular cells on a matrigel layer. Altogether our data suggest that the brain of transgenic mouse models of AD does not constitute a favorable environment to support neoangiogenesis and may explain why vascular insults synergistically precipitate the cognitive presentation of AD. PMID:20739545

  14. Internal jugular versus subclavian vein catheterization for central venous catheterization in orthotopic liver transplantation.

    PubMed

    Torgay, A; Pirat, A; Candan, S; Zeyneloglu, P; Arslan, G; Haberal, M

    2005-09-01

    The aim of this study was to compare incidence rates of mechanical and infectious complications associated with central venous catheterization via the internal jugular vein (IJV) versus the subclavian vein (SV) among 45 consecutive patients undergoing orthotopic liver transplantation (OLT) between January 2000 and June 2004. The subjects were divided into two groups according to the site of central venous catheterization (IJV or SV). We recorded each patient's physical characteristics, international normalized ratio (INR), partial thromboplastin time, platelet levels, number of puncture attempts, success/failure of central venous catheterization, duration of catheter placement, occurrence of catheter tip misplacement, arterial puncture, incidence of hematoma or pneumothorax, catheter-related infection, or bacterial colonization of the catheter. Senior staff anesthesiologists performed 22 SV and 23 IJV catheterizations for the 45 OLT procedures. The SV and IVJ groups both had minor coagulation abnormalities with slightly increased INR values at the time of catheterization. There were no significant differences between the groups with respect to success of central venous catheterization (100% for both), numbers of attempted punctures, duration of catheter placement, and incidence rates of mechanical and infectious complications. Both groups showed high frequencies of catheter tip misplacement, with right atrium as the site of misplacement in all cases. Two patients in the IJV group (8.7%) developed hematomas after accidental carotid artery puncture. The results suggest that, when performed by experienced anesthesiologists, central venous catheterization via the SV is an acceptable alternative to IJV catheterization for patients undergoing OLT.

  15. Orthotopic liver transplantation in an adult with situs inversus: an easy way to fit the liver.

    PubMed

    Hoyos, Sergio; Guzmán, Carlos; Correa, Gonzalo; Restrepo, Juan Carlos; Franco, Hernán; Cárdenas, Andrés

    2006-01-01

    Situs inversus (SI) is a rare congenital disorder with a complete mirror image of thoracic and abdominal organs. In adults with SI and decompensated cirrhosis experience with liver transplantation is limited. Orthotopic liver transplantation (OLT) in an adult with cirrhosis using a technique where the recipient liver was placed using a 90-degree rotation of the graft was previously reported by Klintmalm et al, however no other reports using this technique have been described. We report a case of a 41 year-old man with situs inversus and decompensated cirrhosis who successfully underwent OLT using this technique. The donor liver was rotated 90-degrees towards the left and easily fitted into the recipients'fossa with the left lobe pointing toward the left lower quadrant. The patient had an uneventful recovery and has been followed for 21 months without any complications. This technique has the advantage of preventing compromise of the size of the donor liver, permits an easy reconstruction of vascular and biliary tree and in this case was associated with an excellent outcome.

  16. Risk factors of acute kidney injury after orthotopic liver transplantation in China

    PubMed Central

    Zongyi, Yin; Baifeng, Li; Funian, Zou; Hao, Li; Xin, Wang

    2017-01-01

    In this study, we determined the risk factors for acute kidney injury (AKI) following orthotopic liver transplantation (OLT) in China. We collected 5074 donation after cardiac death (DCD) OLT recipients who underwent surgery between January 1, 2010, and December 31, 2015, in 86 academic hospitals or transplant centers in China. Univariate and multivariate analyses were used to investigate the criticality of donor, graft, or recipient variables in the development of post-OLT AKI. In all, 4482 patients were included (median age, 49.31 years). Post-OLT AKI occurred in 3.97% patients, and 73.6% of all OLT patients were male. The 1- and 5-year cumulative survival rates (CSRs) of the AKI group were 33.95% and 25.24%, respectively, compared with 86.34% and 70.05%, respectively, of the non-AKI group (P < 0.001). The independent risk factors for post-OLT AKI were blood loss, cold ischemia time, warm ischemia time, preoperative serum creatinine, the treatment period with dopamine, overexposure to calcineurin inhibitor, and combined mycophenolate mofetil use (P < 0.05). These had a high prediction accuracy for post-OLT AKI (area under the curve [AUC] = 0.740). PMID:28134286

  17. An improved syngeneic orthotopic murine model of human breast cancer progression.

    PubMed

    Rashid, Omar M; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-10-01

    Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous (OP) injection in the area of the nipple, or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. ODV produced less variable-sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development .

  18. Transcatheter Splenic Artery Occlusion for Treatment of Splenic Artery Steal Syndrome After Orthotopic Liver Transplantation

    SciTech Connect

    Uflacker, Renan; Selby, J. Bayne; Chavin, Kenneth; Rogers, Jeffrey; Baliga, Prabhakar

    2002-08-15

    Purpose: To review some aspects of the problem of splenic artery steal syndrome as cause of ischemia in transplanted livers and treatment by selective splenic artery occlusion. Materials and Methods: Eleven liver transplant patients from a group of 350 patients, nine men and two women,ranging in age from 40 years to 61 years (mean 52 years), presented with biochemical evidences of liver ischemia and failure, ranging from one to 60 days following orthotopic liver transplantation. Diagnosis of splenic artery steal syndrome was suspected by elevated enzymes, Doppler ultrasound and confirmed by celiac angiogram. Patients with confirmed hepatic artery thrombosis before angiography were excluded from the study. Embolization with Gianturco coils was performed. Results: All patients were treated by splenic artery embolization with Gianturco coils. The 11 patients improved clinically within 24 hours of the procedure with significant change in the biochemical and clinical parameters. Followup ranged from one month to two years. One of the 11 patient initially improved, but developed hepatic artery thrombosis within 24 hours of the embolic treatment,requiring surgical repair. Conclusion: Splenicartery steal syndrome following liver transplantation surgery can be diagnosed by celiac angiography, and effectively treated by splenic artery embolization with coils. Embolization is one of the treatments available, it is minimally invasive, and leads to immediate clinical improvement. Hepatic artery thrombosis is a possible complication of the procedure.

  19. 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.

  20. Antitumor effects of hyaluronic acid inhibitor 4-methylumbelliferone in an orthotopic hepatocellular carcinoma model in mice.

    PubMed

    Piccioni, Flavia; Malvicini, Mariana; Garcia, Mariana G; Rodriguez, Andrés; Atorrasagasti, Catalina; Kippes, Nestor; Piedra Buena, Ignacio T; Rizzo, Manglio M; Bayo, Juan; Aquino, Jorge; Viola, Manuela; Passi, Alberto; Alaniz, Laura; Mazzolini, Guillermo

    2012-03-01

    Liver cirrhosis is characterized by an excessive accumulation of extracellular matrix components, including hyaluronan (HA). In addition, cirrhosis is considered a pre-neoplastic disease for hepatocellular carcinoma (HCC). Altered HA biosynthesis is associated with cancer progression but its role in HCC is unknown. 4-Methylumbelliferone (4-MU), an orally available agent, is an HA synthesis inhibitor with anticancer properties. In this work, we used an orthotopic Hepa129 HCC model established in fibrotic livers induced by thioacetamide. We evaluated 4-MU effects on HCC cells and hepatic stellate cells (HSCs) in vitro by proliferation, apoptosis and cytotoxicity assays; tumor growth and fibrogenesis were also analyzed in vivo. Our results showed that treatment of HCC cells with 4-MU significantly reduced tumor cell proliferation and induced apoptosis, while primary cultured hepatocytes remained unaffected. 4-MU therapy reduced hepatic and systemic levels of HA. Tumors systemically treated with 4-MU showed the extensive areas of necrosis, inflammatory infiltrate and 2-3-fold reduced number of tumor satellites. No signs of toxicity were observed after 4-MU therapy. Animals treated with 4-MU developed a reduced fibrosis degree compared with controls (F1-2 vs F2-3, respectively). Importantly, 4-MU induced the apoptosis of HSCs in vitro and decreased the amount of activated HSCs in vivo. In conclusion, our results suggest a role for 4-MU as an anticancer agent for HCC associated with advanced fibrosis.

  1. An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

    PubMed Central

    Reiberger, Thomas; Chen, Yunching; Ramjiawan, Rakesh R; Hato, Tai; Fan, Christopher; Samuel, Rekha; Roberge, Sylvie; Huang, Peigen; Lauwers, Gregory Y; Zhu, Andrew X; Bardeesy, Nabeel; Jain, Rakesh K; Duda, Dan G

    2016-01-01

    Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4−/−Stk3F/− (also known as Mst1−/−Mst2F/−; F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis. PMID:26203823

  2. Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model.

    PubMed

    Yuan, Xiaoning; Wei, Yiyong; Villasante, Aránzazu; Ng, Johnathan J D; Arkonac, Derya E; Chao, Pen-Hsiu Grace; Vunjak-Novakovic, Gordana

    2017-04-04

    Interest in non-invasive injectable therapies has rapidly risen due to their excellent safety profile and ease of use in clinical settings. Injectable hydrogels can be derived from the extracellular matrix (ECM) of specific tissues to provide a biomimetic environment for cell delivery and enable seamless regeneration of tissue defects. We investigated the in situ delivery of human mesenchymal stem cells (hMSCs) in decellularized meniscus ECM hydrogel to a meniscal defect in a nude rat model. First, decellularized meniscus ECM hydrogel retained tissue-specific proteoglycans and collagens, and significantly upregulated expression of fibrochondrogenic markers by hMSCs versus collagen hydrogel alone in vitro. The meniscus ECM hydrogel in turn supported delivery of hMSCs for integrative repair of a full-thickness defect model in meniscal explants after in vitro culture and in vivo subcutaneous implantation. When applied to an orthotopic model of meniscal injury in nude rat, hMSCs in meniscus ECM hydrogel were retained out to eight weeks post-injection, contributing to tissue regeneration and protection from joint space narrowing, pathologic mineralization, and osteoarthritis development, as evidenced by macroscopic and microscopic image analysis. Based on these findings, we propose the use of tissue-specific meniscus ECM-derived hydrogel for the delivery of therapeutic hMSCs to treat meniscal injury.

  3. 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

  4. Matrigel alters the pathophysiology of orthotopic human breast adenocarcinoma xenografts with implications for nanomedicine evaluation.

    PubMed

    Shuhendler, Adam J; Prasad, Preethy; Cai, Ping; Hui, Kelvin K W; Henderson, Jeffrey T; Rauth, Andrew M; Wu, Xiao Yu

    2013-08-01

    Matrigel, a mouse sarcoma-derived basement membrane protein mixture, is frequently used to facilitate human tumor xenograft growth in rodents. Despite its known effects on tumor growth and metastasis, its impact on tumor pathophysiology and preclinical evaluation of nanomedicines in tumor xenografts has not been reported previously. Herein bilateral MDA435 tumors were established orthotopically with (Mat+) or without (Mat-) co-injection of Matrigel. Tumor perfusion, morphology and nanoparticle retention were evaluated. As compared to Mat- tumors, Mat+tumors exhibited enhanced vascular perfusion and lymphatic flow, greater blood vessel and lymphatic growth within the tumor core, and more deformation and collapse of lymphatics in tumor-associated lymph nodes. These changes were accompanied by reduced nanoparticle retention in Mat+tumors. The results suggest that Matrigel is not a passive medium for tumor growth, but rather significantly alters long-term tumor architecture. These findings have significant implications for the evaluation of therapeutic nanomedicine in xenograft mouse models. Matrigel is utilized in facilitating human tumor xenograft growth in rodents. The authors demonstrate that Matrigel is not a passive medium for tumor growth; instead it significantly alters long-term tumor architecture, with major implications in the evaluation of therapeutic nanomedicine in xenograft mouse models. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Peripheral target reinnervation following orthotopic grafting of fetal allogeneic and xenogeneic dorsal root ganglia.

    PubMed

    Rosario, C M; Dubovy, P; Sidman, R L; Aldskogius, H

    1995-04-01

    The sensory reinnervation of dermal papillae and epidermis of glabrous skin, interosseal Pacinian corpuscles, and muscle spindles of the soleus and extensor digitorum longus muscles has been examined 1, 3, and 8 months (allografts) or 3 and 5 weeks (xenografts) following orthotopic grafting of fetal allogeneic or xenogeneic (mouse) dorsal root ganglia (DRG) into ganglionectomized adult rats. Sensory axons in target tissues were identified immunohistochemically by monoclonal antibodies against growth-associated peptide (GAP-43), heavy neurofilament protein (RT-97), anti-mouse-specific membrane glycoprotein Thy-1.2, and polyclonal antibody to calcitonin gene-related peptide (CGRP). Absence of axonal marker staining in target structures of control animals 10 days or 3 months following ipsilateral enucleation of the L3-L6 DRG without grafting indicated an elimination of host normal (intact), regenerating, or collaterally sprouting nerve fibers. The consistent finding of immunolabeled axons ending free and in encapsulated structures in the target tissues of both allo- and xenografted rats indicates that grafted primary sensory neurons can survive and send axonal processes down the full length of the hind limb, to terminate in host target tissues. Axons of xenografted fetal mouse sensory neurons grow in adult rat hosts for distances of 4 cm or more, attaining lengths far greater than called for by their normal developmental programs.

  6. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model

    PubMed Central

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-01-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer. PMID:26840261

  7. Dynamic Quantitative T1 Mapping in Orthotopic Brain Tumor Xenografts1

    PubMed Central

    Herrmann, Kelsey; Erokwu, Bernadette O.; Johansen, Mette L.; Basilion, James P.; Gulani, Vikas; Griswold, Mark A.; Flask, Chris A.; Brady-Kalnay, Susann M.

    2016-01-01

    Human brain tumors such as glioblastomas are typically detected using conventional, nonquantitative magnetic resonance imaging (MRI) techniques, such as T2-weighted and contrast enhanced T1-weighted MRI. In this manuscript, we tested whether dynamic quantitative T1 mapping by MRI can localize orthotopic glioma tumors in an objective manner. Quantitative T1 mapping was performed by MRI over multiple time points using the conventional contrast agent Optimark. We compared signal differences to determine the gadolinium concentration in tissues over time. The T1 parametric maps made it easy to identify the regions of contrast enhancement and thus tumor location. Doubling the typical human dose of contrast agent resulted in a clearer demarcation of these tumors. Therefore, T1 mapping of brain tumors is gadolinium dose dependent and improves detection of tumors by MRI. The use of T1 maps provides a quantitative means to evaluate tumor detection by gadolinium-based contrast agents over time. This dynamic quantitative T1 mapping technique will also enable future quantitative evaluation of various targeted MRI contrast agents. PMID:27084431

  8. Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report.

    PubMed

    Vishnu, P; Jiang, L; Cortese, C; Menke, D M; Tun, H W

    2011-09-01

    Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.

  9. Graft-versus-host disease after orthotopic liver transplantation: multivariate analysis of risk factors.

    PubMed

    Elfeki, Mohamed A; Pungpapong, Surakit; Genco, Petrina V; Nakhleh, Raouf E; Nguyen, Justin H; Harnois, Denise M

    2015-12-01

    Graft-versus-host disease (GVHD) is a rare, fatal complication following orthotopic liver transplantation (OLT). To date, several risk factors have been proposed, but reports on these factors have been inconclusive. This is a retrospective, case-control study of prospectively collected data from 2775 OLTs performed at our institution. Eight cases of GVHD after OLT were diagnosed on the basis of the patient's clinical characteristics, and the findings were confirmed with skin and colonic biopsies. Each case was matched to three controls based on the diagnosis of liver disease, recipient's age, and blood group. Univariate and multivariate analyses were performed to identify risk factors associated with the development of GVHD after OLT. The univariate and multivariate analyses identified two main risk factors associated with development of GVHD in OLT recipients, a difference between recipient and donor age of >20 yr, and any human leukocyte antigen class I matches. Taking these two risk factors into consideration while matching prospective donors and recipients may reduce further incidence of GVHD in OLT patients. However, further studies are recommended to validate these findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Graft versus host anti-Rho(D) following minor Rh-incompatible orthotopic liver transplantation.

    PubMed

    Lee, J H; Mintz, P D

    1993-11-01

    Hemolysis caused by ABO antibodies after ABO-compatible, nonidentical solid organ transplantation has been previously reported. The passenger B lymphocytes within the donor organ presumably generate an acute, primarily red cell-directed graft vs. host (GVH) response. Graft survival may also be compromised. GVH Rh antibodies have also been described, primarily in renal transplants. Only three cases, two only in abstract form, have been reported thus far describing GVH Rh antibodies in liver transplant patients, to which we add a fourth. A 62-year-old blood group A Rho(D)-positive woman with cirrhosis underwent orthotopic liver transplantation from a group A Rho(D)-negative, previously Rho(D)-sensitized donor and subsequently developed acute, self-limited hemolysis requiring four units of packed red cells. Anti-Rho(D) was identified in both serum and red cell eluate. An antibody detection test, identification, and assessment of the antibody reactivity score from the pretransplant donor specimen may identify patients at risk for hemolysis due to GVH Rh antibodies.

  11. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model.

    PubMed

    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-03-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer.

  12. Single implant tooth replacement.

    PubMed

    Briley, T F

    1998-01-01

    It has been shown that direct bone anchorage of dental implants will provide long-term predictability for single tooth implants and multi-unit implants. The function of implant-supported restoration is now routinely achieved. The real challenge facing the restorative dentist and laboratory technician is to achieve optimal aesthetics. The learning objective of this article is to review the prosthodontic procedures essential to maximizing natural aesthetics in implant supported restorations. It will provide a review of master impression techniques, prepable titanium abutments and designing the cement on restoration. Particular emphasis is directed to the soft tissue model from which a series of sequenced techniques can be followed to achieve optimal aesthetics. Analysis of the implant alignment with regard to the neighboring teeth will result in having to make a choice of which prepable abutment will maximize the aesthetic result. The following case outlines how to replace a single missing tooth using an externally hexed implant system and a prefabricated titanium abutment on a 26-year-old male patient.

  13. Reuse, replace, recycle

    PubMed Central

    McMurray, Michael A.; Thorner, Jeremy W.

    2015-01-01

    Septins are guanine nucleotide-binding proteins that form hetero-oligomeric complexes, which assemble into filaments and higher-order structures at sites of cell division and morphogenesis in eukaryotes. Dynamic changes in the organization of septin-containing structures occur concomitantly with progression through the mitotic cell cycle and during cell differentiation. Septins also undergo stage-specific post-translational modifications, which have been implicated in regulating their dynamics, in some cases via purported effects on septin turnover. In our recent study, the fate of two of the five septins expressed in mitotic cells of budding yeast (Saccharomyces cerevisiae) was tracked using two complementary fluorescence-based methods for pulse-chase analysis. During mitotic growth, previously-made molecules of both septins (Cdc10 and Cdc12) persisted through multiple successive divisions and were incorporated equivalently with newly synthesized molecules into hetero-oligomers and higher-order structures. Similarly, in cells undergoing meiosis and the developmental program of sporulation, pre-existing copies of Cdc10 were incorporated into new structures. In marked contrast, Cdc12 was irreversibly excluded from septin complexes and replaced by another septin, Spr3. Here, we discuss the broader implications of these results and related findings with regard to how septin dynamics is coordinated with the mitotic cell cycle and in the yeast life cycle, and how these observations may relate to control of the dynamics of other complex multi-subunit assemblies. PMID:19164941

  14. Hormone replacement therapy.

    PubMed

    Scharbo-Dehaan, M

    1996-12-01

    More than 40 million women in the United States are now going through or are past menopause. Another 3.5 million or more will reach midlife in the next decade. As their life expectancy increases (mean life expectancy of women is now approximately 84 years), so does the need for therapeutic regimens related to reproductive function and aging in woman. Few medical treatments available to menopausal and postmenopausal women have as much potential benefit as well as possible health risks as hormone replacement therapy (HRT). Despite the increasing amount of scientific data available regarding the benefits of HRT, a degree of uncertainty still remains, both in the minds of some women, and with some health professionals, regarding the risks associated with long-term therapy. Even though the literature is voluminous, contradictory, and unclear, health providers must be able to keep abreast of current knowledge about the benefits, risks, and unknowns of these drugs. The purpose of this article is to provide a review and an update on the types of hormones available for HRT, their pharmacology and pharmacokinetics, and their risks, benefits, and contraindications. Newer products, specially compounded formulas, new regimens, and new modes of delivery that offer women alternatives and allow care to be individualized are described. In addition, some of the ongoing management dilemmas that practitioners face with the woman who chooses HRT are presented with practical solutions and suggestions.

  15. Antenna Controller Replacement Software

    NASA Technical Reports Server (NTRS)

    Chao, Roger Y.; Morgan, Scott C.; Strain, Martha M.; Rockwell, Stephen T.; Shimizu, Kenneth J.; Tehrani, Barzia J.; Kwok, Jaclyn H.; Tuazon-Wong, Michelle; Valtier, Henry; Nalbandi, Reza; Wert, Michael; Leung, Patrick

    2010-01-01

    The Antenna Controller Replacement (ACR) software accurately points and monitors the Deep Space Network (DSN) 70-m and 34-m high-efficiency (HEF) ground-based antennas that are used to track primarily spacecraft and, periodically, celestial targets. To track a spacecraft, or other targets, the antenna must be accurately pointed at the spacecraft, which can be very far away with very weak signals. ACR s conical scanning capability collects the signal in a circular pattern around the target, calculates the location of the strongest signal, and adjusts the antenna pointing to point directly at the spacecraft. A real-time, closed-loop servo control algorithm performed every 0.02 second allows accurate positioning of the antenna in order to track these distant spacecraft. Additionally, this advanced servo control algorithm provides better antenna pointing performance in windy conditions. The ACR software provides high-level commands that provide a very easy user interface for the DSN operator. The operator only needs to enter two commands to start the antenna and subreflector, and Master Equatorial tracking. The most accurate antenna pointing is accomplished by aligning the antenna to the Master Equatorial, which because of its small size and sheltered location, has the most stable pointing. The antenna has hundreds of digital and analog monitor points. The ACR software provides compact displays to summarize the status of the antenna, subreflector, and the Master Equatorial. The ACR software has two major functions. First, it performs all of the steps required to accurately point the antenna (and subreflector and Master Equatorial) at the spacecraft (or celestial target). This involves controlling the antenna/ subreflector/Master-Equatorial hardware, initiating and monitoring the correct sequence of operations, calculating the position of the spacecraft relative to the antenna, executing the real-time servo control algorithm to maintain the correct position, and

  16. The influence of chronic heart failure on pulmonary function tests in patients undergoing orthotopic heart transplantation.

    PubMed

    Lizak, M K; Zakliczyński, M; Jarosz, A; Zembala, M

    2009-10-01

    Chronic heart failure and airway obstruction produce overlapping syndromes. Existent criteria for the diagnosis and grading of airway obstruction based on spirometry results may be inadequate in the presence of coexistent cardiac failure. The cardiac component of pulmonary function tests (PFT) can be measured in patients undergoing orthotopic heart transplantation (OHT). Before and 1 year after OHT between 2006 and 2008 PFT were performed in 29 patients according to existent guideline. Willcoxon matched pair tests were used for analysis in Statistica 7.1. The general group characteristic included age, gender, New York Heart Association class, CCS class, body mass index, present medications, blood and chemistry tests, as well as exercise tolerance tests, right heart catheterization, and echocardiography results. One year after OHT we observed significant improvements in forced expiratory volume in the first second (FEV1) and its percent of normal value (FEV1%) as well as forced vital capacity (FVC), FVC%, vital capacity (VC) and VC%: namely, 2.56 L versus 2.96 L; 82% versus 93%; 3.30 L versus 3.81 L; 85% versus 97%; 3.38 L versus 4.04 L and 85% versus 100% (all P < .01). FEV1 and FVC increments of: 0.39 and 0.471 respectively, exceeded the cutoff point of 12% of predicted value established as the spirometry criterion for reversibility of obstruction. Elimination of heart failure by OHT did not significantly change the FEV1 to FVC ratio (FEV1%FVC). Chronic heart failure contributed to significant FEV1 reduction, which limits the usefulness of PFT for diagnosis and grading of airway obstruction. FEV1%FVC, the main diagnostic criterion of chronic obstructive lung disease, seems to be an index independent of concomittant heart function impairment.

  17. Heterotopic and orthotopic autologous chondrocyte implantation using a minipig chondral defect model.

    PubMed

    Lohan, Anke; Marzahn, Ulrike; El Sayed, Karym; Bock, Christopher; Haisch, Andreas; Kohl, Benjamin; Stoelzel, Katharina; John, Thilo; Ertel, Wolfgang; Schulze-Tanzil, Gundula

    2013-10-01

    Implantation of non-articular (heterotopic) chondrocyte-based implants might be an alternative approach to articular cartilage repair. This strategy could be helpful in cases in which there are no or too few articular chondrocytes available. Therefore, this study was undertaken to compare joint cartilage defect healing in the minipig model after implantation of heterotopic auricular and orthotopic articular chondrocytes. Poly-glycolic acid (PGA) associated three-dimensional (3D) constructs were prepared culturing autologous minipig-derived articular and auricular chondrocytes for 7 days in a dynamic culture system. Chondrocyte PGA constructs were implanted into 8mm diameter and ∼1.1mm deep chondral defects within the medial and lateral condyles of the minipig knee joints. Empty defects served as controls for assessment of the intrinsic healing response. Defect healing was monitored 6 months post implantation using a macroscopic and microscopic score system and biomechanical analysis. Neo-cartilage formation could be observed in the PGA constructs seeded with articular and auricular chondrocytes in vivo. The defect healing did not significantly differ at the macroscopic and histological level in response to implantation of either autologous articular or auricular chondrocytes seeded constructs compared with the empty defects. Although the differences were not significant, the auricular chondrocytes-based implants led to a slightly inferior repair quality at the macroscopic level, but a histologically superior healing response when compared with the empty defect group. However, biomechanical analysis revealed a higher stiffness in repair tissues produced by auricular chondrocyte implantation compared with the other groups. Deduced from these results, articular chondrocytes represent the preferable cell source for implantation. Copyright © 2013 Elsevier GmbH. All rights reserved.

  18. 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.

  19. Serious gaming for orthotopic liver transplant anesthesiology: A randomized control trial.

    PubMed

    Katz, Daniel; Zerillo, Jeron; Kim, Sang; Hill, Bryan; Wang, Ryan; Goldberg, Andrew; DeMaria, Samuel

    2017-04-01

    Anesthetic management of orthotopic liver transplantation (OLT) is complex. Given the unequal distributions of liver transplant surgeries performed at different centers, anesthesiology providers receive relatively uneven OLT training and exposure. One well-suited modality for OLT training is the "serious game," an interactive application created for the purpose of imparting knowledge or skills, while leveraging the self-motivating elements of video games. We therefore developed a serious game designed to teach best practices for the anesthetic management of a standard OLT and determined if the game would improve resident performance in a simulated OLT. Forty-four residents on the liver transplant rotation were randomized to either the gaming group (GG) or the control group (CG) prior to their introductory simulation. Both groups were given access to the same educational materials and literature during their rotation, but the GG also had access to the OLT Trainer. Performance on the simulations were recorded on a standardized grading rubric. Both groups experienced an increase in score relative to baseline that was statistically significant at every stage. The improvements in scores were greater for the GG participants than the CG participants. Overall score improvement between the GG and CG (mean [standard deviation]) was statistically significant (GG, 7.95 [3.65]; CG, 4.8 [4.48]; P = 0.02), as were scores for preoperative assessment (GG, 2.67 [2.09]; CG, 1.17 [1.43]; P = 0.01) and anhepatic phase (GG, 1.62 [1.01]; CG, 0.75 [1.28]; P = 0.02). Of the residents with game access, 81% were "very satisfied" or "satisfied" with the game overall. In conclusion, adding a serious game to an existing educational curriculum for liver transplant anesthesia resulted in significant learning gains for rotating anesthesia residents. The intervention was straightforward to implement and cost-effective. Liver Transplantation 23 430-439 2017 AASLD.

  20. Evaluation of pleth variability index as a predictor of fluid responsiveness during orthotopic liver transplantation.

    PubMed

    Konur, Huseyin; Erdogan Kayhan, Gulay; Toprak, Huseyin Ilksen; Bucak, Nizamettin; Aydogan, Mustafa Said; Yologlu, Saim; Durmus, Mahmut; Yılmaz, Sezai

    2016-07-01

    Fluid management is challenging and still remains controversial in orthotopic liver transplantation (OLT). The pleth variability index (PVI) has been shown to be a reliable predictor of fluid responsiveness of perioperative and critically ill patients; however, it has not been evaluated in OLT. This study was designed to examine whether the PVI can reliably predict fluid responsiveness in OLT and to compare PVI with other hemodynamic indexes that are measured using the PiCCO2 monitoring system. Twenty-five patients were enrolled in this study. Each patient was monitored using the noninvasive Masimo and PiCCO2 monitoring system. PVI was obtained with a Masimo pulse oximeter. Cardiac index was obtained using a transpulmonary thermodilution technique (CITPTD). Stroke volume variation (SVV), pulse pressure variation, and systemic vascular resistance index were measured using the PiCCO2 system. Fluid loading (10 mL/kg colloid) was performed at two different phases during the operation, and fluid responsiveness was defined as an increase in CITPTD ≥ 15%. During the dissection phase and the anhepatic phase, respectively, 14 patients (56%) and 18 patients (75%) were classified as responders. There were no differences between the baseline values of the PVI of responders and nonresponders. Area under the curve for PVI was 0.56 (sensitivity 35%, specificity 90%, p = 0.58) at dissection phase, and was 0.55 (sensitivity 55%, specificity 66%, p = 0.58) at anhepatic phase. Of the parameters, a higher area under the curve value was found for SVV. We conclude that PVI was unable to predict fluid responsiveness with sufficient accuracy in patients undergoing OLT, but the SVV parameter was reliable.

  1. Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation.

    PubMed

    Snanoudj, Renaud; Durrbach, Antoine; Gauthier, Eric; Adams, David; Samuel, Didier; Ferlicot, Sophie; Bedossa, Pierre; Prigent, Alain; Bismuth, Henri; Charpentier, Bernard

    2004-07-01

    Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease caused by a point mutation in the gene encoding transthyretin, which is secreted by the liver. Orthotopic liver transplantation (OLT) has been proposed to prevent disease progression. Little is known about long-term changes in renal function and lesions after OLT. The renal function of 33 patients with FAP was evaluated (proteinuria, serum creatinine, creatinine clearance) before OLT and over a period of at least 5 years afterwards. A pre-transplantation renal biopsy was performed in 14 patients and a follow-up biopsy in eight patients. Before transplantation, mean serum creatinine concentration was 86 micromol/l (47-126 micromol/l) and creatinine clearance was 71.9+/-31.6 ml/min/1.73 m(2). Proteinuria was detected in 54% of patients (0.3-4 g/day). Pre-transplant renal biopsies (n = 14) revealed glomerular, tubular and vascular amyloid deposits in 90, 58 and 66% of patients, respectively. Eleven patients (33%) died after OLT. Death occurred most frequently in patients having weight losses >7 kg (P<0.05). After transplantation, 25 patients (76%) suffered acute renal failure but only one required dialysis. One month after transplantation, the mean serum creatinine concentration was 134.1+/-73 micromol/l and remained constant during follow-up. Eight patients underwent a second renal biopsy 2 years after transplantation. No significant changes in deposits or renal toxicity due to calcineurin inhibitors were detected. Although liver transplantation in FAP does not affect existing renal amyloid deposits, it prevents the progression of renal disease.

  2. Predictors of blood product use in orthotopic liver transplantation using the piggyback hepatectomy technique.

    PubMed

    Mangus, R S; Kinsella, S B; Nobari, M M; Fridell, J A; Vianna, R M; Ward, E S; Nobari, R; Tector, A J

    2007-12-01

    Orthotopic liver transplantation (OLT) has historically been associated with massive blood loss and hemodynamic instability related to the coexistence of varices, coagulopathy, thrombocytopenia, and portal hypertension. Piggyback hepatectomy (PGB) is a technique increasingly utilized in OLT to avoid veno-venous bypass and vena cava clamping. This study evaluated the factors associated with blood loss and blood product requirement in PGB. This study is a retrospective review of the anesthesia preoperative and operative notes and computerized lab values for all adult cadaveric liver transplants over a 42-month period. These data were combined with the liver transplant database for analysis. Approximately 98% of the transplants were performed using a standard piggyback approach with no use of veno-venous bypass. Data were included for all 526 transplants performed during this time period. Estimated blood loss (EBL) was 1000 cc. Median transfusion requirement was 3 units packed red blood cells, 7 units fresh frozen plasma, and 6 units platelets. Multivariate linear regression demonstrated that predictors of EBL were age, MELD score, preoperative hemoglobin, initial fibrinogen, initial central venous pressure, and total anesthesia time. Predictors of PRBC useage were age, MELD score, preoperative hemoglobin, initial fibrinogen, and anesthesia time. Postoperatively increased transfusion requirement was associated with increased length of hospital stay and lower 90-day and 1-year graft and patient survivals. These results demonstrate that PGB can be safely accomplished in nearly all liver transplant patients without venovenous bypass or vena cava clamping and with less warm ischemia, which may ultimately be associated with less perioperative morbidity and improved outcomes.

  3. Meiotic activity in orthotopic xenografts derived from human postpubertal testicular tissue.

    PubMed

    Van Saen, D; Goossens, E; Bourgain, C; Ferster, A; Tournaye, H

    2011-02-01

    Grafting of frozen-thawed testicular tissue has been suggested as a novel fertility preservation method for patients undergoing gonadotoxic treatments. However, this technique still needs further optimization before any clinical application. So far, grafting of human testicular tissue has only been performed to the back skin of nude mice and has shown spermatogonial stem-cell survival and occasionally differentiation up to primary spermatocytes. In this study, orthotopic grafting to mouse testes was evaluated as an alternative, and the effect of freezing and the donor's age was studied. Human testicular tissue was obtained from two prepubertal (aged 3 and 5) and two postpubertal (aged 12 and 13) boys. Both fresh and frozen-thawed testicular tissue was grafted to the testis of immuno-deficient nude mice. Four and nine months after transplantation, testes were analyzed by histology and immunohistochemistry. Four and nine months after transplantation, spermatogonial stem cells were observed in all tissue grafts. Germ cell survival was found to be higher in xenografts from the older boys when compared with that from younger donors. Furthermore, no differentiation was observed in the xenografts from younger patients, but the grafts of two older donors showed differentiation up to the primary spermatocyte level, with the presence of secondary spermatocytes in the oldest donor 9 months after transplantation. This xenografting study shows that intratesticular grafting results in high germ cell survival. In grafts derived from the older boys, meiotic activity was maintained in the xenografts for at least 9 months. Although difficult to conduct due to the scarcity of the tissue, more comparative research is needed to elucidate an optimal grafting strategy.

  4. An Improved Syngeneic Orthotopic Murine Model of Human Breast Cancer Progression

    PubMed Central

    Rashid, Omar M.; Nagahashi, Masayuki; Ramachandran, Suburamaniam; Dumur, Catherine; Schaum, Julia; Yamada, Akimitsu; Terracina, Krista P.; Milstien, Sheldon; Spiegel, Sarah; Takabe, Kazuaki

    2014-01-01

    Purpose Breast cancer drug development costs nearly $610 million and 37 months in preclinical mouse model trials with minimal success rates. Despite these inefficiencies, there are still no consensus breast cancer preclinical models. Methods Murine mammary adenocarcinoma 4T1-luc2 cells were implanted subcutaneous (SQ) or orthotopically percutaneous injection in the area of the nipple (OP), or surgically into the chest 2nd mammary fat pad under direct vision (ODV) in Balb/c immunocompetent mice. Tumor progression was followed by in vivo bioluminescence and direct measurements, pathology and survival determined, and tumor gene expression analyzed by genome-wide microarrays. Results ODV produced less variable sized tumors and was a reliable method of implantation. ODV implantation into the chest 2nd mammary pad rather than into the abdominal 4th mammary pad, the most common implantation site, better mimicked human breast cancer progression pattern, which correlated with bioluminescent tumor burden and survival. Compared to SQ, ODV produced tumors that differentially expressed genes whose interaction networks are of importance in cancer research. qPCR validation of 10 specific target genes of interest in ongoing clinical trials demonstrated significant differences in expression. Conclusions ODV implantation into the chest 2nd mammary pad provides the most reliable model that mimics human breast cancer compared from subcutaneous implantation that produces tumors with different genome expression profiles of clinical significance. Increased understanding of the limitations of the different preclinical models in use will help guide new investigations and may improve the efficiency of breast cancer drug development. PMID:25200444

  5. Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System

    PubMed Central

    Domínguez, Pablo D.; Idoate, Miguel Angel; Xipell, Enric; Patiño-García, Ana; Gonzalez-Huarriz, Marisol; García-Moure, Marc; Junier, Marie-Pierre; Chneiweiss, Hervé; El-Habr, Elías; Diez-Valle, Ricardo; Tejada-Solís, Sonia

    2017-01-01

    Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons. PMID:28107439

  6. Agreement between radial and femoral arterial blood pressure measurements during orthotopic liver transplantation.

    PubMed

    Lee, Matthew; Weinberg, Laurence; Pearce, Brett; Scurrah, Nicholas; Story, David A; Pillai, Param; McCall, Peter R; McNicol, Larry P; Peyton, Philip J

    2015-06-01

    To study agreement between radial and femoral arterial pressure measurements in orthotopic liver transplantation (OLTx) surgery to determine whether arterial cannulation sites are interchangeable. Prospective observational study of 25 patients undergoing OLTx surgery. Radial and femoral arteries were cannulated with standardised arterial line kits. Radial and femoral mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and pulse pressure (PP) were measured at four time points (30 minutes after induction of anaesthesia, 30 minutes after the start of the anhepatic phase, 30 minutes after liver graft reperfusion and 30 minutes after the start of bile duct anastomosis). The bias, precision and limits of agreement between radial and femoral arterial pressures were calculated in accordance with Bland-Altman statistics. Radial-femoral differences in MAP (mean difference, 4.8 mmHg [SD, 4.5 mmHg]), limits of agreement (- 13.6 and 8.8, P < 0.001) and DAP showed clinically acceptable agreement between measurement sites across all time points. However, clinically significant differences between radial and femoral SAPs (mean difference, - 14.9 mmHg [SD, 24.8 mmHg]) and limits of agreement (- 63.5 and 33.7, P < 0.001) occurred overall. This difference started after portal vein clamping and remained significant throughout the remainder of the operation. Radial artery SAP underestimates femoral artery measurements significantly but unpredictably. As femoral measurement is more likely to reflect central arterial pressure, radial SAP measurement is not reliable in adults undergoing OLTx.

  7. Development of a Colon Cancer GEMM-Derived Orthotopic Transplant Model for Drug Discovery and Validation

    PubMed Central

    Martin, Eric S.; Belmont, Peter J.; Sinnamon, Mark J.; Richard, Larissa Georgeon; Yuan, Jing; Coffee, Erin M.; Roper, Jatin; Lee, Lydia; Heidari, Pedram; Lunt, Sophia Y.; Goel, Gautam; Ji, Christy; Xie, Julie; Xie, Tao; Lamb, John; Weinrich, Scott; VanArsdale, Todd; Bronson, Roderick T.; Xavier, Ramnik J.; Vander Heiden, Matthew G.; Kan, Julie L. C.; Mahmood, Umar; Hung, Kenneth E.

    2014-01-01

    Purpose Effective therapies for KRAS mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described GEMMs for sporadic Kras mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation. Experimental Design Cell lines were derived from Kras mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis. Results Kras mutant cell lines displayed increased proliferation, MAPK signaling, and PI3K signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biological pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras mutant CRC on oncogenic signaling and on aerobic glycolysis. Conclusions We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts. PMID:23403635

  8. Histologic differences between orthotopic xenograft pancreas models affect Verteporfin uptake measured by fluorescence microscopy and spectroscopy

    NASA Astrophysics Data System (ADS)

    O'Hara, Julia A.; Samkoe, Kimberley S.; Chen, Alina; Isabelle, Martin; Hoopes, P. J.; Hasan, Tayyaba; Pogue, Brian W.

    2012-02-01

    Photodynamic therapy (PDT) that uses the second generation photosensitizer, verteporfin (VP), is a developing therapy for pancreatic cancer. The optimal timing of light delivery related to VP uptake and distribution in pancreatic tumors will be important information to obtain to improve treatment for this intractable disease. In this work we examined uptake and distribution of VP in two orthotopic pancreatic tumors with different histological structure. ASPC-1 (fast-growing) and Panc-1 (slower growing) tumors were implanted in SCID mice and studied when tumors were approximately 100mm3. In a pilot study, these tumors had been shown to differ in uptake of VP using lightinduced fluorescence spectroscopy (LIFS) in vivo and fluorescence imaging ex vivo and that work is extended here. In vivo fluorescence mean readings of tumor and liver increased rapidly up to 15 minutes after photosensitizer injection for both tumor types, and then continued to increase up to 60 minutes post injection to a higher level in ASPC-1 than in Panc-1. There was variability among animals with the same tumor type, in both liver and tumor uptake and no selectivity of tumor over liver. In this work we further examined VP uptake at multiple time points in relation to microvascular density and perfusion, using DiOC7 (to mark blood vessels) and VP fluorescence in the same tissue slices. Analysis of DiOC7 fluorescence indicates that AsPC-1 and Panc-1 have different vascular densities but AsPC-1 vasculature is more perfusive. Analysis of colocalized DiOC7 and VP fluorescence showed ASPC-1 with higher accumulation of VP 3 hrs after injection and more VP at a distance from blood vessels compared to Panc-1. This work shows the need for techniques to analyze photosensitizer distribution in order to optimize photodynamic therapy as an effective treatment for pancreatic tumors.

  9. Comparison of Methods for the Reconstruction of the Hepatic Artery in Mouse Orthotopic Liver Transplantation

    PubMed Central

    He, Jinjing; Li, Song; Lv, Xiangwei; Wang, Liming; Liu, Qinlong

    2015-01-01

    Background The mouse model of arterialized orthotopic liver transplantation (AOLT) has played an important role in biomedical research. The available methods of sutured anastomosis for reconstruction of the hepatic artery are complicated, resulting in a high incidence of complications and failure. Therefore, we developed and evaluated a new model of AOLT in mice. Materials and methods Male inbred C57BL/6 mice were used in this study. A continuous suture approach was applied to connect the suprahepatic inferior vena cava (SHVC). The portal vein and infrahepatic inferior vena cava (IHVC) were connected according to the "two-cuff" method. The common bile duct was connected by a biliary stent. We used the stent (G3 group) or aortic trunk (G2 group) to reconstruct the hepatic artery. The patency of the hepatic artery was verified by transecting the artery near the graft after one week. The survival rate of the recipients and serum alanine aminotransferase (ALT) levels, hepatic pathologic alterations, apoptosis and necrosis were observed at one week postoperatively. Results The patency of the hepatic artery was verified in eight of ten mice in G3 and in six of ten mice in G2. The 7-day survival rate, extents of necrosis and apoptosis, and TGF-β levels were not significantly different among the three groups (P>0.05). However, the serum ALT levels and operation time were markedly lower in G3 compared with G2 or G1 (both P<0.05). Conclusions Reconstruction of the hepatic artery using a stent can be performed quickly with a high rate of patency. This model simplifies hepatic artery anastomosis and should be promoted in the field of biomedical research. PMID:26207367

  10. Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts.

    PubMed

    José, Anabel; Sobrevals, Luciano; Miguel Camacho-Sánchez, Juan; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p less than 0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.

  11. Early prediction of response to Vorinostat in an orthotopic glioma rat model

    PubMed Central

    Wei, Li; Hong, Samuel; Yoon, Younghyoun; Hwang, Scott N.; Park, Jaekeun C.; Zhang, Zhaobin; Olson, Jeffrey J.; Hu, Xiaoping P.; Shim, Hyunsuk

    2012-01-01

    Glioblastoma (GBM) is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. Since survival is short, it is critical to determine the value of therapy early on in treatment. Improved early predictive assessment would allow neuro-oncologists to personalize and adjust or change treatment sooner to maximize use of efficacious therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza; Merck & Co., Inc.) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. A major shortcoming of the use of HDAC inhibitors in treating brain tumor patients is the lack of reliable biomarkers to predict and determine response. Histological evaluation may reflect tumor viability following treatment but it is an invasive procedure and impractical for GBM. Another problem is that response to SAHA therapy is associated with tumor redifferentiation and cytostasis rather than tumor size reduction, thus limiting the use of traditional imaging methods. A noninvasive method to assess drug delivery and efficacy is needed. Here, we investigated whether changes in 1H MRS metabolites could render reliable biomarkers for an early response to SAHA treatment in an orthotopic animal model for glioma. Untreated tumors exhibited significantly elevated alanine and lactate levels and reduced inositol, NAA and creatine, typical changes reported in GBM compared to normal brain tissues. The proton MRS-detectable metabolites of SAHA treated tumors were restored toward those of normal-like brain tissues. In addition, reduced inositol and NAA were found to be potential biomarkers for mood alteration and depression, which may also be alleviated with SAHA treatment. Our study suggests that 1H MRS can provide reliable metabolic biomarkers at the earliest stage

  12. Splenic Artery Syndrome After Orthotopic Liver Transplantation: Treatment With the Amplatzer Vascular Plug

    SciTech Connect

    Maurer, M. H.; Mogl, M. T.; Podrabsky, P.; Denecke, T.; Grieser, C.; Froeling, V.; Scheurig-Muenkler, C.; Guckelberger, O.; Kroencke, T. J.

    2011-12-15

    Purpose: To evaluate the safety and efficacy of the Amplatzer vascular plug (AVP) for embolization of the splenic artery in patients with hepatic hypoperfusion after orthotopic liver transplantation (OLT). Materials and Methods: Thirteen patients (9 men and 4 women) with a mean age of 56 years (range 22-70) who developed splenic artery syndrome after OLT with decreased liver perfusion and clinically relevant impairment of liver function (increased transaminase or serum bilirubin levels, thrombocytopenia, and/or therapy-refractory ascites) were treated by embolization of the proximal third of the splenic artery using the AVP. The plugs ranged in diameter from 6 to 16 mm, and they were introduced through femoral (n = 9), axillary (n = 3), or brachial (n = 1) access using a 5F or 8F guiding catheter. Results: The plugs were successfully placed, and complete occlusion of the splenic artery was achieved in all patients. Placement of two plugs was necessary for complete occlusion in 3 of the 13 patients. Occlusion took on average 10 min (range 4-35). There was no nontarget embolization or plug migration into more distal segments of the splenic artery. All patients showed improved arterial perfusion, including the liver periphery, on postinterventional angiogram. After embolization, liver function parameters (transaminase and bilirubin levels) improved with normalization of concomitant thrombocytopenia and a decrease in ascites volume. Conclusion: Our initial experience in a small patient population with SAS suggests that the AVP enables precise embolization of the proximal splenic artery, thus providing safe and effective treatment for poor liver perfusion after OLT due to SAS.

  13. Insurance and education predict long-term survival after orthotopic heart transplantation in the United States.

    PubMed

    Allen, Jeremiah G; Weiss, Eric S; Arnaoutakis, George J; Russell, Stuart D; Baumgartner, William A; Shah, Ashish S; Conte, John V

    2012-01-01

    Insurance status and education are known to affect health outcomes. However, their importance in orthotopic heart transplantation (OHT) is unknown. The United Network for Organ Sharing (UNOS) database provides a large cohort of OHT recipients in which to evaluate the effect of insurance and education on survival. UNOS data were retrospectively reviewed to identify adult primary OHT recipients (1997 to 2008). Patients were stratified by insurance at the time of transplantation (private/self-pay, Medicare, Medicaid, and other) and college education. All-cause mortality was examined using multivariable Cox proportional hazard regression incorporating 15 variables. Survival was modeled using the Kaplan-Meier method. Insurance for 20,676 patients was distributed as follows: private insurance/self-pay, 12,298 (59.5%); Medicare, 5,227 (25.3%); Medicaid, 2,320 (11.2%); and "other" insurance, 831 (4.0%). Educational levels were recorded for 15,735 patients (76.1% of cohort): 7,738 (49.2%) had a college degree. During 53 ± 41 months of follow-up, 6,125 patients (29.6%) died (6.7 deaths/100 patient-years). Survival differed by insurance and education. Medicare and Medicaid patients had 8.6% and 10.0% lower 10-year survival, respectively, than private/self-pay patients. College-educated patients had 7.0% higher 10-year survival. On multivariable analysis, college education decreased mortality risk by 11%. Medicare and Medicaid increased mortality risk by 18% and 33%, respectively (p ≤ 0.001). Our study examining insurance and education in a large cohort of OHT patients found that long-term mortality after OHT is higher in Medicare/Medicaid patients and in those without a college education. This study points to potential differences in the care of OHT patients based on education and insurance status. Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  14. Impact of Acoustic Radiation Force Impulse Imaging in Clinical Practice of Patients after Orthotopic Liver Transplantation

    PubMed Central

    Wildner, Dane; Strobel, Deike; Konturek, Peter C.; Görtz, Rüdiger S.; Croner, Roland S.; Neurath, Markus F.; Zopf, Steffen

    2014-01-01

    Background Acoustic radiation force impulse (ARFI) elastography is a reliable diagnostic device for quantitative non-invasive assessment of liver fibrosis in patients with chronic liver disease. The aim of our prospective study was to evaluate the impact of ARFI in patients after orthotopic liver transplantation (OLT). Therefore, we compared ARFI shear wave velocities with clinical features, non-invasive markers, and the histology of patients following OLT. Material/Methods Post-transplant patients underwent a clinical examination and blood samples were taken. B-mode and Doppler ultrasound (US) of the portal vein and the hepatic artery were performed. Subsequently, a minimum of 10 valid ARFI values were measured in the left and right liver lobe. Liver biopsy was performed if indicated. Results Between May 2012 and May 2014, 58 Patients after OLT were included in the prospective study. Laboratory markers and aspartate aminotransferase-to-platelet ratio index (APRI) correlated with ARFI values (r=0.44, p<0.001). The histological (n=22) fibrosis score (Ludwig) was significantly correlated with the ARFI of the biopsy site (r=0.55, p=0.008). The mean shear-wave velocities were significantly increased in advanced fibrosis (F≤2 1.57±0.57 m/s; F≥3 2.85±0.66 m/s; p<0.001), obstructive cholestasis and active viral hepatitis. The area under the receiver operating characteristic (AUROC) curves for the accuracy of ARFI were 74% (F≥1), 73% (F≥2), 93% (F≥3), and 80% (=F4). Conclusions ARFI elastography correlates well with laboratory values and with noninvasive and invasive markers of fibrosis in patients after OLT. In this regard, elevated ARFI-velocities should be interpreted with caution in the context of obstructive cholestasis and active viral disease. PMID:25342166

  15. The incidence, morbidity, and mortality of surgical procedures after orthotopic heart transplantation.

    PubMed

    Bhatia, D S; Bowen, J C; Money, S R; Van Meter, C H; McFadden, P M; Kot, J B; Pridjian, A K; Ventura, H O; Mehra, M R; Smart, F W; Ochsner, J L

    1997-06-01

    The authors present their experience with patients having undergone orthotopic heart transplantation (OHT) in whom surgical conditions subsequently developed that required operative intervention. The incidence, morbidity, and mortality of these procedures are reported. Several studies have evaluated the management options of biliary tract disease after OHT. Multiple reports of patients having undergone OHT who subsequently underwent peripheral vascular reconstructions, plastic reconstructive, and thoracic procedures also have been published. A chart review of 349 patients who underwent OHT between 1985 and 1996 was conducted to identify surgical procedures that were required in the post-transplant period. Their outcomes are reported. Of 349 patients who underwent OHT, conditions requiring 94 surgical procedures developed in 54 patients (15%). Biliary tract disease developed in 17 patients (5%) who required cholecystectomy, 2 of the 5 patients with acute cholecystitis died. Eight patients (2%) underwent orthopedic procedures with no operative mortality. Flap advancements for sternal wound infections were performed in five patients and four deaths occurred. Seventeen thoracic procedures were performed in 11 patients with an overall mortality of 45%. Twenty-one vascular procedures were performed on 17 patients with 1 delayed death due to a malignancy. Seven patients underwent procedures of the colon and rectum with no mortality. Seven patients underwent repair of inguinal or incisional hernias with no mortality. Various infections occurred with one resultant death after operative intervention. Six procedures were performed for diseases of the small intestine with no resultant mortalities. Patients having undergone OHT and chronic immunosuppression are at increased risk of having complications develop from infection. Acute cholecystitis and sternal wound infection caused an inordinate risk of complications and death. Malignancies developed in four patients who required

  16. The incidence, morbidity, and mortality of surgical procedures after orthotopic heart transplantation.

    PubMed Central

    Bhatia, D S; Bowen, J C; Money, S R; Van Meter, C H; McFadden, P M; Kot, J B; Pridjian, A K; Ventura, H O; Mehra, M R; Smart, F W; Ochsner, J L

    1997-01-01

    OBJECTIVE: The authors present their experience with patients having undergone orthotopic heart transplantation (OHT) in whom surgical conditions subsequently developed that required operative intervention. The incidence, morbidity, and mortality of these procedures are reported. SUMMARY BACKGROUND DATA: Several studies have evaluated the management options of biliary tract disease after OHT. Multiple reports of patients having undergone OHT who subsequently underwent peripheral vascular reconstructions, plastic reconstructive, and thoracic procedures also have been published. METHODS: A chart review of 349 patients who underwent OHT between 1985 and 1996 was conducted to identify surgical procedures that were required in the post-transplant period. Their outcomes are reported. RESULTS: Of 349 patients who underwent OHT, conditions requiring 94 surgical procedures developed in 54 patients (15%). Biliary tract disease developed in 17 patients (5%) who required cholecystectomy, 2 of the 5 patients with acute cholecystitis died. Eight patients (2%) underwent orthopedic procedures with no operative mortality. Flap advancements for sternal wound infections were performed in five patients and four deaths occurred. Seventeen thoracic procedures were performed in 11 patients with an overall mortality of 45%. Twenty-one vascular procedures were performed on 17 patients with 1 delayed death due to a malignancy. Seven patients underwent procedures of the colon and rectum with no mortality. Seven patients underwent repair of inguinal or incisional hernias with no mortality. Various infections occurred with one resultant death after operative intervention. Six procedures were performed for diseases of the small intestine with no resultant mortalities. CONCLUSIONS: Patients having undergone OHT and chronic immunosuppression are at increased risk of having complications develop from infection. Acute cholecystitis and sternal wound infection caused an inordinate risk of

  17. Maintaining a regular physical activity aggravates intramuscular tumor growth in an orthotopic liposarcoma model.

    PubMed

    Assi, Mohamad; Derbré, Frédéric; Lefeuvre-Orfila, Luz; Saligaut, Dany; Stock, Nathalie; Ropars, Mickael; Rébillard, Amélie

    2017-01-01

    Today, care teams within cancer centers encourage patients to be physically active, after diagnosis, based on data obtained mainly from breast, colon and prostate cancer. Intriguingly, the impact of physical activity (PA) on intramuscular tumors (e.g. sarcomas) has not been specifically addressed and, thus, could be mistakenly confounded with other cancers. In this preclinical study we assessed the impact of PA on intramuscular liposarcoma (LS) evolution. Four-week-old nude male mice were active by voluntary running on wheels, for six weeks. Then, mice were divided into four groups with open or restricted access to wheels, which have received an orthotopic intramuscular injection of either vehicle or human LS, SW872, cells. Active mice presented ~1.5 fold increase in tumor mass, which was mainly due to higher cellular mitosis and proliferation. This bulging intramuscular tumor mass altered muscle function, as evidence by overall muscle strength and maximum running capacity. From a molecular point of view, active mice exhibited poor levels of Phospho-p38(Thr180/Tyr182) and p21 content in tumors and also displayed low amounts of circulating insulin comparing to inactive counterparts. Insulin induced Phospho-p38(Thr180/Tyr182) and p21 expression in SW872 cells, in vitro. The expression of p21 was regulated in a p38-dependent fashion, since inhibition of p38 activity abolished the up-regulation of p21. Our data suggest that insulin-dependent activation of p38 MAPK-p21 pathway is a possible mechanism responsible for delaying tumor growth in inactive mice. Clinically, patients with lower-extremities LS could be advised to reduce or minimize their levels of PA during the preoperative period.

  18. Maintaining a regular physical activity aggravates intramuscular tumor growth in an orthotopic liposarcoma model

    PubMed Central

    Assi, Mohamad; Derbré, Frédéric; Lefeuvre-Orfila, Luz; Saligaut, Dany; Stock, Nathalie; Ropars, Mickael; Rébillard, Amélie

    2017-01-01

    Today, care teams within cancer centers encourage patients to be physically active, after diagnosis, based on data obtained mainly from breast, colon and prostate cancer. Intriguingly, the impact of physical activity (PA) on intramuscular tumors (e.g. sarcomas) has not been specifically addressed and, thus, could be mistakenly confounded with other cancers. In this preclinical study we assessed the impact of PA on intramuscular liposarcoma (LS) evolution. Four-week-old nude male mice were active by voluntary running on wheels, for six weeks. Then, mice were divided into four groups with open or restricted access to wheels, which have received an orthotopic intramuscular injection of either vehicle or human LS, SW872, cells. Active mice presented ~1.5 fold increase in tumor mass, which was mainly due to higher cellular mitosis and proliferation. This bulging intramuscular tumor mass altered muscle function, as evidence by overall muscle strength and maximum running capacity. From a molecular point of view, active mice exhibited poor levels of Phospho-p38Thr180/Tyr182 and p21 content in tumors and also displayed low amounts of circulating insulin comparing to inactive counterparts. Insulin induced Phospho-p38Thr180/Tyr182 and p21 expression in SW872 cells, in vitro. The expression of p21 was regulated in a p38-dependent fashion, since inhibition of p38 activity abolished the up-regulation of p21. Our data suggest that insulin-dependent activation of p38 MAPK-p21 pathway is a possible mechanism responsible for delaying tumor growth in inactive mice. Clinically, patients with lower-extremities LS could be advised to reduce or minimize their levels of PA during the preoperative period. PMID:28560056

  19. Intraductal Delivery of Adenoviruses Targets Pancreatic Tumors in Transgenic Ela-myc Mice and Orthotopic Xenografts

    PubMed Central

    José, Anabel; Sobrevals, Luciano; Camacho-Sánchez, Juan Miguel; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors. PMID:23328228

  20. Optimal timing of same-admission orthotopic heart transplantation after left ventricular assist device implantation

    PubMed Central

    Gulati, Gunsagar; Ouyang, David; Ha, Richard; Banerjee, Dipanjan

    2017-01-01

    AIM To investigate the impact of timing of same-admission orthotopic heart transplant (OHT) after left ventricular assist device (LVAD) implantation on in-hospital mortality and post-transplant length of stay. METHODS Using data from the Nationwide Inpatient Sample from 1998 to 2011, we identified patients 18 years of age or older who underwent implantation of a LVAD and for whom the procedure date was available. We calculated in-hospital mortality for those patients who underwent OHT during the same admission as a function of time from LVAD to OHT, adjusting for age, sex, race, household income, and number of comorbid diagnoses. Finally, we analyzed the effect of time to OHT after LVAD implantation on the length of hospital stay post-transplant. RESULTS Two thousand and two hundred patients underwent implantation of a LVAD in this cohort. One hundred and sixty-four (7.5%) patients also underwent OHT during the same admission, which occurred on average 32 d (IQR 7.75-66 d) after LVAD implantation. Of patients who underwent OHT, patients who underwent transplantation within 7 d of LVAD implantation (“early”) experienced increased in-hospital mortality (26.8% vs 12.2%, P = 0.0483) compared to patients who underwent transplant after 8 d (“late”). There was no statistically significant difference in age, sex, race, household income, or number of comorbid diagnoses between the early and late groups. Post-transplant length of stay after LVAD implantation was also not significantly different between patients who underwent early vs late OHT. CONCLUSION In this cohort of patients who received LVADs, the rate of in-hospital mortality after OHT was lower for patients who underwent late OHT (at least 8 d after LVAD implantation) compared to patients who underwent early OHT. Delayed timing of OHT after LVAD implantation did not correlate with longer hospital stays post-transplant. PMID:28289529

  1. Using your shoulder after replacement surgery

    MedlinePlus

    Joint replacement surgery - using your shoulder; Shoulder replacement surgery - after ... You have had shoulder replacement surgery to replace the bones of your shoulder joint with artificial parts. The parts include a stem made of metal and a ...

  2. Educating My Replacement

    NASA Astrophysics Data System (ADS)

    Tarter, Jill

    , in partnership with the dedicated teachers out there, I think I can help promote the critical thinking skills and scientific literacy of the next generation of voters. Hopefully, I can also help train my replacement to be a better scientist, capable of seizing all the opportunities generated by advances in technology and our improved understanding of the universe to craft search strategies with greater probability of success than those I have initiated.

  3. Glucose Metabolism via the Pentose Phosphate Pathway, Glycolysis and Krebs Cycle in an Orthotopic Mouse Model of Human Brain Tumors

    PubMed Central

    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.

    2013-01-01

    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 an orthotopic mouse model of primary human glioblastoma (GBM) and a brain metastatic renal tumor of clear cell renal cell carcinoma (CCRCC) histology, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-13C2]glucose. The [3-13C]lactate/[2,3-13C2]lactate ratio was similar for both the GBM and renal tumor and their respective surrounding brains (GBM: 0.197 ± 0.011 and 0.195 ± 0.033 (p=1); CCRCC: 0.126 and 0.119 ± 0.033, respectively). This suggests that the rate of glycolysis is significantly greater than PPP flux in these tumors, and that PPP flux into the lactate pool was similar in both tissues. Remarkably, 13C-13C coupling was observed in molecules derived from Krebs cycle intermediates in both tumors, denoting glucose oxidation. In the renal tumor, in contrast to GBM and surrounding brain, 13C multiplets of GABA differed from its precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. Additionally, 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 CCRCC tissue microarray suggesting that GABA synthesis is cell-autonomous in at least a subset of renal tumors. Taken together, these data demonstrate that 13C-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. PMID:22383401

  4. 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.

  5. Efficacy of dietary antioxidants combined with a chemotherapeutic agent on human colon cancer progression in a fluorescent orthotopic mouse model.

    PubMed

    Ma, Huaiyu; Das, Tapas; Pereira, Suzette; Yang, Zhijian; Zhao, Ming; Mukerji, Pradip; Hoffman, Robert M

    2009-07-01

    We report here the efficacy of dietary antioxidants in combination with chemotherapy on tumor growth in the orthotopic COLO-205-green fluorescent protein (GFP) human colon cancer mouse model. The orthotopically-transplanted nude mice used for the study were randomly divided into 5 groups (A-E) after surgical orthotopic implantation (SOI) of tumor tissue. The following diets were given: Diet A, modified AIN-93M mature rodent diet with 4% fish oil; Diet B, modified AIN-93M which contains added antioxidants vitamin A, vitamin E, and selenium at levels present in the standard AIN-93M diet; Diet C, Diet A without added antioxidants vitamin A, vitamin E, or selenium; Diet D, Diet A with 5 times the amount of added antioxidants vitamin A, vitamin E, and selenium present in Diet B. Cisplatin, 7 mg/kg, was administered intraperitoneally on day 16 after SOI. Throughout the course of treatment, noninvasive whole-body imaging, based on the GFP expression of the tumor, permitted visualization of tumor progression. At sacrifice, the mean tumor weights showed significant statistical differences in all of the treated groups compared to the negative control (no cisplatin treatment) (p

  6. 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

  7. 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.

  8. 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

  9. Efficacy and Safety of Transurethral Photoselective Greenlight(™) Laser Vaporization for the Treatment of Orthotopic Ureteroceles in Adults.

    PubMed

    Liu, Cuilong; Chen, Weihao; Xie, Changliang; Guan, Weimin; Zhao, Yubo; Ouyang, Yun; Xu, Yansheng; Wu, Yiguang; Wang, Xiyou; Wang, Yi; Zhang, Xinyu

    2015-06-01

    This study aimed to retrospectively evaluate the safety and efficacy of transurethral photoselective Greenlight(™) laser vaporization in adult patients with orthotopic ureterocele. Thirty adult patients diagnosed with orthotopic urecterocele were recruited at our center. Transurethral photoselective Greenlight laser vaporization was used as the exclusive technique for endoscopic management during the study period. Information, including age, gender, mode of presentation, ureterocele size, vesicoureteral reflux, hydronephrosis status, and incidence of reoperation, were collected for evaluation. Our series included 12 men and 18 women. The mean patient age at presentation was 30.5 years (range, 18-62 years). The mean size of ureterocele was 18 mm (range, 10-41 mm). All patients successfully underwent transurethral photoselective Greenlight laser to vaporize the ureterocele. The operation ranged from 13 min to 38 min (mean 19.6 min). The average blood loss was <10 mL. No patient had intraoperative complications. The average postoperative hospital stay was 18.3 h. All patients were voided after postoperative catheter removal. None of the patients demonstrated any residual ureterocele and/or hydronephrosis when evaluated with ultrasonography after 3 months. Only one patient with a duplex collecting system presented asymptomatic low-grade reflux at 3 months, which was spontaneously resolved after 6 months of follow-up. All patients were free of any symptoms. No reoperative procedures were required at a mean follow-up of 14.2 months (range, 8-16). Transurethral photoselective Greenlight laser vaporization is safe, effective, and efficient for the management of orthotopic urecteroceles in adults. Therefore, this technique should be considered as the initial treatment in most patients.

  10. Pim-3 promotes the growth of human pancreatic cancer in the orthotopic nude mouse model through vascular endothelium growth factor.

    PubMed

    Wang, Chen; Li, Hong-Yu; Liu, Bin; Huang, Sheng; Wu, Li; Li, Ying-Yi

    2013-12-01

    As one of the most lethal cancers, pancreatic cancer presents poor prognosis with an overall 5-y survival of less than 5%. We previously reported that Pim-3, a member of the proto-oncogene Pim family that encodes serine/threonine kinases, is aberrantly expressed in human pancreatic cancer lesions. In the current study, we investigated the role of Pim-3 in promoting tumor growth and angiogenesis in an orthotopic nude mouse model of human pancreatic cancer. We constructed retroviral vectors for human Pim-3 and a kinase-dead mutant of human Pim-3 (K69M); the retroviral supernatants generated from these vectors were then used to infect the human pancreatic cancer cell line MiaPaCa-2 to establish stable cell lines. We assessed cell proliferation using CCK-8, tumor growth, and angiogenesis in vivo in an orthotopic mouse model of pancreatic cancer. While tumor size was measured using magnetic resonance imaging, the tumor tissues were excised for protein extraction and histological analysis to detect vascular endothelium growth factor (VEGF) expression and vessel density. We established an orthotopic nude mouse model of human pancreatic cancer. We observed that Pim-3 promoted the proliferation of human pancreatic cancer cells, both in vitro and in vivo. Moreover, Pim-3 is required for vasculogenesis of primary human pancreatic tumors in vivo and promotion of angiogenesis through the induction of VEGF expression. Pim-3 can promote tumor growth and angiogenesis by stimulating the VEGF pathway. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Is MRCP equivalent to ERCP for diagnosing biliary obstruction in orthotopic liver transplant recipients? A meta-analysis

    PubMed Central

    Jorgensen, Jennifer E.; Waljee, Akbar K.; Volk, Michael L.; Sonnenday, Christopher J.; Elta, Grace H.; Al-Hawary, Mahmoud M.; Singal, Amit G.; Taylor, Jason R.; Elmunzer, B. Joseph

    2017-01-01

    Background Biliary complications are the second leading cause of morbidity and mortality in orthotopic liver transplant (OLT) recipients. Endoscopic retrograde cholangiography (ERC) is considered the diagnostic criterion standard for post-orthotopic liver transplantation biliary obstruction, but incurs significant risks. Objective To determine the diagnostic accuracy of MRCP for biliary obstruction in OLT patients. Design A systematic literature search identified studies primarily examining the utility of MRCP in detecting post-orthotopic liver transplantation biliary obstruction. A meta-analysis was then performed according to the Quality of Reporting Meta-Analyses statement. Setting Meta-analysis of 9 studies originally performed at major transplantation centers. Patients A total of 382 OLT patients with clinical suspicion of biliary obstruction. Interventions MRCP and ERCP or clinical follow-up. Main Outcome Measurements Sensitivity and specificity of MRCP for diagnosis of biliary obstruction. Results The composite sensitivity and specificity were 0.96 (95% CI, 0.92–0.98) and 0.94 (95% CI, 0.90–0.97), respectively. The positive and negative likelihood ratios were 17 (95% CI, 9.4–29.6) and 0.04 (95% CI, 0.02–0.08), respectively. Limitations All but 1 included study had significant design flaws that may have falsely increased the reported diagnostic accuracy. Conclusions The high sensitivity and specificity demonstrated in this meta-analysis suggest that MRCP is a promising test for diagnosing biliary obstruction in patients who have undergone liver transplantation. However, given the significant design flaws in most of the component studies, additional high-quality data are necessary before unequivocally recommending MRCP in this setting. PMID:21316670

  12. [Ascending aorta replacement late after aortic valve replacement].

    PubMed

    Hayashi, Yasunari; Ito, Toshiaki; Maekawa, Atsuo; Sawaki, Sadanari; Fujii, Genyo; Hoshino, Satoshi; Tokoro, Masayoshi; Yanagisawa, Junji

    2013-07-01

    Replacement of the asceding aorta is indicated in patients undergoing aortic valve replacement( AVR), if the diameter of the ascending aorta is greater than 5.0 cm. If the diameter of the asceding aorta is from 4.0 to 5.0 cm, it was arguable whether replacement of the ascending aorta should be performed. Nine patients who underwent reoperative ascending aorta replacement after AVR were reviewed retrospectively. Reoperation on the asending aorta replacement was performed 11.8±7.2 years (range 1y5m~23y3m) after AVR. Mean patient age was 69.9±6.3 (range 60~81). In 2 cases, reoperations were performed early year after AVR. Although ascending aorta was dilated at the 1st operation, replacement wasn't performed for the age and minimally invasive cardiac surgery (MICS). In 3 cases, reoperations were performed more than 10 years later. On these cases, ascending aorta aneurysm and dissection occurred with no pain and were pointed out by computed tomography(CT) or ultrasonic cardiogram(UCG). We think that patients with dilatation of the ascending aorta should undergo AVR and aorta replacement at the 1st operation regardness of age. It is important that patients who underwent AVR should undergo a regular checkup on the ascending aorta.

  13. Percutaneous Valve Replacement: Significance of Different Delivery Systems In Vitro and In Vivo

    SciTech Connect

    Attmann, Tim; Lutter, Georg Quaden, Rene; Jahnke, Thomas; Rumberg, Kristin; Cremer, Jochen; Muller-Hulsbeck, Stefan

    2006-06-15

    Background and purpose. Percutaneous heart valve replacement is an exciting growing field in cardiovascular medicine yet still with some major problems. Only sophisticated improvement of the instruments could make it a real alternative to conventional surgery. Therefore, the aim of this study was to evaluate different delivery devices for percutaneous heart valve replacement in vitro and in vivo. Methods. A catheter prototype designed by our group, and two commercially available devices for the delivery of esophageal stents and aortic endoprostheses, were tested. After in vitro experiments, an ovine animal model of transfemoral pulmonary valve implantation was established using biological valved self-expanding stents. Only the delivery device for aortic endografts (Medtronic, Talent, Santa Rosa, CA, USA) allowed fast in vitro procedures without material fatigue. This device was chosen for the in vivo tests. Results. Technical success was achieved in 9 of 10 animals (90%). One animal died after perforation of the ventricular wall. Orthotopic pulmonary placement was performed in 6 animals and intentional supravalvular valved stent placement in 3 animals. Conclusions. An adequate in vitro model for this evolving field of interventional heart valve replacement is presented. Furthermore, the present study pinpoints the key characteristics that are mandatory for a delivery system in percutaneous pulmonary valve implantation. With regard to the delivery device's ductility observed during this 'venous' study, an approach to transfemoral aortic valve implantation seems feasible.

  14. Engineered Multifunctional Nanomedicine for Simultaneous Stereotactic Chemotherapy and Inhibited Osteolysis in an Orthotopic Model of Bone Metastasis.

    PubMed

    Li, Chunyan; Zhang, Yejun; Chen, Guangcun; Hu, Feng; Zhao, Kui; Wang, Qiangbin

    2017-04-01

    A novel multifunctional Ag2 S quantum dot (QD)-based nanomedicine of alendronate (Ald)/doxorubicin (DOX)@Ag2 S is developed for highly effective bone tumor therapy in an orthotopic model. The bone-targeting and osteolysis inhibition of Ald and the chemotherapeutic effect of DOX on the bone tumor are in situ visualized by Ag2 S QDs with emission in the second near-infrared window. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Fully functional bioengineered tooth replacement as an organ replacement therapy

    PubMed Central

    Ikeda, Etsuko; Morita, Ritsuko; Nakao, Kazuhisa; Ishida, Kentaro; Nakamura, Takashi; Takano-Yamamoto, Teruko; Ogawa, Miho; Mizuno, Mitsumasa; Kasugai, Shohei; Tsuji, Takashi

    2009-01-01

    Current approaches to the development of regenerative therapies have been influenced by our understanding of embryonic development, stem cell biology, and tissue engineering technology. The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies. The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues. This study represents a substantial advance and emphasizes the potential for bioengineered organ replacement in future regenerative therapies. PMID:19666587

  16. Fully functional bioengineered tooth replacement as an organ replacement therapy.

    PubMed

    Ikeda, Etsuko; Morita, Ritsuko; Nakao, Kazuhisa; Ishida, Kentaro; Nakamura, Takashi; Takano-Yamamoto, Teruko; Ogawa, Miho; Mizuno, Mitsumasa; Kasugai, Shohei; Tsuji, Takashi

    2009-08-11

    Current approaches to the development of regenerative therapies have been influenced by our understanding of embryonic development, stem cell biology, and tissue engineering technology. The ultimate goal of regenerative therapy is to develop fully functioning bioengineered organs which work in cooperation with surrounding tissues to replace organs that were lost or damaged as a result of disease, injury, or aging. Here, we report a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region. We propose this technology as a model for future organ replacement therapies. The bioengineered tooth, which was erupted and occluded, had the correct tooth structure, hardness of mineralized tissues for mastication, and response to noxious stimulations such as mechanical stress and pain in cooperation with other oral and maxillofacial tissues. This study represents a substantial advance and emphasizes the potential for bioengineered organ replacement in future regenerative therapies.

  17. INNOPLANT Total Hip Replacement System.

    PubMed

    Harper, Tisha A M

    2017-07-01

    Total hip replacement is a salvage procedure that is done to alleviate discomfort secondary to osteoarthritis in the hip, which is most often a result of hip dysplasia. Commercially available total hip replacement implants for small animal patients are classified as cemented or cementless. The INNOPLANT Total Hip Replacement system includes modular, screw-in cementless components that were developed to improve implant stability by maintaining as much normal anatomic structure, and by extension biomechanics of the coxofemoral joint, as possible. As a newer system, there are few data and no long-term studies available in the veterinary literature. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Adrenergic Receptor Polymorphism and Maximal Exercise Capacity after Orthotopic Heart Transplantation

    PubMed Central

    Feliciano, Helene; Martin, David; Regamey, Julien; Tozzi, Piergiorgio; Meyer, Philippe; Hullin, Roger

    2016-01-01

    Background Maximal exercise capacity after heart transplantion (HTx) is reduced to the 50–70% level of healthy controls when assessed by cardiopulmonary exercise testing (CPET) despite of normal left ventricular function of the donor heart. This study investigates the role of donor heart β1 and β2- adrenergic receptor (AR) polymorphisms for maximal exercise capacity after orthotopic HTx. Methods CPET measured peak VO2 as outcome parameter for maximal exercise in HTx recipients ≥9 months and ≤4 years post-transplant (n = 41; mean peak VO2: 57±15% of predicted value). Donor hearts were genotyped for polymorphisms of the β1-AR (Ser49Gly, Arg389Gly) and the β2-AR (Arg16Gly, Gln27Glu). Circumferential shortening of the left ventricle was measured using magnetic resonance based CSPAMM tagging. Results Peak VO2 was higher in donor hearts expressing the β1-Ser49Ser alleles when compared with β1-Gly49 carriers (60±15% vs. 47±10% of the predicted value; p = 0.015), and by trend in cardiac allografts with the β1-AR Gly389Gly vs. β1-Arg389 (61±15% vs. 54±14%, p = 0.093). Peak VO2 was highest for the haplotype Ser49Ser-Gly389, and decreased progressively for Ser49Ser-Arg389Arg > 49Gly-389Gly > 49Gly-Arg389Arg (adjusted R2 = 0.56, p = 0.003). Peak VO2 was not different for the tested β2-AR polymorphisms. Independent predictors of peak VO2 (adjusted R2 = 0.55) were β1-AR Ser49Gly SNP (p = 0.005), heart rate increase (p = 0.016), and peak systolic blood pressure (p = 0.031). Left ventricular (LV) motion kinetics as measured by cardiac MRI CSPAMM tagging at rest was not different between carriers and non-carriers of the β1-AR Gly49allele. Conclusion Similar LV cardiac motion kinetics at rest in donor hearts carrying either β1-AR Gly49 or β1-Ser49Ser variant suggests exercise-induced desensitization and down-regulation of the β1-AR Gly49 variant as relevant pathomechanism for reduced peak VO2 in β1-AR Gly49 carriers. PMID:27669015

  19. Metformin sensitizes sorafenib to inhibit postoperative recurrence and metastasis of hepatocellular carcinoma in orthotopic mouse models.

    PubMed

    You, Abin; Cao, Manqing; Guo, Zhigui; Zuo, Bingfeng; Gao, Junrong; Zhou, Hongyuan; Li, Huikai; Cui, Yunlong; Fang, Feng; Zhang, Wei; Song, Tianqiang; Li, Qiang; Zhu, Xiaolin; Yin, Haifang; Sun, Huichuan; Zhang, Ti

    2016-03-08

    minimized postoperative recurrence and lung metastasis of HCC in orthotopic mouse model. Combined therapy inhibited CD31 and Ki67 expression but promoted TUNEL expression. Metformin may potentially enhance the effect of sorafenib to inhibit HCC recurrence and metastasis after liver resection by regulating the expression of HIF-2α and TIP30.

  20. Myocardial tissue remodeling after orthotopic heart transplantation: a pilot cardiac magnetic resonance study.

    PubMed

    Coelho-Filho, Otavio Rizzi; Shah, Ravi; Lavagnoli, Carlos Fernando Ramos; Barros, Jose Carlos; Neilan, Tomas G; Murthy, Venkatesh L; de Oliveira, Pedro Paulo Martins; Souza, Jose Roberto Matos; de Oliveira Severino, Elaine Soraya Barbosa; de Souza Vilarinho, Karlos Alexandre; da Mota Silveira Filho, Lindemberg; Garcia, Jose; Semigran, Marc J; Coelho, Otavio Rizzi; Jerosch-Herold, Michael; Petrucci, Orlando

    2016-07-20

    After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47 ± 7 years, 30 % female, median follow-up post-OHT 6 months) and 30 age-matched healthy volunteers (mean age 50.5 ± 15 years; LVEF 63.5 ± 7 %). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3 ± 11 %) with higher LV mass relative to age-matched healthy volunteers (114 ± 27 vs. 85.8 ± 18 g; p < 0.001). There was no late gadolinium enhancement in either group. Both myocardial extracellular volume fraction (ECV) and intracellular lifetime of water (τic), a measure of cardiomyocyte hypertrophy, were higher in patients post-OHT (ECV: 0.39 ± 0.06 vs. 0.28 ± 0.03, p < 0.0001; τic: 0.12 ± 0.08 vs. 0.08 ± 0.03, p < 0.001). ECV was associated with LV mass (r = 0.74, p < 0.001). In follow-up, OHT recipients with normal biopsies by pathology (ISHLT grade 0R) in the first year post-OHT exhibited a lower ECV relative to patients with any rejection ≥2R (0.35 ± 0.02 for 0R vs. 0.45 ± 0, p < 0.001). Higher ECV but not LVEF was significantly associated with a reduced rejection-free survival. After OHT, markers of tissue remodeling by CMR (ECV and τic) are elevated and associated with myocardial hypertrophy. Interstitial myocardial remodeling (by ECV) is associated with cellular rejection. Further research on the impact of graft preservation and early immunosuppression on tissue-level remodeling of the allograft is necessary to delineate the clinical implications of these findings.

  1. 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.

  2. Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder.

    PubMed

    Guihaire, Julien; Itagaki, Ryo; Stubbendorff, Mandy; Hua, Xiaoqin; Deuse, Tobias; Ullrich, Sebastian; Fadel, Elie; Dorfmüller, Peter; Robbins, Robert C; Reichenspurner, Hermann; Schumacher, Udo; Schrepfer, Sonja

    2016-12-01

    Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day 7 (BN7 , n = 6; RNU7 , n = 7) or Day 28 (BN28 , n = 6; RNU28 , n = 6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells was observed in the BN group on Day 28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P < 0.001 and P = 0.035). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (IgG) in the BN group compared to RNU (respectively, 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P = 0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P = 0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P = 0.005). Similarly, S100A4 was highly expressed in response to human MNCs compared to stimulation by T-cell-depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P < 0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be

  3. Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging

    PubMed Central

    England, Christopher G.; Huang, Justin S.; James, Kurtis T.; Zhang, Guandong; Gobin, André M.; Frieboes, Hermann B.

    2015-01-01

    Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5±8.2 and 23.3±4.1 particles/100μm2 within 10μm from the nearest source and few nanoparticles beyond 50μm, respectively. The spleen had 35.5±9.3 particles/100μm2 within 10μm with penetration also limited to 50μm. For SGN, the liver showed 31.1±4.1 particles/100μm2 within 10μm of the nearest source with penetration hindered beyond 30μm. The spleen and tumor showed uptake of 22.1±6.2 and 15.8±6.1 particles/100μm2 within 10μm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/μm2) was 1.09±0.14 in the liver, 0.74±0.12 in the spleen, and 0.43±0.07 in the tumor. SGN average concentration (nanoparticles/μm2) was 0.43±0.07 in the liver, 0.30±0.06 in the spleen, and 0.20±0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in pancreatic tumors with the goal to improve

  4. Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging.

    PubMed

    England, Christopher G; Huang, Justin S; James, Kurtis T; Zhang, Guandong; Gobin, André M; Frieboes, Hermann B

    2015-01-01

    Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5 ± 8.2 and 23.3 ± 4.1 particles/100 μm2 within 10 μm from the nearest source and few nanoparticles beyond 50 μm, respectively. The spleen had 35.5 ± 9.3 particles/100 μm2 within 10 μm with penetration also limited to 50 μm. For SGN, the liver showed 31.1 ± 4.1 particles/100 μm2 within 10 μm of the nearest source with penetration hindered beyond 30 μm. The spleen and tumor showed uptake of 22.1 ± 6.2 and 15.8 ± 6.1 particles/100 μm2 within 10 μm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/μm2) was 1.09 ± 0.14 in the liver, 0.74 ± 0.12 in the spleen, and 0.43 ± 0.07 in the tumor. SGN average concentration (nanoparticles/μm2) was 0.43 ± 0.07 in the liver, 0.30 ± 0.06 in the spleen, and 0.20 ± 0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in

  5. Role of interleukin-17A in early graft rejection after orthotopic lung transplantation in mice

    PubMed Central

    Chen, Qi-Rui; Wang, Li-Feng; Xia, Si-Si; Zhang, Ya-Mei; Xu, Jiang-Nan

    2016-01-01

    Background The cellular and molecular mechanisms underlying lung allograft rejection remain poorly understood. We investigated the potential role of interleukin (IL)-17A in lung transplant rejection in a mouse model, because previous studies in clinical and rodent models have implicated IL-17A in both acute and chronic rejection. Methods To generate an orthotopic lung transplantation model, lungs from C57BL/6 or BALB/c mice were transplanted into C57BL/6 mice (isograft and allograft models, respectively). The effects of anti-IL-17A treatment in allograft recipients were investigated. The histological features and rejection status of isografts and allografts were assessed at 3, 7, and 28 days after transplantation, and differences in graft infiltrating cells and mRNA expression of relevant cytokines were quantified at 3 and 7 days after transplantation. Results As expected, isografts showed no obvious signs of rejection, whereas allografts exhibited minimal-to-mild rejection (grade A1–A2) by day 3 and moderate-to-severe rejection (grade A3–A4) by day 7, without evidence of obliterative bronchiolitis (OB). However, by 28 days, evidence of OB was observed in 67% (2/3) of allografts and severe rejection (grade A4) was observed in all. IL-17 mRNA expression in allografts was increased with rejection, and interferon (IFN)-γ and IL-6 mRNA expression levels followed a similar pattern. In contrast, IL-22 expression in allografts was only slightly increased. Antibody (Ab) neutralization of IL-17A diminished the signs of acute rejection at 7 days after transplantation in allografts, and this early protection was accompanied by a decrease in cellular stress according to histological evaluation, suggesting the involvement of IL-17A in the development of early post-transplantation lesions. Conclusions Our data indicate that IL-17A is important in the pathophysiology of allograft rejection, and neutralization of IL-17A is a potential therapeutic strategy to preventing lung

  6. Efficacy of Salmonella typhimurium A1-R versus chemotherapy on a pancreatic cancer patient-derived orthotopic xenograft (PDOX).

    PubMed

    Hiroshima, Yukihiko; Zhao, Ming; Maawy, Ali; Zhang, Yong; Katz, Matthew H G; Fleming, Jason B; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Suetsugu, Atsushi; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2014-07-01

    The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R (A1-R) on pancreatic cancer patient-derived orthotopic xenografts (PDOX). The PDOX model was originally established from a pancreatic cancer patient in SCID-NOD mice. The pancreatic cancer PDOX was subsequently transplanted by surgical orthotopic implantation (SOI) in transgenic nude red fluorescent protein (RFP) mice in order that the PDOX stably acquired red fluorescent protein (RFP)-expressing stroma for the purpose of imaging the tumor after passage to non-transgenic nude mice in order to visualize tumor growth and drug efficacy. The nude mice with human pancreatic PDOX were treated with A1-R or standard chemotherapy, including gemcitabine (GEM), which is first-line therapy for pancreatic cancer, for comparison of efficacy. A1-R treatment significantly reduced tumor weight, as well as tumor fluorescence area, compared to untreated control (P = 0.011), with comparable efficacy of GEM, CDDP, and 5-FU. Histopathological response to treatment was defined according to Evans's criteria and A1-R had increased efficacy compared to standard chemotherapy. The present report is the first to show that A1-R is effective against a very low-passage patient tumor, in this case, pancreatic cancer. The data of the present report suggest A1-1 will have clinical activity in pancreatic cancer, a highly lethal and treatment-resistant disease and may be most effectively used in combination with other agents.

  7. Lumbar puncture-administered resveratrol inhibits STAT3 activation, enhancing autophagy and apoptosis in orthotopic rat glioblastomas

    PubMed Central

    Xue, Song; Xiao-Hong, Shu; Lin, Sha; Jie, Bian; Li-Li, Wang; Jia-Yao, Gu; Shun, Shi; Pei-Nan, Li; Mo-Li, Wu; Qian, Wang; Xiao-Yan, Chen; Qing-You, Kong; Peng, Zhang; Hong, Li; Jia, Liu

    2016-01-01

    Trans-resveratrol suppresses glioblastoma growth in vitro, but its effects on intracranial glioblastomas remain untested. Resveratrol crosses the blood–brain barrier, and lumbar puncture (LP) greatly increases its bioavailability in rat brains; therefore, we investigated the effectiveness of LP-administered resveratrol on orthotopic rat glioblastomas. Twenty-four tumor-bearing rats were separated into two groups: Group 1 receiving 100 μl saline containing 0.3% DMSO and Group 2 receiving 100 μl resveratrol (300 μM). Treatments started 3 days after transplantation in 2-day intervals until death. Intracranial drug availabilities, tumor sizes, average life spans and the impacts on STAT3 signaling, apoptosis and autophagy rates were evaluated. MRI imaging revealed that average tumor size in the LP group (495.8 ± 22.3 mm2) was smaller than the control groups (810.3 ± 56.4 mm2; P<0.05). The mean survival time in the LP group (22.2 ± 2.1 d) was longer than control animals (16.0 ± 1.8 d; P<0.05). LP resveratrol-treated glioblastomas showed less Cyclin D1 staining, enhanced autophagy with up-regulated LC3 and Beclin1 expression, and widely distributed apoptotic foci around tumor capillaries with suppressed STAT3 expression and nuclear translocation. In conclusion, LP-delivered resveratrol efficiently inhibited orthotopic rat glioblastoma growth by inactivating STAT3 signaling and enhancing autophagy and apoptosis. PMID:27716625

  8. Impact of MHC Class II Incompatibility on Localization of Mononuclear Cell Infiltrates to the Bronchiolar Compartment of Orthotopic Lung Allografts

    PubMed Central

    Nakashima, Shinji; Soong, T. Rinda; Fox-Talbot, Karen; Qian, Zhiping; Rahimi, Salma; Wasowska, Barbara A.; Rohde, Charles A.; Chen, Sabrina; Garcia, Joe G.N.; Baldwin, William M.

    2005-01-01

    Chronic pathological changes in transplanted lungs are unique because they center on the airways. We examined the relative role of MHC class I and II antigens in causing bronchial pathology in orthotopic lung transplants to rats maintained on cyclosporin A (CsA). Transplants mismatched for MHC class II antigens had significantly more peri-bronchiolar infiltrates than MHC class I incompatible transplants. No significant increase in infiltrates was found in lung transplants incompatible for MHC class I plus II antigens compared to MHC class II antigens alone. Immunohistochemistry demonstrated that MHC class II antigen expression was confined to macrophages in MHC class I incompatible transplants, but was upregulated on bronchial epithelium in transplants with MHC class II incompatibilities. Vascular endothelium was notably devoid of MHC class II antigen expression in all transplants. However, both peri-bronchial and peri-vascular infiltrates were frequently cuffed by alveolar macrophages and type II pneumocytes that expressed MHC class II antigens. PCR analysis demonstrated that IFN-γ and regulated on activation, normal T cells expressed and secreted (RANTES) were upregulated in MHC class II incompatible transplants. Thus, MHC class II incompatible orthotopic lung transplants in rats maintained on CsA immunosuppression undergo a bronchiolcentric upregulation of alloantigens. PMID:15760392

  9. 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.

  10. Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model.

    PubMed

    Jantscheff, Peter; Ziroli, Vittorio; Esser, Norbert; Graeser, Ralph; Kluth, Jessica; Sukolinskaya, Alena; Taylor, Lenka A; Unger, Clemens; Massing, Ulrich

    2009-01-01

    Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies.

  11. Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases

    PubMed Central

    2013-01-01

    Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three critical needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-organic nanoparticles with flexible and robust radiochemistry. Herein, we validate the first in vivo application of 64Cu-porphysomes in clinically relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies. PMID:23544841

  12. Applicable apparent diffusion coefficient of an orthotopic mouse model of gastric cancer by improved clinical MRI diffusion weighted imaging

    PubMed Central

    Sun, Jia; Zhang, Xiao-Peng; Li, Xiao-Ting; Tang, Lei; Cui, Yong; Zhang, Xiao-Yan; Sun, Ying-Shi

    2014-01-01

    In vivo imaging studies in animal models are hindered by variables that contribute to poor image quality and measurement reliability. As such we sought to improve the diffusion coefficient (ADC) of an orthotopic mouse model of gastric cancer in diffusion-weighted images (DWI) using alginate moulding and Ultrasonic coupling medium. BGC-823 human gastric cancer cells were subcutaneously injected into the abdomen of nude mice and 1 mm3 primary tumour was orthotopically transplanted. Alginate and coupling medium were applied to the mice and MRI (T2 and DWI) was performed for 6 weeks. Regions of interest (ROI) were drawn and liver and tumour ADC were evaluated. Using alginate moulding, the mean quality total score of DW imaging was 8.53; however, in control animals this value was 5.20 (p < 0.001). The coefficient of variation of ADC of liver in experimental and control groups were 0.071 and 0.270 (p < 0.001), respectively, suggesting this method may be helpful for DWI studies of important human diseases such as gastric cancer. PMID:25123166

  13. Models of Human Metastatic Colon Cancer in Nude Mice Orthotopically Constructed by Using Histologically Intact Patient Specimens

    NASA Astrophysics Data System (ADS)

    Fu, Xinyu; Besterman, Jeffrey M.; Monosov, Ann; Hoffman, Robert M.

    1991-10-01

    There is an important need for clinically relevant animal models for human cancers. Toward this goal, histologically intact human colon-cancer specimens derived surgically from patients were implanted orthotopically to the colon or cecum of nude mice. We have observed extensive orthotopic growth in 13 of 20 cases of implanted patient colon tumors. These showed various growth patterns with subsequent regional, lymph-node, and liver metastasis, as well as general abdominal carcinomatosis. Thus, models for human colon cancer have been developed that show (i) local growth, (ii) abdominal metastasis, (iii) general abdominal carcinomatosis with extensive peritoneal seeding, (iv) lymph-node metastasis, (v) liver metastasis, and (vi) colonic obstruction. These models permit the passage of the tumors to form large cohorts. They will facilitate research into the biology of colon cancer metastatic capability and the development of new drugs active against metastatic cancer. These models may also predict the clinical course and the in vivo response to drugs of the cancer of individual patients.

  14. Inherently multimodal nanoparticle-driven tracking and real-time delineation of orthotopic prostate tumors and micrometastases.

    PubMed

    Liu, Tracy W; Macdonald, Thomas D; Jin, Cheng S; Gold, Joseph M; Bristow, Robert G; Wilson, Brian C; Zheng, Gang

    2013-05-28

    Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three critical needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-organic nanoparticles with flexible and robust radiochemistry. Herein, we validate the first in vivo application of (64)Cu-porphysomes in clinically relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies.

  15. Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy.

    PubMed

    Tumati, Vasu; Mathur, Sanjeev; Song, Kwang; Hsieh, Jer-Tsong; Zhao, Dawen; Takahashi, Masaya; Dobin, Timothy; Gandee, Leah; Solberg, Timothy D; Habib, Amyn A; Saha, Debabrata

    2013-05-01

    The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3‑KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments.

  16. 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.

  17. 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.

  18. 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

  19. SLT-VEGF reduces lung metastases, decreases tumor recurrence, and improves survival in an orthotopic melanoma model.

    PubMed

    Ackerman, Rachel; Backer, Joseph M; Backer, Marina; Skariah, Sini; Hamby, Carl V

    2010-09-01

    SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT) subunit A fused to human vascular endothelial growth factor (VEGF). It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1) and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 10(6) cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007), reduced the incidence of lung metastasis (p = 0.038), and improved survival (p = 0.002). These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.

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

    SciTech Connect

    Jarmila, Lastovickova 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 treating 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.

  1. Development of a locally advanced orthotopic prostate tumor model in rats for assessment of combined modality therapy

    PubMed Central

    TUMATI, VASU; MATHUR, SANJEEV; SONG, KWANG; HSIEH, JER-TSONG; ZHAO, DAWEN; TAKAHASHI, MASAYA; DOBIN, TIMOTHY; GANDEE, LEAH; SOLBERG, TIMOTHY D.; HABIB, AMYN A.; SAHA, DEBABRATA

    2013-01-01

    The purpose of this study was to develop an aggressive locally advanced orthotopic prostate cancer model for assessing high-dose image-guided radiation therapy combined with biological agents. For this study, we used a modified human prostate cancer (PCa) cell line, PC3, in which we knocked down a tumor suppressor protein, DAB2IP (PC3-KD). These prostate cancer cells were implanted into the prostate of nude or Copenhagen rats using either open surgical implantation or a minimally invasive procedure under ultrasound guidance. We report that: i) these DAB2IP-deficient PCa cells form a single focus of locally advanced aggressive tumors in both nude and Copenhagen rats; ii) the resulting tumors are highly aggressive and are poorly controlled after treatment with radiation alone; iii) ultrasound-guided tumor cell implantation can be used successfully for tumor development in the rat prostate; iv) precise measurement of the tumor volume and the treatment planning for radiation therapy can be obtained from ultrasound and MRI, respectively; and v) the use of a fiducial marker for enhanced radiotherapy localization in the rat orthotopic tumor. This model recapitulates radiation-resistant prostate cancers which can be used to demonstrate and quantify therapeutic response to combined modality treatments. PMID:23525451

  2. Targeting Hypoxia-inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment

    PubMed Central

    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

    2015-01-01

    Tissue hypoxia and necrosis represent pathophysiological and histological 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 >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. PMID:26083570

  3. Bilateral Single System Orthotopic Ureterocele with Bilateral Multiple Calculi Presented with Retention of Urine - an Urological Emergency

    PubMed Central

    Gupta, Sweta; Khan, Dawood; Basu, Supriya

    2017-01-01

    The ureterocele is an uncommon congenital anomaly of the lower ureter. Ureterocele with a single pelvicalyceal system, bilateral, and orthotopic variety is less common. Calculi within bilateral ureterocele are a rare occurrence. To the best of our knowledge, only a few similar cases have been reported in the literature. Among the all reported presentations of this type of ureterocele, presentation with Acute Urinary Retention (AUR) has not been described in the literature. We present a case of nine-year-old child having bilateral, single system orthotopic ureterocele with calculi in bilateral ureterocele and presented with AUR due to obstructive bulbar urethral calculus. The bilateral endoscopic incision was given and all four calculi were removed endoscopically through percutaneous route. Voiding cystourethrography after two years follow-up was non-refluxing. The purpose of reporting this case is the rarity of the disease and to emphasize that delay in diagnosis and treatment of these cases may lead to complications such as recurrent urinary tract infection and renal failure. PMID:28892967

  4. Fracture After Total Hip Replacement

    MedlinePlus

    ... er Total Hip Replacement cont. • Dislocation • Limb length inequality • Poor fracture healing • Repeat fracture • Lack of in- ... Surgeons (AAOS). To learn more about your orthopaedic health, please visit orthoinfo.org. Page ( 5 ) AAOS does ...

  5. An encephalocele replacing nose completely.

    PubMed

    Dasgupta, G

    1999-01-01

    Congenital encephalocele presenting in the nasal region is extremely rare. We present here a case ot tncephaloce lecompletely replacing the nose of a five year old boy and duscuss about similar swellings in this region.

  6. What Is a Hip Replacement?

    MedlinePlus

    ... reduce joint pain and stiffness. It can increase muscle strength and joint range of motion (how much you ... goals after hip replacement surgery are to: Increase muscle strength Increase your blood circulation and overall fitness Avoid ...

  7. Single Project Replaces District's Windows.

    ERIC Educational Resources Information Center

    American School and University, 1981

    1981-01-01

    The towns of Maplewood and South Orange (New Jersey) earmarked over $1 million, raised from a bond issue, to replace with thermal aluminum-framed units the 2400 worn out windows in eight 50-year-old schools. (Author)

  8. The development and testing of new nicotine replacement treatments: from 'nicotine replacement' to 'smoking replacement'.

    PubMed

    Hajek, Peter

    2015-07-01

    Griffith Edwards, unusually in the 1970s, saw tobacco use as falling within the remit of addiction research, and brought Michael Russell to the Addiction Research Unit [ARU] to initiate research into smoking. The work of the tobacco section of ARU paved the way to a better understanding of tobacco dependence and to developing nicotine replacement treatments. Michael Russell pioneered the idea of attractive nicotine replacement products with an acceptable safety profile replacing cigarettes on the open market and ending the tobacco epidemic, envisaging a transition from medicinal and temporary 'nicotine replacement' to recreational and potentially permanent 'smoking replacement'. Mike's prediction that the pharmaceutical industry would develop such devices did not materialize. Instead, two such products were generated by the tobacco industry (snus) and independent developers (electronic cigarettes). Another of Mike's hopes was that regulators would adopt rational policies, and that tobacco control activists would become supportive of smoking replacement once they thought through the implications. Until now, the 'smoking replacement' idea has been met with vigorous opposition from some tobacco control activists. The voices of researchers with historical links to ARU are prominent in arguing in favour of harm reduction and e-cigarettes. The most important debate ever to occur in tobacco control is under way and it carries the signature of Griffith Edwards' ARU. © 2015 Society for the Study of Addiction.

  9. Prioritization Methodology for Chemical Replacement

    NASA Technical Reports Server (NTRS)

    Cruit, W.; Schutzenhofer, S.; Goldberg, B.; Everhart, K.

    1993-01-01

    This project serves to define an appropriate methodology for effective prioritization of efforts required to develop replacement technologies mandated by imposed and forecast legislation. The methodology used is a semiquantitative approach derived from quality function deployment techniques (QFD Matrix). This methodology aims to weigh the full environmental, cost, safety, reliability, and programmatic implications of replacement technology development to allow appropriate identification of viable candidates and programmatic alternatives. The results are being implemented as a guideline for consideration for current NASA propulsion systems.

  10. Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models.

    PubMed

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

    2017-03-01

    We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. © 2016 Wiley Periodicals, Inc.

  11. Establishment of an orthotopic transplantation tumor model in nude mice using a drug-resistant human ovarian cancer cell line with a high expression of c-Kit.

    PubMed

    Yi, Cunjian; Zhang, Lei; Li, Li; Liu, Xiangqiong; Ling, Shengrong; Zhang, Fayun; Liang, Wei

    2014-12-01

    The resistance of ovarian cancer to platinum-based chemotherapy is a critical issue in the clinical setting. The present study aimed to establish animal models to replicate this clinical condition, as well as to investigate the resistance mechanisms of ovarian cancer. A cisplatin (DDP)-resistant human ovarian cancer cell line, SKOV3/DDP, was screened, validated and injected subcutaneously into the neck of female nude mice. Following tumor establishment, the tumor was collected and cut into small sections, which were subsequently implanted into the ovaries of other nude mice. The growth of the orthotopic tumors was observed and the tumor-bearing mice were sacrificed and dissected. The orthotopic and metastatic tumor tissues were collected, sectioned, stained with hematoxylin and eosin and analyzed. In the present study, 16 nude mice underwent orthotopic transplantation surgery and a tumor model was successfully established in 14/16 of the mice, with an in situ tumor formation rate of 87.5%. Following euthanasia, a laparotomy demonstrated the tumor formation at the site of transplantation, as well as varying degrees of metastasis to additional organs and tissues. Therefore, the present study successfully established an orthotopic tumor transplantation model in nude mice using a c-Kit-positive DDP-resistant human ovarian cancer cell line. This model may represent a useful tool for investigating the resistance mechanism of ovarian cancer, as well as evaluating the efficacy of therapeutic strategies.

  12. In vivo imaging of hypoxia-inducible factor regulation in a subcutaneous and orthotopic GL261 glioma tumor model using a reporter gene assay.

    PubMed

    Bürgi, Sandra; Seuwen, Aline; Keist, Ruth; Vom Berg, Johannes; Grandjean, Joanes; Rudin, Markus

    2014-01-01

    Intratumoral hypoxia changes the metabolism of gliomas, leading to a more aggressive phenotype with increased resistance to radio- and chemotherapy. Hypoxia triggers a signaling cascade with hypoxia-inducible factor (HIF) as a key regulator. We monitored activation of the HIF pathway longitudinally in murine glioma tumors. GL261 cells, stably transfected with a luciferase reporter driven under the control of a promoter comprising the HIF target gene motive hypoxia response element, were implanted either subcutaneously or orthotopically. In vivo experiments were carried out using bioluminescence imaging. Tumors were subsequently analyzed using immunofluorescence staining for hypoxia, endothelial cells, tumor perfusion, and glucose transporter expression. Transient upregulation of the HIF signaling was observed in both subcutaneous and orthotopic gliomas. Immunofluorescence staining confirmed hypoxic regions in subcutaneous and, to a lesser extent, intracranial tumors. Subcutaneous tumors showed substantial necrosis, which might contribute to the decreased bioluminescence output observed toward the end of the experiment. Orthotopic tumors were less hypoxic than subcutaneous ones and did not develop extensive necrotic areas. Although this may be the result of the overall smaller size of orthotopic tumors, it might also reflect differences in the local environment, such as the better intrinsic vascularization of brain tissue compared to the subcutaneous tissue compartment.

  13. Prioritization methodology for chemical replacement

    NASA Technical Reports Server (NTRS)

    Cruit, Wendy; Goldberg, Ben; Schutzenhofer, Scott

    1995-01-01

    Since United States of America federal legislation has required ozone depleting chemicals (class 1 & 2) to be banned from production, The National Aeronautics and Space Administration (NASA) and industry have been required to find other chemicals and methods to replace these target chemicals. This project was initiated as a development of a prioritization methodology suitable for assessing and ranking existing processes for replacement 'urgency.' The methodology was produced in the form of a workbook (NASA Technical Paper 3421). The final workbook contains two tools, one for evaluation and one for prioritization. The two tools are interconnected in that they were developed from one central theme - chemical replacement due to imposed laws and regulations. This workbook provides matrices, detailed explanations of how to use them, and a detailed methodology for prioritization of replacement technology. The main objective is to provide a GUIDELINE to help direct the research for replacement technology. The approach for prioritization called for a system which would result in a numerical rating for the chemicals and processes being assessed. A Quality Function Deployment (QFD) technique was used in order to determine numerical values which would correspond to the concerns raised and their respective importance to the process. This workbook defines the approach and the application of the QFD matrix. This technique: (1) provides a standard database for technology that can be easily reviewed, and (2) provides a standard format for information when requesting resources for further research for chemical replacement technology. Originally, this workbook was to be used for Class 1 and Class 2 chemicals, but it was specifically designed to be flexible enough to be used for any chemical used in a process (if the chemical and/or process needs to be replaced). The methodology consists of comparison matrices (and the smaller comparison components) which allow replacement technology

  14. [Detubularized U-shaped enterocystoplasty after cystoprostatectomy].

    PubMed

    el Mrini, M; Aboutaieb, R; el Fatimi, A; Sarf, I; Joual, A; Bennani, S; Elmoussaoui, A; Benjelloun, S

    1996-01-01

    We reviewed the charts of 58 patients who underwent orthotopic bladder replacement after total cystoprostatectomy for muscle invasive bladder cancer. Mean age was 56 years. As described by Camey, 60 centimetres of small bowel, are isolated, detubularised then folded upon itself to form a U shaped reservoir, which is anastomosed to the urethra. Death occurred in 5%. Urologic complications observed were: urinary leakage (15%), ureteral reflux (6.8%), ureteral stenosis (8.6%) and stones of the neobladder (5.1%). 64.2% of the patients were immediately continent during the day. Nocturnal continence was obtained for 50% immediately and for 80% three months postoperatively. Detubularised and U shaped cystoplasty achieve a low pressure reservoir, with protection of the upper urinary tract, and a diurnal continence. Nocturnal continence is achieved later.

  15. Optimization of station battery replacement

    NASA Astrophysics Data System (ADS)

    Jancauskas, J. R.; Shook, D. A.

    1994-08-01

    During a loss of ac power at a nuclear generating station (including diesel generators), batteries provide the source of power which is required to operate safety-related components. Because traditional lead-acid batteries have a qualified life of 20 years, the batteries must be replaced a minimum of once during a station's lifetime, twice if license extension is pursued, and more often depending on actual in-service dates and the results of surveillance tests. Replacement of batteries often occurs prior to 20 years as a result of systems changes caused by factors such as Station Blackout Regulations, control system upgrades, incremental load growth, and changes in the operating times of existing equipment. Many of these replacement decisions are based on the predictive capabilities of manual design basis calculations. The inherent conservatism of manual calculations may result in battery replacements occurring before actually required. Computerized analysis of batteries can aid in optimizing the timing of replacements as well as in interpreting service test data. Computerized analysis also provides large benefits in maintaining the as-configured load profile and corresponding design margins, while also providing the capability to quickly analyze proposed modifications and respond to internal and external audits.

  16. Neoadjuvant chemoradiation followed by orthotopic liver transplantation in cholangiocarcinomas: the emory experience

    PubMed Central

    Landry, Jerome C.

    2016-01-01

    Background Cholangiocarcinoma (CCA) is a bile duct tumor with a grim prognosis. The median survival after radiotherapy of unresectable disease is 9-12 months. The following is a review of our experience with neoadjuvant (NEO) chemoradiation followed by orthotopic liver transplantation (OLT) for CCA. Methods Ten patients with CCAs were selected as candidates for NEO-OLT between 2008-2011. Patients with unresectable CCA above the cystic duct without intra or extrahepatic metastases were eligible. Primary sclerosing cholangitis (PSC) patients were included due to their poor resection response. Patients initially received external-beam radiation [via conventional fields or volumetric-modulated arc therapy (VMAT)] plus capecitabine (XEL) or 5-fluorouracil (5-FU), followed by either Iridium192 (Ir192) brachytherapy high dose rate (HDR) or external boost. 5-FU or XEL was administered until OLT. Patients underwent periodic surveillance computed tomography (CT)/MRIs after OLT. Primary endpoints included actuarial rates (AR)/crude rates (CR) of overall survival (OS), and local control (LC) at 6, 12, and 24 months. Results Five males and five females were identified. Mean age was 58.3 years (range, 38-71 years). Mean composite radiation dose delivered was 59.0 Gy (range, 54-71.4 Gy). Forty percent of patients had an HDR boost. Fifty percent of patients received XEL during NEO. Two patients were excluded from the analysis as they did not go on to OLT due to metastases (n=1) and death due to GI bleed (n=1). Thirty-eight percent of the OLT patients had a pathological complete response (pCR) after NEO, while 25% required a Whipple due to positive margins. Median follow-up for the OLT group was 23 months (range, 6.5-37 months). Six, twelve, and twenty-four months LC AR was 100%. LC CR was 100% at longest interval (30 months). Six, twelve, and twenty-four months OS AR was 100%, 87.5%, and 87.5%, respectively. Mean OS AR was 30.2 months (95% CI: 22.8-37.7). OS CR was 75% at longest

  17. Novel intrapulmonary model for orthotopic propagation of human lung cancers in athymic nude mice.

    PubMed

    McLemore, T L; Liu, M C; Blacker, P C; Gregg, M; Alley, M C; Abbott, B J; Shoemaker, R H; Bohlman, M E; Litterst, C C; Hubbard, W C

    1987-10-01

    A major impediment to the study of human lung cancer pathophysiology, as well as to the discovery and development of new specific antitumor agents for the treatment of lung cancer, has been the lack of appropriate experimental animal models. This paper describes a new model for the propagation of human lung tumor cells in the bronchioalveolar regions of the right lungs of athymic NCr-nu/nu mice via an intrabronchial (i.b.) implantation procedure. Over 1000 i.b. implantations have been performed to date, each requiring 3 to 5 min for completion and having a surgery-related mortality of approximately 5%. The model was used successfully for the orthotopic propagation of four established human lung cancer cell lines including: an adenosquamous cell carcinoma (NCI-H125); an adenocarcinoma (A549); a large cell undifferentiated carcinoma (NCI-H460), and a bronchioloalveolar cell carcinoma (NCI-H358). When each of the four cell lines was implanted i.b. using a 1.0 X 10(6) tumor cell inoculum, 100 +/- 0% (SD) tumor-related mortality was observed within 9 to 61 days. In contrast, when the conventional s.c. method for implantation was used at the same tumor cell inoculum, only minimal (2.5 +/- 5%) tumor-related mortality was observed within 140 days (P less than 0.001). Similarly, when a 1.0 X 10(5) or 1.0 X 10(4) cell inoculum was used, a dose-dependent, tumor-related mortality was observed when cells were implanted i.b. (56 +/- 24% or 25 +/- 17%) as compared with the s.c. method (5 +/- 5.7% or 0.0 +/- 0%) (P less than 0.02 and P less than 0.05, respectively). Most (greater than 90%) of the lung tumors propagated by i.b. implantation were localized to the right lung fields as documented by necropsy and/or high-resolution chest roentgenography techniques which were developed for these studies. The intrapulmonary model was also used for establishment and propagation of xenografts derived directly from enzymatically digested, fresh human lung tumor specimens obtained at the

  18. (68)Ga-labeled 3PRGD2 for dual PET and Cerenkov luminescence imaging of orthotopic human glioblastoma.

    PubMed

    Fan, Di; Zhang, Xin; Zhong, Lijun; Liu, Xujie; Sun, Yi; Zhao, Huiyun; Jia, Bing; Liu, Zhaofei; Zhu, Zhaohui; Shi, Jiyun; Wang, Fan

    2015-06-17

    β-Emitters can produce Cerenkov radiation that is detectable by Cerenkov luminescence imaging (CLI), allowing the combination of PET and CLI with one radiotracer for both tumor diagnosis and visual guidance during surgery. Recently, the clinical feasibility of CLI with the established therapeutic reagent Na(131)I and the PET tracer (18)F-FDG was demonstrated. (68)Ga possesses a higher Cerenkov light output than (18)F and (131)I, which would result in higher sensitivity for CLI and improve the outcome of CLI in clinical applications. However, the research on (68)Ga-based tumor-specific tracers for CLI is limited. In this study, we examined the use of (68)Ga-radiolabeled DOTA-3PRGD2 ((68)Ga-3PRGD2) for dual PET and CLI of orthotopic U87MG human glioblastoma. For this purpose, the Cerenkov efficiencies of (68)Ga and (18)F were measured with the IVIS Spectrum system (PerkinElmer, USA). The CLI signal intensity of (68)Ga was 15 times stronger than that of (18)F. PET and CLI of (68)Ga-3PRGD2 were performed in U87MG human glioblastoma xenografts. Both PET and CLI revealed a remarkable accumulation of (68)Ga-3PRGD2 in the U87MG human glioblastoma xenografts at 1 h p.i. with an extremely low background in the brain when compared with (18)F-FDG. Furthermore, (68)Ga-3PRGD2 was used for dual PET and CLI of orthotopic human glioblastoma. The orthotopic human glioblastoma was clearly visualized by both imaging modalities. In addition, the biodistribution of (68)Ga-3PRGD2 was assessed in normal mice to estimate the radiation dosimetry. The whole-body effective dose is 20.1 ± 3.3 μSv/MBq, which is equal to 3.7 mSv per whole-body PET scan with a 5 mCi injection dose. Thus, (68)Ga-3PRGD2 involves less radiation exposure in patients when compared with (18)F-FDG (7.0 mSv). The use of (68)Ga-3PRGD2 in dual PET and CLI shows great promise for tumor diagnosis and image-guided surgery.

  19. [Hip replacement in military personnel].

    PubMed

    Maksimov, I B; Paniushin, K A; Brizhan', L K; Buriachenko, B P; Varfolomeev, D I; Mimanchev, O V

    2014-01-01

    Hip joint diseases and injuries are common for orthopedic pathology among military personnel. Hip replacement is one of the most frequent operations. Authors evaluated hip replacement in 136 servicemen treated at the center of traumatology and orthopedics of Burdenko General Military Clinical Hospital of the Ministry of Defense of Russia in 2010-2013. On the basis of the conducted analysis the main disease groups were revealed, peculiarities of pathology among this category of patients. Authors proposed surgical doctrine for the treatment of this contingent. Effective surgical treatment, in particular, hip replacement surgery, conducted with the use of the proposed principles, as a rule, fully functionally cured patients and contributes to return them in the system that contributes to the strengthening of defensibility of the country.

  20. Prioritization methodology for chemical replacement

    NASA Technical Reports Server (NTRS)

    Goldberg, Ben; Cruit, Wendy; Schutzenhofer, Scott

    1995-01-01

    This methodology serves to define a system for effective prioritization of efforts required to develop replacement technologies mandated by imposed and forecast legislation. The methodology used is a semi quantitative approach derived from quality function deployment techniques (QFD Matrix). QFD is a conceptual map that provides a method of transforming customer wants and needs into quantitative engineering terms. This methodology aims to weight the full environmental, cost, safety, reliability, and programmatic implications of replacement technology development to allow appropriate identification of viable candidates and programmatic alternatives.

  1. [Nicotine replacement therapy during pregnancy].

    PubMed

    Jiménez Ruiz, Carlos A

    2006-08-01

    In spite of the fact that smoking is the main cause of obstetric morbidity and mortality, 20% of North American women smoke during pregnancy. In Spain, this figure is as high as 30% to 35%. Treating smoking addiction in these patients should be the first and most important therapeutic measure undertaken by health professionals responsible for the care of pregnant women. All experts recommend the use of nicotine replacement therapy when more conservative treatments have failed. This article reviews the indications and contraindications for nicotine replacement therapy during pregnancy as well as other issues relating to the safety of this type of treatment.

  2. Prioritization methodology for chemical replacement

    NASA Technical Reports Server (NTRS)

    Goldberg, Ben; Cruit, Wendy; Schutzenhofer, Scott

    1995-01-01

    This methodology serves to define a system for effective prioritization of efforts required to develop replacement technologies mandated by imposed and forecast legislation. The methodology used is a semi quantitative approach derived from quality function deployment techniques (QFD Matrix). QFD is a conceptual map that provides a method of transforming customer wants and needs into quantitative engineering terms. This methodology aims to weight the full environmental, cost, safety, reliability, and programmatic implications of replacement technology development to allow appropriate identification of viable candidates and programmatic alternatives.

  3. HST Replacement Battery Initial Performance

    NASA Technical Reports Server (NTRS)

    Krol, Stan; Waldo, Greg; Hollandsworth, Roger

    2009-01-01

    The Hubble Space Telescope (HST) original Nickel-Hydrogen (NiH2) batteries were replaced during the Servicing Mission 4 (SM4) after 19 years and one month on orbit.The purpose of this presentation is to highlight the findings from the assessment of the initial sm4 replacement battery performance. The batteries are described, the 0 C capacity is reviewed, descriptions, charts and tables reviewing the State Of Charge (SOC) Performance, the Battery Voltage Performance, the battery impedance, the minimum voltage performance, the thermal performance, the battery current, and the battery system recharge ratio,

  4. Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis.

    PubMed

    Roth, Beat; Jayaratna, Isuru; Sundi, Debasish; Cheng, Tiewei; Melquist, Jonathan; Choi, Woonyoung; Porten, Sima; Nitti, Giovanni; Navai, Neema; Wszolek, Matthew; Guo, Charles; Czerniak, Bogdan; McConkey, David; Dinney, Colin

    2016-08-02

    Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.

  5. 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.

  6. Development of an orthotopic model of human metastatic prostate cancer in the NOD-SCIDγ mouse (Mus musculus) anterior prostate.

    PubMed

    Cifuentes, Federico F; Valenzuela, Rodrigo H; Contreras, Héctor R; Castellón, Enrique A

    2015-10-01

    Prostate cancer is one of the most prevalent oncological diseases in males worldwide, and the mortalities resulting from this type of cancer are mainly due to metastasis. The most common models for the study of metastasis are transgenic and immunocompromised mice, which enable the study of the metastatic process in a controlled way by the injection of prostate cancer cells into the mice. In the present study, NOD-SCIDγ mice were injected orthotopically with PC3 cells in the anterior prostate in order to establish a metastatic model. The results demonstrated the development and growth of a primary tumor that preceded the formation of micrometastases in the lung, liver and pancreas, followed by macrometastases in the liver. This model adequately represents the dynamics of the metastatic process, and may be useful for novel therapeutic assays and post-surgical relapse studies.

  7. Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model.

    PubMed

    Weng, Ling-Ling; Xiang, Jian-Feng; Lin, Jin-Bo; Yi, Shang-Hui; Yang, Li-Tao; Li, Yi-Sheng; Zeng, Hao-Tao; Lin, Sheng-Ming; Xin, Dong-Wei; Zhao, Hai-Liang; Qiu, Shu-Qi; Chen, Tao; Zhang, Min-Guang

    2014-01-01

    Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

  8. Fluorescence-guided surgery in combination with UVC irradiation cures metastatic human pancreatic cancer in orthotopic mouse models.

    PubMed

    Hiroshima, Yukihiko; Maawy, Ali; Zhang, Yong; Sato, Sho; Murakami, Takashi; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2014-01-01

    The aim of this study is to determine if ultraviolet light (UVC) irradiation in combination with fluorescence-guided surgery (FGS) can eradicate metastatic human pancreatic cancer in orthotopic nude-mouse models. Two weeks after orthotopic implantation of human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 24). After BLS, mice were randomized into 3 treatment groups; BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8). The residual tumors were resected using a hand-held portable imaging system under fluorescence navigation in mice treated with FGS and FGS-UVC. The surgical resection bed was irradiated with 2700 J/m2 UVC (254 nm) in the mice treated with FGS-UVC. The average residual tumor area after FGS (n = 16) was significantly smaller than after BLS only (n = 24) (0.135±0.137 mm2 and 3.338±2.929 mm2, respectively; p = 0.007). The BLS treated mice had significantly reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p<0.001 and p<0.001, respectively) and overall survival (OS) (p<0.001 and p<0.001, respectively). FGS-UVC-treated mice had increased RFS and OS compared to FGS-only treated mice (p = 0.008 and p = 0.025, respectively); with RFS lasting at least 150 days indicating the animals were cured. The results of the present study suggest that UVC irradiation in combination with FGS has clinical potential to increase survival.

  9. 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

  10. Intravesical administration of exogenous microRNA-145 as a therapy for mouse orthotopic human bladder cancer xenograft

    PubMed Central

    Inamoto, Teruo; Taniguchi, Kohei; Takahara, Kiyoshi; Iwatsuki, Ayako; Takai, Tomoaki; Komura, Kazumasa; Yoshikawa, Yuki; Uchimoto, Taizo; Saito, Kenkichi; Tanda, Naoki; Kouno, Junko; Minami, Koichiro; Uehara, Hirofumi; Hirano, Hajime; Nomi, Hayahito; Kiyama, Satoshi; Akao, Yukihiro; Azuma, Haruhito

    2015-01-01

    We previously reported that the level of microRNA (miR)-145 is attenuated in human bladder cancer cells. In this current study, we investigated whether intravesical administration of miR-145 could be a potential therapeutic strategy for controlling bladder cancer by using an orthotopic human bladder cancer xenograft model. Following transfection of 253J B-V cells with miR-145, the effects of the ectopic expression of miR-145 were examined by performing MTT, Western blotting analysis, Hoechst33342 staining, and wound healing assay in vitro. Also, a mouse orthotopic human bladder cancer model was established by inoculating 253J B-V cells into the bladder wall of mice. The anti-cancer effects of intravesical injections of miR-145 into these mice were then assessed. Transfection of 253J B-V cells with miR-145 induced apoptosis and suppression of cell migration in vitro. Western blotting showed that the levels of c-Myc, socs7, FSCN1, E-cadherin, β-catenin, and catenin δ-1 were decreased and that the PI3K/Akt and Erk1/2 signaling pathways were increased in compensatory fashion. In vivo, mice treated with miR-145 showed 76% inhibition of tumor growth, with a significant prolongation of animal survival (p = 0.0183 vs. control). Western blotting showed that both apoptosis and cell motility-related genes were significantly decreased as seen in vitro. Furthermore, PI3k/Akt and Erk1/2 signaling pathways, which were activated in a compensatory manner in vitro, were decreased in vivo. Intravesical administration of exogenous miR-145 was thus concluded to be a valid therapy for bladder cancer in this human bladder cancer xenograft model. PMID:26036261

  11. TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth.

    PubMed

    Derosier, Leo Christopher; Vickers, Selwyn M; Zinn, Kurt R; Huang, Zhi; Wang, Wenquan; Grizzle, William E; Sellers, Jeffrey; Stockard, Cecil R; Zhou, Tong; Oliver, Patsy G; Arnoletti, Pablo; Lobuglio, Albert F; Buchsbaum, Donald J

    2007-12-01

    To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model. Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed. All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8. Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.

  12. The therapeutic efficacy of I131-PSCA-mAb in orthotopic mouse models of prostate cancer

    PubMed Central

    2013-01-01

    Background Prostate stem cell antigen (PSCA) is upregulated in prostate cancer tissues. Here we aimed to study the therapeutic efficacy of a monoclonal antibody of PSCA-labeled I131 (I131-PSCA-mAb) in orthotopic mouse models of prostate cancer. Methods The proliferation, apoptosis and invasion abilities of PC-3 and LNCaP cells treated with I131-PSCA-mAb were measured by methyl thiazolyl tetrazolium assay, flow cytometry and transwell culture, respectively. The human prostate cancer models were established by orthotopic implantation of PC-3 and LNCaP cells in nude mice. I131-PSCA-mAb distribution and tumor cell apoptosis in the tumor-bearing nude mice were measured. Results The inhibitory and apoptosis rates of PC-3 and LNCaP cells treated with I131-PSCA-mAb reached a maximum of 84%, 80% and 50%, 46%, respectively, which were obviously higher than in the cells treated with I131-IgG or PSCA-mAb. The invaded number of PC-3 and LNCaP cells treated with I131-PSCA-mAbe was significantly reduced (P < 0.01) compared with the control group. The ratios of I131-PSCA-mAb in tumor to intramuscular I131-PSCA-mAb (T/NT) in tumor-bearing nude mice were increased with time and reached the highest level after 8 h. T/NT stayed above 3.0 after 12 h, and the tumor could still be developed after 24 h. The number of apoptotic cells in tumor tissue of nude mice treated with I131-PSCA-mAb was larger than that in the control group. Conclusion I131-PSCA-mAb has the potential to become a new targeted therapy drug for the treatment of prostate cancer. PMID:24330823

  13. 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.

  14. An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis.

    PubMed

    Goldstein, Seth D; Hayashi, Masanori; Albert, Catherine M; Jackson, Kyle W; Loeb, David M

    2015-10-01

    Overall survival rates for pediatric high-grade sarcoma have improved greatly in the past few decades, but prevention and treatment of distant metastasis remain the most compelling problems facing these patients. Traditional preclinical mouse models have not proven adequate to study the biology and treatment of spontaneous distant sarcoma metastasis. To address this deficit, we developed an orthotopic implantation/amputation model in which patient-derived sarcoma xenografts are surgically implanted into mouse hindlimbs, allowed to grow, then subsequently amputated and the animals observed for development of metastases. NOD/SCID/IL-2Rγ-null mice were implanted with either histologically intact high grade sarcoma patient-derived xenografts or cell lines in the pretibial space and affected limbs were amputated after tumor growth. In contrast to subcutaneous flank tumors, we were able to consistently detect spontaneous distant spread of the tumors using our model. Metastases were seen in 27-90 % of animals, depending on the xenograft, and were repeatable and predictable. We also demonstrate the utility of this model for studying the biology of metastasis and present preliminary new insights suggesting the role of arginine metabolism and macrophage phenotype polarization in creating a tumor microenvironment that facilitates metastasis. Subcutaneous tumors express more arginase than inducible nitric oxide synthase and demonstrate significant macrophage infiltration, whereas orthotopic tumors express similar amounts of inducible nitric oxide synthase and arginase and have only a scant macrophage infiltrate. Thus, we present a model of spontaneous distant sarcoma metastasis that mimics the clinical situation and is amenable to studying the biology of the entire metastatic cascade.

  15. Fluorescence-Guided Surgery in Combination with UVC Irradiation Cures Metastatic Human Pancreatic Cancer in Orthotopic Mouse Models

    PubMed Central

    Hiroshima, Yukihiko; Maawy, Ali; Zhang, Yong; Sato, Sho; Murakami, Takashi; Yamamoto, Mako; Uehara, Fuminari; Miwa, Shinji; Yano, Shuya; Momiyama, Masashi; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M.

    2014-01-01

    The aim of this study is to determine if ultraviolet light (UVC) irradiation in combination with fluorescence-guided surgery (FGS) can eradicate metastatic human pancreatic cancer in orthotopic nude–mouse models. Two weeks after orthotopic implantation of human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 24). After BLS, mice were randomized into 3 treatment groups; BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8). The residual tumors were resected using a hand-held portable imaging system under fluorescence navigation in mice treated with FGS and FGS-UVC. The surgical resection bed was irradiated with 2700 J/m2 UVC (254 nm) in the mice treated with FGS-UVC. The average residual tumor area after FGS (n = 16) was significantly smaller than after BLS only (n = 24) (0.135±0.137 mm2 and 3.338±2.929 mm2, respectively; p = 0.007). The BLS treated mice had significantly reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p<0.001 and p<0.001, respectively) and overall survival (OS) (p<0.001 and p<0.001, respectively). FGS-UVC-treated mice had increased RFS and OS compared to FGS-only treated mice (p = 0.008 and p = 0.025, respectively); with RFS lasting at least 150 days indicating the animals were cured. The results of the present study suggest that UVC irradiation in combination with FGS has clinical potential to increase survival. PMID:24924955

  16. CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer.

    PubMed

    Ninalga, Christina; Loskog, Angelica; Klevenfeldt, Magdalena; Essand, Magnus; Tötterman, Thomas H

    2005-01-01

    Bacillus Calmette-Guerin (BCG) instillation is standard immunotherapy for superficial bladder carcinoma. However, many patients become refractory to BCG, giving impetus to the development of alternative therapies. CpG oligodeoxynucleotide (ODN) therapy has been shown to promote T(H)1-oriented antitumor responses in various tumor models. To investigate its therapeutic effect in bladder cancer, we used different CpG ODNs to treat C57BL/6 mice bearing the subcutaneous murine bladder tumor MB49. CpG type B ODN 1668 was superior at inhibiting tumor growth, leading to complete regression of large tumors. More importantly, CpG ODN 1668 also regressed orthotopically growing MB49 tumors for the first time. Rechallenge of CpG ODN-cured mice with MB49 showed that a majority of the mice were protected long term, demonstrating that CpG ODN therapy evokes a memory response. Adenoviral vectors (Ad) encoding CD40L, tumor necrosis factor-related activation-induced cytokine, lymphotactin, interleukin (IL) 2, and IL-15 were also investigated. AdCD40L and AdIL-15 transduction could abolish MB49 tumorigenicity, and these vectors were combined with CpG ODN 1668 to investigate any enhanced effects. No such effects were seen. All groups of mice treated with CpG ODNs, alone or in combination with adenoviral vector, exhibited increased serum concentrations of IL-12, indicative of a T(H)1 response. Our results show that CpG ODN therapy cures established subcutaneous and orthotopic bladder cancer via a T(H)1-mediated response and provides long-lasting protective immunity.

  17. 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

  18. 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.

  19. Replaceable Sleeve Protects Welder Coil

    NASA Technical Reports Server (NTRS)

    Baker, W. L.; Simpson, C., E.

    1983-01-01

    New replaceable carbon insert for deflection coil in electron-beam welder promises to decrease maintenance costs. Inserts made from materials other than carbon (not yet tried) are less expensive, thus reducing costs even further. With carbon insert, deflection coils last longer and are easier to maintain.

  20. Testing of Replacement Bag Material

    SciTech Connect

    Laurinat, J.E.

    1998-11-03

    Recently, the FB-Line bagout material was changed to simplify the processing of sand, slag, and crucible.The results of the strength tests and the outgassing measurements and calculations demonstrate that the proposed replacement nylon bag materials (HRMP and orange anti-static material) are acceptable substitutes for LDPE and the original nylon with respect to mechanical properties.

  1. Will peanut hulls replace oil

    SciTech Connect

    Not Available

    1980-12-01

    A low-cost, fast-curing wood adhesive has been recently developed by the University of Georgia, in which up to 80% of the petroleum ingredients can be replaced with a substance extracted from peanut hulls. An outline of the process is given.

  2. Replaceable Sleeve Protects Welder Coil

    NASA Technical Reports Server (NTRS)

    Baker, W. L.; Simpson, C., E.

    1983-01-01

    New replaceable carbon insert for deflection coil in electron-beam welder promises to decrease maintenance costs. Inserts made from materials other than carbon (not yet tried) are less expensive, thus reducing costs even further. With carbon insert, deflection coils last longer and are easier to maintain.

  3. MELFI-3 Electronic Unit Replacement

    NASA Image and Video Library

    2011-07-01

    ISS028-E-013797 (1 July 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, replaces a failed electronic unit for the Minus Eighty Laboratory Freezer for ISS 3 (MELFI-3) with a spare unit in the Kibo laboratory of the International Space Station.

  4. MELFI-3 Electronic Unit Replacement

    NASA Image and Video Library

    2011-07-01

    ISS028-E-013799 (1 July 2011) --- NASA astronaut Mike Fossum, Expedition 28 flight engineer, replaces a failed electronic unit for the Minus Eighty Laboratory Freezer for ISS 3 (MELFI-3) with a spare unit in the Kibo laboratory of the International Space Station.

  5. Bonding over Dentin Replacement Materials.

    PubMed

    Meraji, Naghmeh; Camilleri, Josette

    2017-08-01

    Dentin replacement materials are necessary in large cavities to protect the pulp and reduce the bulk of filling material. These materials are layered with a composite resin restorative material. Microleakage caused by poor bonding of composite resin to underlying dentin replacement material will result in pulp damage. The aim of this study was to characterize the interface between dentin replacement materials and composite resin and to measure the shear bond strength after dynamic aging. Biodentine (Septodont, Saint Maur-des-Fosses, France), Theracal LC (Bisco, Schaumburg, IL), and Fuji IX (GC, Tokyo, Japan) were used as dentin replacement materials. They were then overlaid with a total-etch and bonding agent or a self-etch primer and composite resin or a glass ionomer cement. All combinations were thermocycled for 3000 cycles. The interface was characterized using scanning electron microscopy and elemental mapping. Furthermore, the shear bond strength was assessed. The Biodentine surface was modified by etching. The Theracal LC and Fuji IX microstructure was unchanged upon the application of acid etch. The Biodentine and glass ionomer interface showed an evident wide open space, and glass particles from the glass ionomer adhered to the Biodentine surface. Elemental migration was shown with aluminum, barium, fluorine, and ytterbium present in Biodentine from the overlying composite resin. Calcium was more stable. The bond strength between Theracal LC and composite using a total-etch technique followed by self-etch primer achieved the best bond strength values. Biodentine exhibited the weakest bond with complete failure of bonding shown after demolding and thermocycling. Dynamic aging is necessary to have clinically valid data. Bonding composite resin to water-based dentin replacement materials is still challenging, and further alternatives for restoration of teeth using such materials need to be developed. Copyright © 2017 American Association of Endodontists

  6. [Pre- and post-orthotopic heart transplantation electrocardiogram characteristics of 998 patients].

    PubMed

    Guan, H Q; Chen, Z J; Zhou, Y; Liu, J; Sun, W X; Yuan, J; Liao, Y H; Dong, N G; Liu, J P; Feng, K G; Zhang, Q; Zhao, X; Qian, C; Hu, F

    2017-04-24

    Objective: To analyze pre- and post-operation electrocardiograms (ECGs) features of patients underwent orthotopic heart transplantation (OHT), and provide evidences for identifying and analyzing post OHT ECGs. Methods: Nine hundreds and ninty-eight pre- and post- OHT standard 12-leads ECGs from 110 consecutive patients, who underwent OHT in our hospital from May 2008 to May 2014, were analyzed. Results: The mean heart rate(HR)was (86.9±16.4) beats per minute before OHT, and (100.0±0.4) beats per minute after OHT. P wave's amplitude, duration, amplitude multiplied by duration of donor heart in lead Ⅱ were (0.124±0.069)mV, (111.1±17.2)ms, (14.34±9.51)mV·ms before OHT; (0.054±0.037)mV, (86.9±27.0)ms, (5.02±4.03)mV·ms at 1 month after OHT; (0.073±0.049)mV, (93.9±17.5) ms, (7.00±4.81)mV·ms at 6 years after OHT. ECGs rotation occurred in 83.64%(92/110) patients after OHT, and prevalence of clockwise rotation was 76.36%(84/110). Sinus tachycardia was evidenced in 99.09%(109/110) patients after OHT, and incomplete right bundle branch block was present in 60.91%(67/110) patients after OHT. Pseudo complete atrioventricular block mostly occurred at 2 days after OHT. Prevalence of double sinus rhythm was 27.95%(263/941) post OHT, 40% of them occurred between the 1st and the 2nd month post OHT; the atrial rate of recipient hearts was (104.0±10.2) beats per minucte between the 3rd and the 6th month post OHT, and was (95.3±4.2) beats per minucte between the 4th year and the 5th year. P wave's amplitude, duration, amplitude multiplied by duration of recipient heart in lead Ⅱ were (0.066±0.055) mV, (52.8±34.7) ms, (4.67±4.95) mV·ms at 1 month after OHT, (0.043±0.040)mV, (44.4±40.5) ms , (3.11±3.61) mV·ms between the 1st year and 2nd year after OHT. The absolute value of P-wave(originating from the donor heart) terminal force in chest leads increased in 48.99%(461/941) patients post OHT, the P-wave terminal force of V(1) , V(2) and V(3) were -0

  7. Pseudoaneurysm after ICD battery replacement.

    PubMed

    Schulz, S L; Lehmkuhl, H; Zipfel, K B; Hetzer, R

    2007-02-01

    False aneurysms of the extracranial carotid arteries are rare and mainly of traumatic origin. We report on a patient who presented with a sudden onset mass in his right neck 2 weeks after routine replacement of his ICD battery. He had received systemic anticoagulation since an aortic valve replacement 5 years before. By color Doppler sonography the mass was identified as a partly thrombosed false aneurysm originating from the common carotid artery. As no spontaneous resolution occurred during the following days the aneurysm was removed surgically 5 days later without further complications. However no connection to the common carotid artery was found at surgery. Yet in the histopathological examination the specimen showed the morphological characteristics of a pseudoaneurysm. There was no history of neck-trauma and no attempted vascular access during the recent operation.

  8. [MINIMALLY INVASIVE AORTIC VALVE REPLACEMENT].

    PubMed

    Tabata, Minoru

    2016-03-01

    Minimally invasive aortic valve replacement (MIAVR) is defined as aortic valve replacement avoiding full sternotomy. Common approaches include a partial sternotomy right thoracotomy, and a parasternal approach. MIAVR has been shown to have advantages over conventional AVR such as shorter length of stay and smaller amount of blood transfusion and better cosmesis. However, it is also known to have disadvantages such as longer cardiopulmonary bypass and aortic cross-clamp times and potential complications related to peripheral cannulation. Appropriate patient selection is very important. Since the procedure is more complex than conventional AVR, more intensive teamwork in the operating room is essential. Additionally, a team approach during postoperative management is critical to maximize the benefits of MIAVR.

  9. Hurricane intensity and eyewall replacement.

    PubMed

    Houze, Robert A; Chen, Shuyi S; Smull, Bradley F; Lee, Wen-Chau; Bell, Michael M

    2007-03-02

    Observations made during the historic 2005 hurricane season document a case of "eyewall replacement." Clouds outside the hurricane eyewall coalesce to form a new eyewall at a greater radius from the storm center, and the old eyewall dies. The winds in the new eyewall are initially weaker than those in the original eyewall, but as the new eyewall contracts, the storm reintensifies. Understanding this replacement mechanism is vital to forecasting variations in hurricane intensity. Processes in the "moat" region between the new and old eyewall have been particularly unclear. Aircraft data now show that the moat becomes dynamically similar to the eye and thus is converted into a region inimical to survival of the inner eyewall. We suggest that targeting aircraft to key parts of the storm to gain crucial input to high-resolution numerical models can lead to improvements in forecasting hurricane intensity.

  10. Gene replacement in Lactobacillus helveticus.

    PubMed Central

    Bhowmik, T; Fernández, L; Steele, J L

    1993-01-01

    An efficient method for gene replacement in Lactobacillus helveticus CNRZ32 was developed by utilizing pSA3 as an integration vector. This plasmid is stably maintained in CNRZ32 at 37 degrees C but is unstable at 45 degrees C. This method consisted of a two-step gene-targeting technique: (i) chromosomal integration of a plasmid carrying an internal deletion in the gene of interest via homologous recombination and (ii) excision of the vector and the wild-type gene via homologous recombination, resulting in gene replacement. By using this procedure, the chromosomal X-prolyl dipeptidyl aminopeptidase gene (pepXP) of CNRZ32 was successfully inactivated. Images PMID:8104928

  11. Hinge total knee replacement revisited

    PubMed Central

    Cameron, Hugh U.; Hu, Cungen; Vyamont, Didier

    1997-01-01

    Objective To determine if aseptic loosening is a major problem in hinge total knee replacement. Design A cohort study. Setting A university-affiliated institute, specializing in elective orthopedic surgery. Patients Fifty-eight patients, mainly those requiring revision, in whom the conditions were such that it was felt only a totally constrained implant was appropriate. In 7 patients the implant was press-fitted; in the remainder it was cemented. Five patients required fusion or revision, and 8 died less than 2 years after implantation, leaving 45 for review. Follow-up was 2 to 13 years. Intervention Total knee replacement with a Guepar II prosthesis. Main outcome measures Radiolucency determined by the Cameron system and clinical scoring using the Hospital for Special Surgery system. Results Of the cemented components, 91% of femoral stems were type IA (no lucency), 9% were type IB (partial lucency), with no type II or III lucency. Tibial lucency was 87% type IA and 13% type IB, with no type II or III lucency. Of the noncemented components, 58% of femoral components were type IA and 42% type IB. Tibial lucency was 71% type IA and 29% type IB. Lucency was mainly present in zones 1 and 2 adjacent to the knee. Clinical rating was 18% excellent, 20% good, 20% fair and 42% poor. Postoperative complications included infection (13%), aseptic loosening (7%), quadriceps lag (16%) and extensor mechanism problems (16%). Conclusions Aseptic loosening is an uncommon problem in hinge total knee replacement. The complication rate in cases of sufficient severity as to require a hinge replacement remains high. Current indications for a hinge prosthesis are anteroposterior instability with a very large flexion gap, complete absence of the collateral ligaments and complete absence of a functioning extensor mechanism. PMID:9267296

  12. Endoscopic Treatment of Anastomotic Biliary Stenosis in Patients With Orthotopic Liver Transplantation

    PubMed Central

    Grosso, Claudio; Zanasi, Giulio; Gambitta, Pietro; Bini, Marta; de Carlis, Luciano; Arcidiacono, Raffaele

    1995-01-01

    The choledocho-choledochostomy stricture is one of the most frequent complications occurring after liver transplantation. Today endoscopic retrograde cholangiopancreatography may be considered one of the most common methodologic approaches for the diagnosis; at the same time it provides an effective treatment of the stenosis, avoiding more invasive surgery. Biliary flow through a strictured anastomosis definitely improves after endoscopic stenting which, in most cases, resolves the biliary obstruction syndrome; moreover, the stent could allow restoration of the anatomical and functional integrity of the common bile duct. We have successfully treated eight liver transplanted patients with biliary anastomotic stenosis by endoscopic stenting of the common bile duct or by balloon dilation (one patient). The stents were replaced every 3 to 4 months and then removed after 1 year of follow-up. We observed one patient with acute cholangitis due to the clogging of the prosthetic device. PMID:18493388

  13. Nicotine Replacement Therapy: An Overview

    PubMed Central

    Wadgave, Umesh; Nagesh, L

    2016-01-01

    Today tobacco use is the single greatest preventable cause of death in the world. Tobacco use is often incorrectly perceived to be solely a personal choice. This is contradicted by the fact that when fully aware of the health impact, most tobacco users want to quit but find it difficult to stop due to the addictiveness of nicotine. Henceforth, Nicotine replacement therapy (NRT) came into existence which temporarily replaces much of the nicotine from tobacco to reduce motivation to consume tobacco and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Various alternative nicotine sources (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) have been incorporated into tobacco cessation programs. Recent research is more focusing on rapid delivery of nicotine (Nicotine preloading, true pulmonary inhaler) and immunological approaches (nicotine vaccine) to tackle nicotine dependence. These NRTs are in general well tolerated and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used to treat nicotine dependence, and to give an overview about future possible approaches to treat tobacco use disorder. PMID:27610066

  14. The caudal septum replacement graft.

    PubMed

    Foda, Hossam M T

    2008-01-01

    To describe a technique for reconstructing the lost tip support in cases involving caudal septal and premaxillary deficiencies. The study included 120 patients with aesthetic and functional nasal problems resulting from the loss of caudal septal and premaxillary support. An external rhinoplasty approach was performed to reconstruct the lost support using a cartilaginous caudal septum replacement graft and premaxillary augmentation with Mersilene mesh. The majority of cases (75%) involved revisions in patients who had previously undergone 1 or more nasal surgical procedures. A caudal septum replacement graft was combined with premaxillary augmentation in 93 patients (77.5%). The mean follow-up period was 3 years (range, 1-12 years). The technique succeeded in correcting the external nasal deformities in all patients and resulted in a significant improvement in breathing in 74 patients (86%) with preoperative nasal obstruction. There were no cases of infection, displacement, or extrusion. The caudal septum replacement graft proved to be very effective in restoring the lost tip support in patients with caudal septal deficiency. Combining the graft with premaxillary augmentation using Mersilene mesh helped increase support and stability over long-term follow-up.

  15. Selective and efficient retardation of cancers expressing cytoskeleton-associated protein 2 by targeted RNA replacement.

    PubMed

    Ban, Guyee; Jeong, Jin-Sook; Kim, Areum; Kim, Sung Jin; Han, Sang-Young; Kim, In-Hoo; Lee, Seong-Wook

    2011-08-15

    Human cytoskeleton-associated protein 2 (hCKAP2) is upregulated and highly expressed in various human malignances. hCKAP2 has microtubule-stabilizing characteristics and potentially regulates the dynamics and assembly of the mitotic spindle and chromosome segregation, indicating that hCKAP2 plays important functions during mitosis. In this study, we evaluated hCKAP2 as a plausible anticancer target through development and validation of a targeted cancer gene therapy strategy based on targeting and replacement of hCKAP2 RNA using a trans-splicing ribozyme. This targeted RNA replacement triggered transgene activity via accurate trans-splicing reaction selectively in human cancer cells expressing the hCKAP2 RNA and simultaneously reduced the expression level of the RNA in the cells. Adenoviral vector encoding the hCKAP2-specific trans-splicing ribozyme selectively induced cytotoxicity in tumor cells expressing hCKAP2. Moreover, intratumoral injection of the virus produced selective and efficient regression of tumor that had been subcutaneously inoculated with hCKAP2-positive colon cancer cells in mice with minimal liver toxicity. Furthermore, orthotopically multifocal hCKAP2-positive hepatocarcinoma established in mice were efficiently regressed by systemic delivery of adenoviral vector encoding the specific ribozyme under the control of a liver-selective phosphoenolpyruvate carboxykinase promoter with least hepatotoxicity. The results indicate that hCKAP2 RNA is a promising target for anticancer approach based on trans-splicing ribozyme-mediated RNA replacement. Copyright © 2011 UICC.

  16. Therapeutic efficacy of tumor-targeting Salmonella typhimurium A1-R on human colorectal cancer liver metastasis in orthotopic nude-mouse models.

    PubMed

    Murakami, Takashi; Hiroshima, Yukihiko; Zhao, Ming; Zhang, Yong; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2015-10-13

    Liver metastasis is the most frequent cause of death from colon and other cancers. Generally, liver metastasis is recalcitrant to treatment. The aim of this study is to determine the efficacy of tumor-targeting Salmonella typhimurium A1-R on liver metastasis in orthotopic mouse models. HT-29 human colon cancer cells expressing red fluorescent protein (RFP) were used in the present study. S. typhimurium A1-R infected HT-29 cells in a time-dependent manner, inhibiting cancer-cell proliferation in vitro. S. typhimurium A1-R promoted tumor necrosis and inhibited tumor growth in a subcutaneous tumor mouse model of HT-29-RFP. In orthotopic mouse models, S. typhimurium A1-R targeted liver metastases and significantly reduced their growth. The results of this study demonstrate the future clinical potential of S. typhimurium A1-R targeting of liver metastasis.

  17. Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancerassociated fibroblast accumulation

    PubMed Central

    Tanabe, Yamato; Sasaki, Soichiro; Mukaida, Naofumi; Baba, Tomohisa

    2016-01-01

    We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites through the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression. PMID:27340784

  18. Polymeric nanoparticle-docetaxel for the treatment of advanced solid tumors: phase I clinical trial and preclinical data from an orthotopic pancreatic cancer model

    PubMed Central

    Song, Si Yeol; Kim, Kyu-pyo; Jeong, Seong-Yun; Park, Jin; Park, Jaesook; Jung, Joohee; Chung, Hye Kyung; Lee, Sa-Won; Seo, Min Hyo; Lee, Jung-shin; Jung, Kyung Hae; Choi, Eun Kyung

    2016-01-01

    We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m2 escalated to 35 mg/m2, 45 mg/m2, 60 mg/m2 and 75 mg/m2. Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP-DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The Cmax of 60 mg/m2 PNP-DTX and AUClast of 45 mg/m2 PNP-DTX were measured to be comparable to those of 75 mg/m2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m2 was tentatively determined. The PNP-DTX of 45 mg/m2 had the same pharmacokinetic profile with that of 75 mg/m2 DTX. PMID:27764799

  19. 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

  20. Routes of delivery for CpG and anti-CD137 for the treatment of orthotopic kidney tumors in mice.

    PubMed

    Westwood, Jennifer A; Potdevin Hunnam, Titaina C U; Pegram, Hollie J; Hicks, Rodney J; Darcy, Phillip K; Kershaw, Michael H

    2014-01-01

    We have found previously that the tumor cell lines, Renca (a renal cancer) and MC38 (a colon tumor) which had been injected subcutaneously in mice, could be successfully treated with a combination therapy of an oligodeoxynucleotide (CpG1826) (injected intratumorally) and anti-CD137 antibody (injected intraperitoneally). Thus the combination treatment was expected to initiate a "danger" signal via TLR9 on immune cells, and the anti-CD137 was expected to further activate T cells. In the present study, we found that several other tumor types injected subcutaneously could also be successfully treated with this combination therapy. In addition, we wished to determine if the treatment could work as effectively in an orthotopic metastatic model, which is more physiologically relevant to cancer in humans. Renca was selected as we were familiar with injecting this orthotopically into the outer cortex of the kidney in mice, and it spontaneously metastasizes to lung and abdominal sites. We tested various routes of delivery of CpG combined with intraperitoneal delivery of anti-CD137. Orthotopic tumors were injected with CpG intratumorally, using ultrasound-guided delivery on multiple occasions, combined with anti-CD137 intraperitoneally. A reduction in primary tumor size was observed following intratumoral injection of CpG compared to other treatments. We found that there was a statistically significant increase in survival of mice with orthotopic Renca tumor following intratumoral injection of CpG. However, we determined that the most effective route of delivery of CpG was intravenous, which led to further significantly enhanced survival of mice when combined with anti-CD137 intraperitoneally, likely due to inhibition of metastatic disease. Our data supports future development of this combination therapy for cancer.

  1. 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

    2017-03-16

    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 3(rd) passage was made in the same manner. Five UPS tumors from each passage in both RFP and non-colored mouse models were harvested. The FV1000 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. This article is protected by copyright. All rights reserved.

  2. Targeted Therapy Against VEGFR and EGFR With ZD6474 Enhances the Therapeutic Efficacy of Irradiation in an Orthotopic Model of Human Non-Small-Cell Lung Cancer

    SciTech Connect

    Shibuya, Keiko; Komaki, Ritsuko; Shintani, Tomoaki; Itasaka, Satoshi; Ryan, Anderson; Juergensmeier, Juliane M.; Milas, Luka; Ang, Kian; Herbst, Roy S.; O'Reilly, Michael S.

    2007-12-01

    Purpose: Conventional therapies for patients with lung cancer have reached a therapeutic plateau. We therefore evaluated the feasibility of combined vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and epidermal growth factor (EGF) receptor (EGFR) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer. Methods and Materials: Effects of irradiation and/or ZD6474, a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays. The feasibility of combining ZD6474 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma. Lung tumor burden and spread within the thorax were assessed, and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters, including CD31, VEGF, VEGFR2, EGF, EGFR, matrix metalloproteinase-2 and -9, and basic fibroblast growth factor. Results: ZD6474 enhanced the radioresponse of NCI-H441 human lung adenocarcinoma cells by a factor of 1.37 and markedly inhibited sublethal damage repair. In vivo, the combined blockade of VEGFR2 and EGFR by ZD6474 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy. Conclusions: When radiation therapy is combined with VEGFR2 and EGFR blockade, significant enhancement of antiangiogenic, antivascular, and antitumor effects are seen in an orthotopic model of lung cancer. These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer.

  3. 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 Central

    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

    2017-01-01

    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. PMID:27602776

  4. Fusion following failed total ankle replacement.

    PubMed

    Wünschel, Markus; Leichtle, Ulf G; Leichtle, Carmen I; Walter, Christian; Mittag, Falk; Arlt, Eva; Suckel, Andreas

    2013-04-01

    Although mid- to long-term results after total ankle replacement have improved because of available second- and third-generation devices, failure of total ankle replacement is still more common compared with total hip replacement and total knee replacement. The portfolio of available total ankle replacement revision component options is small. Furthermore, the bone stock of the tibiotalar region is scarce making it difficult and in some situations impossible to perform revision total ankle replacement. In these cases tibiotalar and tibiotalocalcaneal fusions are valuable options. This article describes which surgical procedures should be performed depending on the initial situation and gives detailed advice on surgical technique, postoperative care, and clinical results.

  5. Alendronate decreases orthotopic PC-3 prostate tumor growth and metastasis to prostate-draining lymph nodes in nude mice

    PubMed Central

    Tuomela, Johanna M; Valta, Maija P; Väänänen, Kalervo; Härkönen, Pirkko L

    2008-01-01

    Background Metastatic prostate cancer is associated with a high morbidity and mortality but the spreading mechanisms are still poorly understood. The aminobisphosphonate alendronate, used to reduce bone loss, has also been shown to inhibit the invasion and migration of prostate cancer cells in vitro. We used a modified orthotopic PC-3 nude mouse tumor model of human prostate cancer to study whether alendronate affects prostate tumor growth and metastasis. Methods PC-3 cells (5 × 105) were implanted in the prostates of nude mice and the mice were treated with alendronate (0.5 mg/kg/day in PBS, s.c.) or vehicle for 4 weeks. After sacrifice, the sizes of tumor-bearing prostates were measured and the tumors and prostate-draining regional iliac and sacral lymph nodes were excised for studies on markers of proliferation, apoptosis, angiogenesis and lymphangiogenesis, using histomorphometry and immunohistochemistry. Results Tumor occurrence in the prostate was 73% in the alendronate-treated group and 81% in the control group. Mean tumor size (218 mm3, range: 96–485 mm3, n = 11) in the alendronate-treated mice was 41% of that in the control mice (513 mm3, range: 209–1350 mm3, n = 13) (p < 0.05). In the iliac and sacral lymph nodes of alendronate-treated mice, the proportion of metastatic area was only about 10% of that in control mice (p < 0.001). Immunohistochemical staining of tumor sections showed that alendronate treatment caused a marked decrease in the number of CD34-positive endothelial cells in tumors (p < 0.001) and an increase in that of ISEL positive apoptotic cells in tumors as well as in lymph node metastases (p < 0.05) compared with those in the vehicle-treated mice. The density of m-LYVE-1-stained lymphatic capillaries was not changed. Conclusion Our results demonstrate that alendronate treatment opposes growth of orthotopic PC-3 tumors and decreases tumor metastasis to prostate-draining lymph nodes. This effect could be at least partly explained by

  6. Metallofullerene-based Nanoplatform for Brain Tumor Brachytherapy and Longitudinal Imaging in a Murine Orthotopic Xenograft Model

    PubMed Central

    Shultz, Michael D.; Wilson, John D.; Fuller, Christine E.; Zhang, Jianyuan; Dorn, Harry C.

    2011-01-01

    Purpose: To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd3N@C80) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (177Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (177Lu-DOTA-f-Gd3N@C80), provide an anchor to deliver effective brachytherapy. Materials and Methods: All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd3N@C80 alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of 177Lu-DOTA-f-Gd3N@C80. Survival data were evaluated by using Kaplan-Meier statistical methods. Results: MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd3N@C80 nanoplatform, which enabled longitudinal imaging. Successful coupling of 177Lu to the f-Gd3N@C80 surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (>2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage. Conclusion: The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe

  7. 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.

  8. Imaging of Orthotopic Glioblastoma Xenografts in Mice Using a Clinical CT Scanner: Comparison with Micro-CT and Histology

    PubMed Central

    Kirschner, Stefanie; Mürle, Bettina; Felix, Manuela; Arns, Anna; Groden, Christoph; Wenz, Frederik; Hug, Andreas; Glatting, Gerhard; Kramer, Martin

    2016-01-01

    Purpose There is an increasing need for small animal in vivo imaging in murine orthotopic glioma models. Because dedicated small animal scanners are not available ubiquitously, the applicability of a clinical CT scanner for visualization and measurement of intracerebrally growing glioma xenografts in living mice was validated. Materials and Methods 2.5x106 U87MG cells were orthotopically implanted in NOD/SCID/ᵞc-/- mice (n = 9). Mice underwent contrast-enhanced (300 μl Iomeprol i.v.) imaging using a micro-CT (80 kV, 75 μAs, 360° rotation, 1,000 projections, scan time 33 s, resolution 40 x 40 x 53 μm) and a clinical CT scanner (4-row multislice detector; 120 kV, 150 mAs, slice thickness 0.5 mm, feed rotation 0.5 mm, resolution 98 x 98 x 500 μm). Mice were sacrificed and the brain was worked up histologically. In all modalities tumor volume was measured by two independent readers. Contrast-to-noise ratio (CNR) and Signal-to-noise ratio (SNR) were measured from reconstructed CT-scans (0.5 mm slice thickness; n = 18). Results Tumor volumes (mean±SD mm3) were similar between both CT-modalities (micro-CT: 19.8±19.0, clinical CT: 19.8±18.8; Wilcoxon signed-rank test p = 0.813). Moreover, between reader analyses for each modality showed excellent agreement as demonstrated by correlation analysis (Spearman-Rho >0.9; p<0.01 for all correlations). Histologically measured tumor volumes (11.0±11.2) were significantly smaller due to shrinkage artifacts (p<0.05). CNR and SNR were 2.1±1.0 and 1.1±0.04 for micro-CT and 23.1±24.0 and 1.9±0.7 for the clinical CTscanner, respectively. Conclusion Clinical CT scanners may reliably be used for in vivo imaging and volumetric analysis of brain tumor growth in mice. PMID:27829015

  9. Orthotopic murine model of a primary malignant bone tumor in the spine: functional, bioluminescence, and histological correlations.

    PubMed

    Fahim, Daniel K; Tatsui, Claudio E; Suki, Dima; Gumin, Joy; Lang, Frederick F; Rhines, Laurence D

    2014-09-01

    There is currently no reproducible animal model of human primary malignant bone tumors in the spine to permit laboratory investigation of the human disease. Therefore, the authors sought to adapt their previously developed orthotopic model of spinal metastasis to a model for primary malignant bone tumors of the spine. A transperitoneal surgical approach was used to implant osteosarcoma (Krib-1) into the L-3 vertebral body of nude mice via a drill hole. Motor function was evaluated daily using the previously validated qualitative key milestones of tail dragging, dorsal stepping, hindlimb sweeping, and paralysis. A subset of these animals was euthanized upon reaching the various milestones, and the spines were removed, sectioned, and stained. The degree of spinal cord compression was correlated with the occurrence of milestones and assessed by a ratio between the neural elements divided by the area of the spinal canal. Another subset of animals received stably transfected Krib-1 cells with the luciferase gene, and bioluminescence was measured at 10, 20, and 30 days postimplantation. Osteosarcoma xenografts grew in all animals according to a reliable and reproducible time course; the mean time for development of behavioral milestones was noted in relation to the day of implantation (Day 1). Tail dragging (Milestone 1) occurred on Day 19.06 (95% CI 16.11-22.01), dorsal stepping (Milestone 2) occurred on Day 28.78 (95% CI 26.79-30.77), hindlimb sweeping (Milestone 3) occurred on Day 35.61 (95% CI 32.9-38.32), and paralysis of the hindlimb (Milestone 4) occurred on Day 41.78 (95% CI 39.31-44.25). These clinically observed milestones correlated with increasing compression of the spinal cord on histological sections. The authors observed a progressive increase in the local bioluminescence (in photons/cm²/sec) of the implanted level over time with a mean of 2.17 (range 0.0-8.61) at Day 10, mean 4.68 (range 1.17-8.52) at Day 20, and mean 5.54 (range 1.22-9.99) at Day 30

  10. Effective Metabolic Targeting of Human Osteosarcoma Cells In Vitro and in Orthotopic Nude-mouse Models with Recombinant Methioninase.

    PubMed

    Igarashi, Kentaro; Kawaguchi, Kei; Kiyuna, Tasuku; Miyake, Kentaro; Murakami, Takashi; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Tsuchiya, Hiroyuki; Hoffman, Robert M

    2017-09-01

    Methionine dependence may be the only known general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]) (recombinant methioninase [rMETase]), which was subsequently tested in mouse models of various types of human tumors. The present study aimed to investigate the efficacy of rMETase on human osteosarcoma cells in vitro and in vivo. Human osteosarcoma cell lines 143B, HOS and SOSN2 were tested in vitro for survival during a 72-h exposure to rMETase using the WST-8 assay. Half-maximal inhibitory concentrations were calculated for in vitro efficacy experiments. 143B cells were orthotopically transplanted into the tibia of nude mice. Mouse models were randomized into the following groups 1 week after transplantation: Group 1, untreated control; Group 2, cisplatinum (CDDP) [intraperitoneal (i.p.) injection at 6 mg/kg weekly, for 3 weeks], positive control; Group 3, rMETase, 100 units/mouse i.p. daily, for 21 days. Tumor sizes and body weight were measured with calipers and a digital balance once per week, respectively. rMETase significantly inhibited osteosarcoma cell growth, in a dose-dependent manner, in vitro. Both CDDP and rMETase treatment significantly inhibited tumor volume compared to untreated control mice at 5 weeks after initiation. Tumor volumes were as follows: Group 1, untreated, control: 1808.2 ± 344 mm(3); Group 2, CDDP: 1102.2 ± 316 mm(3), p=0.0008 compared to untreated control; Group 3, rMETase: 884.8 ± 361 mm(3), p=0.0001 compared to untreated control. There were no animal deaths in any group. The body weight of mice was not significantly different between any group. rMETase showed promising efficacy against osteosarcoma, a recalcitrant tumor type. Future studies will investigate the efficacy of rMETase on patient-derived orthotopic xenograft (PDOX) models of osteosarcoma as a bridge to testing rMETase in the clinic

  11. Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model.

    PubMed

    Niedergethmann, M; Alves, F; Neff, J K; Heidrich, B; Aramin, N; Li, L; Pilarsky, C; Grützmann, R; Allgayer, H; Post, S; Gretz, N

    2007-11-19

    The prognosis of pancreatic adenocarcinoma is affected by early metastases and local tumour invasion beyond surgical margins. Gene expression profiling in pancreatic cancer tissue is complicated due to the high amount of RNAses being present in human tissue and that of suitable models. In order to demonstrate early metastases, the models should take into account the anatomical environment of the tumour. Using the orthotopic transplantation of pancreatic tumour cells in SCID (severe combined immunodeficiency) mice, these interactions are taken into consideration. In order to identify genes associated with local tumour invasion and metastases in ductal pancreatic cancer, we investigated a human pancreatic tumour cell line derived from an orthopic pancreatic tumour model in SCID mice. Differential gene expression was performed on the basis of microarray technique. The human MiaPaca-2 cell line was implanted orthotopically in SCID mice. Transcriptional profiling was performed on fresh frozen tissue derived from the primary tumour, the tumour invasion front and the liver metastases. Differentially expressed genes were identified using statistical analyses, and were validated with external databases and with immunohistochemistry. A total of 1066 of 14 500 genes were significantly differentially expressed. Comparing the primary tumour with the tumour invasion front, there were 614 statistically significant up- and 348 downregulated genes. Twenty-five statistically significant up- and 181 downregulated genes were identified comparing the liver metastases with the primary tumour. Eight genes (PAI-1, BNIP3l, VEGF, NSE, RGS4, HSP27, GADD45A, PTPN14) were chosen and validated in a semi-quantitative immunohistochemical analysis, which revealed a positive correlation to the array data. Overrepresentation analyses revealed a total of 66 significantly regulated pathways associated with cell proliferation, cell stress, cell communication metabolic and cytokine function. In

  12. 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.

  13. Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models.

    PubMed

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

    2017-01-01

    Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDA-MB-231 tumors were resected. The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC. Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  14. Development of a Novel Orthotopic Non-small Cell Lung Cancer Model and Therapeutic Benefit of 2′-(2-bromohexadecanoyl)-Docetaxel Conjugate Nanoparticles

    PubMed Central

    Peng, Lei; Feng, Lan; Yuan, Hong; Benhabbour, Soumya R.; Mumper, Russell J.

    2014-01-01

    The aims of these studies were to establish an orthotopic non-small-cell lung cancer (NSCLC) mouse model, and to investigate the therapeutic efficacy of lipid-based nanoparticles (NPs) containing 2′-(2-bromohexadecanoyl)-docetaxel (Br-C16-DX) in this new model. A novel orthotopic NSCLC model was established in nude mice through dorsal side injection of luciferase-expressing A549 cells. The model was characterized by survival study, histological staining, bioluminescence imaging and PET/CT imaging. The therapeutic efficacy of the Br-C16-DX NPs versus Taxotere® was investigated in this model. The results demonstrated that mouse survival time was significantly prolonged by weekly intravenous administration of the NPs or Taxotere. Furthermore, the NPs group had 35 days longer progression-free survival and 27 days longer median survival compared to the Taxotere group. It was concluded that the developed orthotopic NSCLC model represents a feasible, reproducible, and clinically-relevant experimental mouse model to test current and potential therapies including nanomedicines. PMID:24709328

  15. Recruitment of Cancer-Associated Fibroblasts and Blood Vessels by Orthotopic Liver Tumors Imaged in Red Fluorescent Protein (RFP) Transgenic Nude Mice.

    PubMed

    Suetsugu, Atsushi; Hiroshima, Yukihiko; Matsumoto, Takuro; Hasagawa, Kosuke; Nakamura, Miki; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Bouvet, Michael; Hoffman, Robert M

    2015-11-01

    The tumor microenvironment (TME) is critical for tumor growth and progression. We report here an imageable model of the TME of orthotopic liver cancer. The transgenic red fluorescent protein (RFP)-expressing nude mouse was used as the host. The RFP nude mouse expresses RFP in all organs. Non-colored Huh-7 human hepatoma cells were injected in the spleen of RFP nude mice to establish an orthotopic liver cancer model. TME formation resulting from the orthotopic liver tumor was observed using the Olympus OV100 small animal fluorescence imaging system. Non-colored liver cancer cells formed tumor colonies in the liver 28 days after cell transplantation to the spleen. RFP-expressing host cells and blood vessels were recruited by the liver tumors as visualized by fluorescence imaging. A desmin- and sirus-red-positive area increased around and within the liver tumor over time. These results indicate cancer-associated fibroblasts (CAFs) were recruited by the liver tumors suggesting that CAFs, along with the angiogenic tumor blood vessels, were necessary for liver-tumor growth and could serve as visible therapeutic targets. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. Tumor-derived mesenchymal stem cells and orthotopic site increase the tumor initiation potential of putative mouse mammary cancer stem cells derived from MMTV-PyMT mice.

    PubMed

    Lanza, Denise Grant; Ma, Jun; Guest, Ian; Uk-Lim, Chang; Glinskii, Anna; Glinsky, Gennadi; Sell, Stewart

    2012-12-01

    The ability to transplant mammary cancer stem cells, identified by the phenotype CD24(+)CD29(+)CD49f(+)Sca-1(low), is dependent on the microenvironment in which the cells are placed. Using the MMTV-PyMT mouse model of mammary cancer, we now report two methods of tumor growth enhancement: contributions of tumor stroma in the form of tumor-derived mesenchymal stem cells and orthotopic vs. heterotopic transplantation sites. To support evidence of stem cell function, tumor-derived mesenchymal stem cells differentiated into adipocyte- and osteocyte-like cells after culture in specific medium. Co-injection of tumor-initiating cells with tumor-derived mesenchymal stem cells significantly increased tumor initiation compared to subcutaneous injection of TICs alone; co-injection also allowed tumor initiation with a single TIC. Interestingly, we observed the formation of sarcomas after co-injections of tumor-derived mesenchymal stem cells or mouse embryonic fibroblasts with TICs; sarcomas are not observed in spontaneous MMTV-PyMT tumors and rarely observed in injections of TICs alone. Tumor initiation was also significantly increased in the orthotopic injection site compared to heterotopic injections. We conclude that tumor stroma and orthotopic sites both enhance tumor initiation by mammary cancer stem cells.

  17. Bufalin Inhibits HCT116 Colon Cancer Cells and Its Orthotopic Xenograft Tumor in Mice Model through Genes Related to Apoptotic and PTEN/AKT Pathways

    PubMed Central

    Wang, Jie; Chen, Chao; Wang, Shiying; Zhang, Yong; Yin, Peihao; Gao, Zhongxiang; Xu, Jie; Feng, Dianxu; Zuo, Qinsong; Zhao, Ronghua; Chen, Teng

    2015-01-01

    Aims. To investigate the anticolorectal cancer (CRC) effects of Bufalin, a bioactive polyhydroxysteroid from Venenum Bufonis, using HCT116 human CRC cell and an established orthotopic xenograft model in mice, and to explore the mechanisms of action. Material and Methods. Cultured HCT116 cells or BALB/c mice with orthotopic tumor were treated by Bufalin (positive control: 5-FU). Cell proliferation, apoptosis, and cycling were determined by MTT, Annexin V/PI staining, and flow cytometry, respectively. In mice, tumor inhibition rate and animal survival were calculated. The expressions of PTEN/phosphate-PTEN, AKT/phosphate-AKT, Bad, Bcl-xl, Bax, or Caspase-3 in cells and/or tumors were determined by Western blot or immunohistochemical staining. Results. Bufalin significantly inhibited cell proliferation and induced cell apoptosis and cycle arrest in a dose/time-dependent manner. In the animal model, Bufalin treatment resulted in significant inhibition of tumor growth and prolonged survival. In the Bufalin-treated cultured cells and/or xenograft tumors, the expressions of PTEN, Bad, Bax, and Caspase-3 were significantly increased, while p-AKT and Bcl-xL significantly decreased. Conclusions. Our results indicate that Bufalin inhibit cell proliferation and orthotopic tumor growth by inducing cell apoptosis through the intrinsic apoptotic pathway, which is of pivotal significance in the identification of an anticancer drug that may synergize with Bufalin. PMID:26770191

  18. [Studying the tumor growth inhibitory effect of modified GnRH-III-anthracycline bioconjugates in subcutaneous vs. orthotopic models in vivo].

    PubMed

    Kapuvári, Bence; Schulcz, Ákos; Hegedüs, Rózsa; Szabó, Ildikó; Manea, Marilena; Vincze, Borbála; Tóvári, József; Gacs, Alexandra; Tejeda, Miguel; Gaál, Dezsõ; Mezõ, Gábor

    2015-12-01

    Targeted tumor therapy is a perspective procedure to specifically destroy the cancer tissues with eliminating or at least decreasing the side effects of anticancer drugs. For this purpose the drug molecule is attached to a targeting moiety (e.g. peptide hormones) that recognizes tumor specific or overexpressed receptors on cancer cells. The in vitro cytostatic or cytotoxic assays do not give proper information whether the tumor growth inhibitory effect of the conjugate is better than the activity of the free drug. Only in vivo studies are adequate to answer this question. However, the selection of the appropriate tumor model is important to eliminate the false positive results. In our studies a gonadotropin-releasing hormone analog (GnRH-III) was applied as targeting moiety in drug conjugates. The in vivo antitumor activity of these conjugates was investigated on mice bearing subcutaneously or orthotopically szigdeveloped tumors. The subcutaneously implanted tumor model which is isolated from its surroundings may provide false results in tumor growth inhibition. In contrast, the orthotopically developed tumor is a better model representing appropriate anatomical and clinical status of cancer. Therefore, the orthotopical colon cancer developed in our laboratory is a suitable model for the study of the antitumor activity of the conjugates prepared for targeted tumor therapy.

  19. [2-Deoxy-D-glucose combined with Taxol inhibits VEGF expression and induces apoptosis in orthotopically transplanted breast cancer in C3H mice].

    PubMed

    Zhang, Qianwen; Gan, Huaiyong; Cheng, Zenong; Zhao, Surong; Chen, Chao; Jiang, Chenchen; Liu, Hao; Jiang, Zhiwen

    2014-02-01

    To investigate the antineoplastic effects of 2-Deoxy-D-glucose (2-DG) combined with Taxol on orthotopically transplanted breast cancer in C3H mice and explore the mechanism. C3H mice bearing orthotopically transplanted breast cancer xenograft were randomly divided into 4 groups, namely the control group, 2-DG group, Taxol group, and 2-DG+Taxol group. The corresponding drugs were administered intraperitoneally every 3 days for 18 consecutive days, and the tumor volume was measured every 3 days to draw the tumor growth curve. The mice were then sacrificed to measure the tumor weight on day 19 and examine tumor cell apoptosis with TUNEL assay and VEGF expression using immunohistochemistry. 2-DG combined with Taxol obviously suppressed the tumor growth with a tumor inhibition rate of 66.06% as compared to the rate of 36.97% in Taxol group. The combined treatment also caused more obvious cell apoptosis and significantly reduced VEGF expression in the tumor cells as compared with the other groups. 2-DG can enhance the inhibitory effect of Taxol on orthotopically transplanted breast cancer xenograft in C3H mice probably by inducing tumor cell apoptosis and lowering VEGF expressions.

  20. Effect of low- and high-linear energy transfer radiation on in vitro and orthotopic in vivo models of osteosarcoma by activation of caspase-3 and -9

    PubMed Central

    Kim, Eun Ho; Kim, Mi-Sook; Lee, Kyung-Hee; Sai, Sei; Jeong, Youn Kyoung; Koh, Jae-Soo; Kong, Chang-Bae

    2017-01-01

    Osteosarcoma (OS) is a malignant tumor of the bone derived from primitive transformed cells of the mesenchymal origin. Local low-linear energy transfer (LET) radiotherapy has limited benefits on OS owing to its radioresistance. Thus, this study aimed to investigate the effects of high-LET radiation on human OS. Therefore, the human OS cell lines, U2O2 and KHOS/NP, were examined in vitro, or an orthotopic mouse xenograft model was studied in vivo after treatment with low-LET (gamma-ray) and high-LET (neutron) radiation. Notably, OS cells were significantly more sensitive to high-LET radiation in vitro and in the orthotopic xenograft tumor model. Specifically, neutron radiation treatment increased the relative percentage of apoptotic sub-G1 phase cells via caspase-3/9 activation; increased intracellular reactive oxygen species, autophagy, and DNA damage; and decreased invasion and migration. Similarly, the mean size of gamma-irradiated (8 Gy) orthotopic KHOS/NP OS was 195 mm3 at 6 weeks after gamma-irradiation (8 Gy), but it was only 150 mm3 in mice treated with high-LET neutron radiotherapy. Significantly, our results provide a rationale for the use of high-LET radiotherapy to treat patients with OS. PMID:28849129

  1. Surgical outcomes of isolated tricuspid valve procedures: repair versus replacement.

    PubMed

    Ejiofor, Julius I; Neely, Robert C; Yammine, Maroun; McGurk, Siobhan; Kaneko, Tsuyoshi; Leacche, Marzia; Cohn, Lawrence H; Shekar, Prem S

    2017-05-01

    Isolated tricuspid valve (ITV) operations are infrequent and the decision to operate is controversial. We report a series of ITV operations to outline the current disease status requiring this uncommon procedure with an emphasis on the results of tricuspid valve repair (TVr) versus replacement (TVR). Using our prospective cardiac surgery database, 57 patients who underwent ITV operations between 01/02-03/14 were identified. Median follow up time was 3.5 years [interquartile range (IQR), 0.8-6.7 years]. Fifty-seven patients underwent ITV surgery with a mean age of 54.4±14.9 yrs and 61% were women. Baseline characteristics were similar between patients who underwent TVr (n=18) or TVR (n=39). The etiologies of TV dysfunction were: ITV endocarditis 14/57 (25%), persistent TV regurgitation after left-sided valve surgery in 12/57 (21%), traumatic biopsies and iatrogenic injury from pacing leads in 11/57 (19%), orthotopic heart transplant 9/57 (16%), carcinoid syndrome 3/57 (5%), congenital 2/57 (5%) and idiopathic 5/57 (9%). Overall, 32/57 (56%) patients had prior heart surgery; of which 10/32 (31%) were TV procedures. Bioprosthetic prostheses were used in 34/39 (87%) patients. Of those who had repair, 11/18 (61%) had ring annuloplasty, 3/18 (17%) bicuspidization, and 3/18 (17%) De Vega annuloplasty and one had vegetectomy. Operative mortality was 5.1% (n=2) and 16.7% (n=3) for TVR and TVr groups, respectively (P=0.32), with an overall mortality rate of 8.6%. Postoperative complications included new onset renal failure in 6/39 (15%) of TVr and 2/18 (11%) of TVR (P=0.71) and there were no strokes. Overall survival rates and degree of residual RV dysfunction were similar for the two groups (both P=0.3). Five-year survival was 77% and 84% for TVr and TVR respectively (P=0.52). There was no difference in rates of recurrent tricuspid regurgitation for TVr and TVR (35.7% vs. 23.5%, respectively, P=0.4). ITV surgery is associated with improved but still relatively high

  2. Robotically assisted mitral valve replacement.

    PubMed

    Gao, Changqing; Yang, Ming; Xiao, Cangsong; Wang, Gang; Wu, Yang; Wang, Jiali; Li, Jiachun

    2012-04-01

    In the present study, we determined the safety and efficacy of robotic mitral valve replacement using robotic technology. From January 2007 through March 2011, more than 400 patients underwent various types of robotic cardiac surgery in our department. Of these, 22 consecutive patients underwent robotically assisted mitral valve replacement. Of the 22 patients with isolated rheumatic mitral valve stenosis (9 men and 13 women), the mean age was 44.7 ± 19.8 years (range, 32-65). Preoperatively, all patients underwent a complete workup, including coronary angiography and transthoracic echocardiography. Of the 22 patients, 15 had concomitant atrial fibrillation. The surgical approach was through 4 right-side chest ports with femoral perfusion. Aortic occlusion was performed with a Chitwood crossclamp, and antegrade cardioplegia was administered directly by way of the anterior chest. Using 3 port incisions in the right side of the chest and a 2.5- to 3.0-cm working port, all the procedures were completed with the da Vinci S robot. All patients underwent successful robotic surgery. Of the 22 patients, 16 received a mechanical valve and 6 a tissue valve. The mean cardiopulmonary bypass time and aortic crossclamp time was 137.1 ± 21.9 minutes (range, 105-168) and 99.3 ± 17.9 minutes (range, 80-133), respectively. No operative deaths, stroke, or other complications occurred, and no incisional conversions were required. After surgery, all the patients were followed up echocardiographically. Robotically assisted mitral valve replacement can be performed safely in patients with isolated mitral valve stenosis, and surgical results are excellent. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  3. Solvent replacement for green processing.

    PubMed Central

    Sherman, J; Chin, B; Huibers, P D; Garcia-Valls, R; Hatton, T A

    1998-01-01

    The implementation of the Montreal Protocol, the Clean Air Act, and the Pollution Prevention Act of 1990 has resulted in increased awareness of organic solvent use in chemical processing. The advances made in the search to find "green" replacements for traditional solvents are reviewed, with reference to solvent alternatives for cleaning, coatings, and chemical reaction and separation processes. The development of solvent databases and computational methods that aid in the selection and/or design of feasible or optimal environmentally benign solvent alternatives for specific applications is also discussed. Images Figure 2 Figure 3 PMID:9539018

  4. Senate committee recommends replacing FEMA

    NASA Astrophysics Data System (ADS)

    Zielinski, Sarah

    2006-05-01

    Flaws in the U.S. Federal Emergency Management Agency (FEMA) that were exposed after Hurricane Katrina struck the U.S. Gulf Coast in August 2005 are too substantial to be fixed, and the agency should be replaced with a more capable structure, recommends a 27 April report released by the Senate Committee on Homeland Security and Government Affairs. ``FEMA is discredited, demoralized, and dysfunctional. It is beyond repair. Just tweaking the organizational chart will not solve the problem,'' said Committee Chair Sen. Susan Collins (R-Maine).

  5. Liver Replacement for Pediatric Patients

    PubMed Central

    Starzl, Thomas E.; Koep, Lawrence J.; Schröter, Gerhard P. J.; Halgrimson, Charles G.; Porter, Kendrick A.; Weil, Richard

    2010-01-01

    Between March 1963 and January 1978, 74 patients 18 years of age or younger have had liver replacements at the University of Colorado Medical Center, Denver. The most common cause of native liver failure was biliary atresia (48/74, 65%); the second most common cause was chronic aggressive hepatitis (12/74, 16%). Twenty-nine patients (39%) lived for at least one year, and 16 are still alive one to nine years after transplantation. Technical surgical problems, rejection, and infection were the main causes of death. Improved immunosuppression is needed; nevertheless, the quality of life in the long-term survivors has encouraged continuation of this difficult work. PMID:377201

  6. In Defense of Artificial Replacement.

    PubMed

    Shiller, Derek

    2017-02-03

    If it is within our power to provide a significantly better world for future generations at a comparatively small cost to ourselves, we have a strong moral reason to do so. One way of providing a significantly better world may involve replacing our species with something better. It is plausible that in the not-too-distant future, we will be able to create artificially intelligent creatures with whatever physical and psychological traits we choose. Granted this assumption, it is argued that we should engineer our extinction so that our planet's resources can be devoted to making artificial creatures with better lives.

  7. [Proximal and total femur replacement].

    PubMed

    Pennekamp, P H; Wirtz, D C; Dürr, H R

    2012-07-01

    Reconstruction of segmental bone defects of the proximal femur following wide tumor resection or revision arthroplasty. Aggressive benign or primary malignant bone tumors of the proximal femur; destructive metastases; massive segmental bone defects of the proximal femur; periprosthetic fractures. Local infection; very short life expectancy (< 3 months); massive deficiency of acetabular bone stock. Anterolateral approach. Exposure and detachment of the iliopsoas and gluteus medius muscle from the proximal femur with a sufficient safety margin to the bone; distal transsection of the vastus lateralis/intermedius and rectus femoris muscle according to the extraosseous tumor extension; distal femur osteotomy al least 3 cm beyond the farthest point of tumor extension; in case of total femur replacement, additional lateral arthrotomy of the knee with resection of the ligaments and menisci; reaming of the medullary canal after securing the shaft with a Verbrugge clamp; trial assembly and reduction followed by the definitive implantation of the prosthesis with adjustment of the femoral neck anteversion in 5° increments; soft tissue reconstruction and fixation to an attachment tube covering the prosthesis; in case of total femur replacement, the preparation of the tibia is followed by the coupling of the tibial and femoral components. Infection prophylaxis, 20 kg partial weight bearing, continuous passive motion. A total of 20  patients with proximal femur replacement and 2 patients with total femur replacement implanted between June 2007 and December 2011 were retrospectively reviewed. Three patients had primary malignant bone tumors, while 19 patients underwent resection for metastatic disease. The mean age at surgery was 62.0 ± 18.1 years (18-82 years). Fifteen patients with a mean follow-up of 20.3 ± 17.2 months (4-51 months) were studied. Among the 22 cases, periprosthetic infection occurred in 3 patients (13.6%), dislocation in 2 patients (9

  8. Biliary tract complications after orthotopic liver transplantation: still the "Achilles heel"?

    PubMed

    Perrakis, A; Förtsch, T; Schellerer, V; Hohenberger, W; Müller, V

    2010-12-01

    Postoperative biliary tract complications after liver transplantation (LT) still lead to early and late morbidity and mortality. Modern interventional endoscopic techniques can replace surgical repair as the first line of treatment. Nevertheless surgical intervention plays an important role in specific situations. We performed a retrospective analysis of patients with biliary complications after LT over a 12-year period. We compared treatment programs based on duration and success rate. The rate of biliary complications was 24.5% (60/245). The side-to-side choledocholedochostomy (CDC) technique showed the significantly lowest rate. The rate of complications after hepaticojejunostomy (HJS) was considerably lower, albeit not significantly. Eighty-one percent of complications after CDC were treated with interventional endoscopy. The duration of treatment of strictures, was 10 times greater than that of leakages. Surgical repair was necessary for 19% of complications occurring after CDC. The treatment options after HJS largely comprised surgical repairs. From a surgical standpoint, choosing the correct method for biliary reconstruction and ensuring normal arterial flow are the best preventive techniques to avoid biliary complications. Over the past 10 years, the primary treatment regimen has moved from surgical repair to interventional endoscopy. Only when endoscopy fails, should one consider surgical repair. The treatment after HJS is still primarily surgical. Percutaneous transhepatic approaches should be avoided. Creation of an inspection stoma to allow endoscopic access is an option. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. Smokers Prone to Problems After Joint Replacement

    MedlinePlus

    ... fullstory_164137.html Smokers Prone to Problems After Joint Replacement: Study Cessation programs help reduce the rate ... that smokers do worse than non-smokers after joint replacements, and now this research shows there's good ...

  10. Hip Replacement: MedlinePlus Health Topic

    MedlinePlus

    ... Arthritis and Musculoskeletal and Skin Diseases) Also in Spanish Total Hip Replacement (American Academy of Orthopaedic Surgeons) - PDF Also in Spanish Total Hip Replacement (Arthroplasty) (Beyond the Basics) (UpToDate) ...

  11. Knee Replacement: MedlinePlus Health Topic

    MedlinePlus

    ... Arthritis and Musculoskeletal and Skin Diseases) Also in Spanish Knee Replacement (Mayo Foundation for Medical Education and ... American Academy of Orthopaedic Surgeons) - PDF Also in Spanish Total Knee Replacement (Arthroplasty) (Beyond the Basics) (UpToDate) ...

  12. B Plant process piping replacement feasibility study

    SciTech Connect

    Howden, G.F.

    1996-02-07

    Reports on the feasibility of replacing existing embedded process piping with new more corrosion resistant piping between cells and between cells and a hot pipe trench of a Hanford Site style canyon facility. Provides concepts for replacement piping installation, and use of robotics to replace the use of the canyon crane as the primary means of performing/supporting facility modifications (eg, cell lining, pipe replacement, equipment reinstallation) and operational maintenenace.

  13. Total hip replacement in dancers.

    PubMed

    Buyls, Inge R A E; Rietveld, A B M Boni; Ourila, Tiia; Emerton, Mark E; Bird, H A

    2013-04-01

    A case report of a professional contemporary dancer who successfully returned to the stage after bilateral total hip replacements (THR) for osteoarthritis is presented, together with her own commentary and a retrospective cohort study of total hip replacements in dancers. In the presented cohort, there were no post-operative dislocations or infections, the original pain had been relieved, rehabilitation was objectively normal and all resumed their dance (teaching) activities. Nevertheless, they were disappointed about the prolonged rehabilitation. Due to their high demands as professional dancers, post-operative expectations were too optimistic in view of the usual quick and favourable results of THR in the older and less physically active, general population. In all dancers with unilateral osteoarthritis, the left hip was involved, which may reflect the tendency to use the left leg as standing leg and be suggestive that strenuous physical activity may lead to osteoarthritis. Better rehabilitation guidelines are needed for dancer patients undergoing THR, especially drawing their attention to realistic post-operative expectations.

  14. The Mitochondrial Replacement 'Therapy' Myth.

    PubMed

    Rulli, Tina

    2016-12-30

    This article argues that two forms of mitochondrial replacement therapy, maternal spindle transfer (MST) and pro-nuclear transfer (PNT), are not therapies at all because they do not treat children who are coming into existence. Rather, these technologies merely create healthy children where none was inevitable. Even if creating healthy lives has some value, it is not to be confused with the medical value of a cure or therapy. The article addresses a recent Bioethics article, 'Mitochondrial Replacement: Ethics and Identity,' by Wrigley, Wilkinson, and Appleby, who argue that PNT is morally favorable to MST due to the Non-Identity Problem. Wrigley et al. claim that PNT, since it occurs post-conception, preserves the identity of the resulting child, whereas MST, since it occurs pre-conception, is an identity-altering technique. As such, a child born with mitochondrial disease could complain that her parents failed to use PNT, but not MST. The present article argues that the authors are mistaken: both MST and PNT are identity-affecting techniques. But this is of little matter, for we should be cautious in drawing any moral conclusions from the application of the Non-Identity Problem to cases. The article then argues that the authors are mistaken in inferring that PNT is a type of embryonic cure or therapy for children with mitochondrial disease. The article cautions against the mistaken life-saving rhetoric that is common in bioethics discussions of MRTs.

  15. Fetal tissue engineering: diaphragmatic replacement.

    PubMed

    Fauza, D O; Marler, J J; Koka, R; Forse, R A; Mayer, J E; Vacanti, J P

    2001-01-01

    Prosthetic repair of congenital diaphragmatic hernia has been associated with high complication rates. This study was aimed at applying fetal tissue engineering to diaphragmatic replacement. Fetal lambs underwent harvest of skeletal muscle specimens. Once expanded in vitro, fetal myoblasts were suspended in a collagen hydrogel submitted to controlled radial tension. The construct was then placed in a bioreactor. After birth, all animals underwent creation of 2 diaphragmatic defects. One defect was repaired with the autologous-engineered construct placed in between 2 acellular supporting membranes and the other with an identical construct but without any cells. Each animal was its own control (graft, n = 10). Animals were killed at different time-points postimplantation for histologic examination. Statistical analysis was by analysis of variance (ANOVA). Fetal myoblasts expanded up to twice as fast as neonatal cells. Hydrogel-based radial tension enhanced construct architecture by eliciting cell organization within the scaffold. No eventration was present in 4 of 5 engineered constructs but in 0 of 5 acellular grafts (P<.05). At harvest, engineered constructs were thick and histologically resembled normal skeletal muscle, whereas acellular grafts were thin, floppy, and showed low cell density with increased fibrosis. Unlike acellular grafts, engineered cellular diaphragmatic constructs are anatomically and histologically similar to normal muscle. Fetal tissue engineering may be a viable alternative for diaphragmatic replacement.

  16. Should the patella be replaced in total knee replacement?

    PubMed

    Badhe, N; Dewnany, G; Livesley, P J

    2001-01-01

    In 170 total knee arthroplasties for osteoarthritis 71 did not receive a patellar replacement (group A), while 99 knees had a cemented polyethylene patella (group B). The mean follow-up time was 36 months (30-50 months). In group A 10 patients underwent second-stage patellar resurfacing and in group B 2 knees underwent revision of the patellar component. Radiologically the average patellar congruency was similar. In both groups there were 21 non-congruent knees. In group A 8 were symptomatic and had low scores compared to 2 in group B (P<0.05). The mean HSS score and patellar score were higher in group B than in group A (P<0.05).

  17. Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth in vitro and in orthotopic murine.

    PubMed

    Wang, Lu-Lu; Feng, Chen-Lin; Zheng, Wen-Sheng; Huang, Shuai; Zhang, Wen-Xuan; Wu, Hong-Na; Zhan, Yun; Han, Yan-Xing; Wu, Song; Jiang, Jian-Dong

    2017-10-01

    Small active RNA (saRNA)-induced gene activation (RNAa) is a novel strategy to treat cancer. Our previous work proved that the p21-saRNA-322 successfully hindered colorectal cancer growth by activating p21 gene. However, the barrier for successful saRNA therapy is lack of efficient drug delivery. In the present study, a rectal delivery system entitled p21-saRNA-322 encapsulated tumor-selective lipopolyplex (TSLPP-p21-saRNA-322) which consist of PEI/p21-saRNA-322 polyplex core and hyaluronan (HA) modulated lipid shell was developed to treat colorectal cancer. Our results showed that this system maintained at the rectum for more than 6 h and preferentially accumulated at tumor site. CD44 knock down experiment instructed that the superb cellular uptake of TSLPP-p21-saRNA-322 attributed to HA-CD44 recognition. An orthotopic model of bio-luminescence human colorectal cancer in mice was developed using microsurgery and TSLPP-p21-saRNA-322 demonstrated a superior antitumor efficacy in vitro and in vivo. Our results provide preclinical proof-of-concept for a novel method to treat colorectal cancer by rectal administration of TSLPP formulated p21-saRNA-322. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Magnetic resonance imaging for the evaluation of a novel metastatic orthotopic model of human neuroblastoma in immunodeficient mice.

    PubMed

    Moats, R; Ma, L Q; Wajed, R; Sugiura, Y; Lazaryev, A; Tyszka, M; Jacobs, R; Fraser, S; Nelson, M D; DeClerck, Y A

    2000-01-01

    Neuroblastoma is the second most common solid tumor in children. So far few tumor models for this cancer have been reported in mice. We have created a murine tumor model for studying human neuroblastoma based on surgical orthotopic implantation in scid mice. Small fragments of subcutaneous tumors of SK-N-BE(2) human neuroblastoma cells expressing enhanced green fluorescent protein were surgically implanted near the left adrenal gland of scid mice. One hundred percent of the animals (n = 21) successfully implanted developed a large retroperitoneal tumor and became moribund between 22 and 57 days after implantation (mean survival time = 41 days). At the time of sacrifice the presence of bone marrow metastasis was detected by RT-PCR for green fluorescent protein in 95% of the cases. The growth of small tumor implants could be easily visualized and quantified by surveillance MR imaging, with a resolution of 117 x 117 x 750 microm in two orthogonal planes allowing accurate volume measurements, as well as assessment of necrosis and tissue invasion. This novel model should be a valuable tool to study the biology and therapeutic approaches to neuroblastoma.

  19. Orthotopic animal model of pseudomyxoma peritonei: An in vivo model to test anti-angiogenic drug effects.

    PubMed

    Dohan, Anthony; Lousquy, Ruben; Eveno, Clarisse; Goere, Diane; Broqueres-You, Dong; Kaci, Rachid; Lehmann-Che, Jacqueline; Launay, Jean-Marie; Soyer, Philippe; Bonnin, Philippe; Pocard, Marc

    2014-07-01

    Pseudomyxoma peritonei (PMP) is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was i.p. grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice a week either during tumor growth or after cytoreductive surgery. In vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler ultrasonography of the superior mesenteric artery revealed a twofold increase in blood flow velocity compared with tumor-free mice (P < 0.001). Bevacizumab administration was correlated with the normalization of tumor vascularity when injected during tumor growth and with the stabilization of the histological and hemodynamic findings when injected after cytoreductive surgery. Our PMP models mimic human PMP. Our results confirmed the presence of tumor angiogenesis related to PMP growth. Our murine model allows researchers to actually bench test and evaluate, in preclinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies.

  20. Sodium orthovanadate inhibits growth of human hepatocellular carcinoma cells in vitro and in an orthotopic model in vivo.

    PubMed

    Wu, Yaohua; Ma, Yong; Xu, Zhilin; Wang, Dawei; Zhao, Baolei; Pan, Huayang; Wang, Jizhou; Xu, Dongsheng; Zhao, Xiaoyang; Pan, Shangha; Liu, Lianxin; Dai, Wenjie; Jiang, Hongchi

    2014-08-28

    The transition metal vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. As a well known vanadium compound, sodium orthovanadate (SOV) has shown promising antineoplastic activity in several human cancers. However, the effects of SOV on liver cancer are still unknown. In this study, for the first time, we showed that SOV could effectively suppress proliferation, induce G2/M cell cycle arrest and apoptosis, and diminish the mitochondrial membrane potential (MMP) of HCC cells in vitro. In addition, our in vitro results were recapitulated in vivo, showing that SOV exhibited a dose-dependent inhibition of growth of human HCC in an orthotopic model, evidenced by the reduction in tumor size, proliferation index and microvessel density, and increase in cell apoptosis. Most important, we found that SOV could inhibit autophagy in HCC cells in vitro and in vivo, which plays a prodeath role. Thus, our findings suggest that SOV could effectively suppress the growth of human HCC through the regulations of proliferation, cell cycle, apoptosis and autophagy, and thus may act as a potential therapeutic agent in HCC treatment.

  1. A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging.

    PubMed

    Bornmann, C; Graeser, R; Esser, N; Ziroli, V; Jantscheff, P; Keck, T; Unger, C; Hopt, U T; Adam, U; Schaechtele, C; Massing, U; von Dobschuetz, E

    2008-03-01

    Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (Ø: 36 nm: 47% entrapment). Its anti-tumoral activity was tested on MIA PaCa-2 cells growing orthotopically in nude mice. Bioluminescence measurement mediated by the stable integration of the luciferase gene was employed to randomize the mice, and monitor tumor growth. GemLip (4 and 8 mg/kg), Gemcitabine (240 mg/kg), and empty liposomes (equivalent to 8 mg/kg GemLip) were injected intravenously once weekly for 5 weeks. GemLip (8 mg/kg) stopped tumor growth, as measured via in vivo bioluminescence, reducing the primary tumor size by 68% (SD +/- 8%; p < 0.02), whereas Gemcitabine hardly affected tumor size (-7%; +/- 1.5%). In 80% of animals, luciferase activity in the liver indicated the presence of metastases. All treatments, including the empty liposomes, reduced the metastatic burden. Thus, GemLip shows promising antitumoral activity in this model. Surprisingly, empty liposomes attenuate the spread of metastases similar to Gemcitabine and GemLip. Further, luciferase marked tumor cells are a powerful tool to observe tumor growth in vivo, and to detect and quantify metastases.

  2. Cardiovascular risk after orthotopic liver transplantation, a review of the literature and preliminary results of a prospective study

    PubMed Central

    Pisano, Giuseppina; Fracanzani, Anna L; Caccamo, Lucio; Donato, Maria F; Fargion, Silvia

    2016-01-01

    Improved surgical techniques and greater efficacy of new anti-rejection drugs have significantly improved the survival of patients undergoing orthotopic liver transplantation (OLT). This has led to an increased incidence of metabolic disorders as well as cardiovascular and cerebrovascular diseases as causes of morbidity and mortality in OLT patients. In the last decade, several studies have examined which predisposing factors lead to increased cardiovascular risk (i.e., age, ethnicity, diabetes, NASH, atrial fibrillation, and some echocardiographic parameters) as well as which factors after OLT (i.e., weight gain, metabolic syndrome, immunosuppressive therapy, and renal failure) are linked to increased cardiovascular mortality. However, currently, there are no available data that evaluate the development of atherosclerotic damage after OLT. The awareness of high cardiovascular risk after OLT has not only lead to the definition of new but generally not accepted screening of high risk patients before transplantation, but also to the need for careful patient follow up and treatment to control metabolic and cardiovascular pathologies after transplant. Prospective studies are needed to better define the predisposing factors for recurrence and de novo occurrence of metabolic alterations responsible for cardiovascular damage after OLT. Moreover, such studies will help to identify the timing of disease progression and damage, which in turn may help to prevent morbidity and mortality for cardiovascular diseases. Our preliminary results show early occurrence of atherosclerotic damage, which is already present a few weeks following OLT, suggesting that specific, patient-tailored therapies should be started immediately post OLT. PMID:27833378

  3. Comparative analysis of the results of orthotopic liver transplantation in patients with and without portal vein thrombosis.

    PubMed

    Gimeno, F A; Calvo, J; Loinaz, C; Meneu, J C; Pérez, B; Gomez, R; Jiménez, C; Abradelo, M; Moreno, A; Sesma, A; García, I; Moreno, E

    2005-11-01

    Portal vein thrombosis (PVT), which had been considered an absolute contraindication to orthotopic liver transplantation (OLT), is currently considered a risk factor that increases morbi-mortality. The objective of this study was to compare OLT outcomes in patients with vs without PVT. Between April 1986 and December 2003, a sample of 83 patients with PVT was compared with another sample of 83 patients without PVT among 962 OLT performed in our department. Both groups were homogeneous in terms of epidemiological variables, surgical technique, immunosuppression, and donor-related variables. There were no differences with respect to graft function during the first week following surgery. Surgical time and anhepatic phase duration was longer in the PVT group, albeit the differences were not significant. PVT patients also required more transfusions; a strong statistical association was observed with respect to blood (P = .12) and plasma (P = .11) transfusions and statistically significant differences regarding platelet transfusions (P = .02). Time on mechanical ventilation and the length of stay in the ICU were longer but not significant among PVT patients. The only statistically significant difference was the incidence of portal rethrombosis (P = .02). With respect to mean and global patient and graft actuarial survivals after 1, 3, 5, and 10 years, we have observed no significant intergroup differences, although both patient (P = .48; NS) and graft (P = .96, NS) survivals were lower among PVT cases. PVT should not only cease to be considered a contraindication for OLT, but there were no significant differences between the outcomes despite this finding.

  4. Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

    PubMed

    Murakami, Takashi; Li, Shukuan; Han, Qinghong; Tan, Yuying; Kiyuna, Tasuku; Igarashi, Kentaro; Kawaguchi, Kei; Hwang, Ho Kyoung; Miyake, Kentaro; Singh, Arun S; Nelson, Scott D; Dry, Sarah M; Li, Yunfeng; Hiroshima, Yukihiko; Lwin, Thinzar M; DeLong, Jonathan C; Chishima, Takashi; Tanaka, Kuniya; Bouvet, Michael; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

    2017-03-01

    Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.

  5. The application of surgical navigation system using optical molecular imaging technology in orthotopic breast cancer and metastasis studies

    NASA Astrophysics Data System (ADS)

    Chi, Chongwei; Zhang, Qian; Kou, Deqiang; Ye, Jinzuo; Mao, Yamin; Qiu, Jingdan; Wang, Jiandong; Yang, Xin; Du, Yang; Tian, Jie

    2014-02-01

    Currently, it has been an international focus on intraoperative precise positioning and accurate resection of tumor and metastases. The methods such as X-rays, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) have played an important role in preoperative accurate diagnosis. However, most of them are inapplicable for intraoperative surgery. We have proposed a surgical navigation system based on optical molecular imaging technology for intraoperative detection of tumors and metastasis. This system collects images from two CCD cameras for real-time fluorescent and color imaging. For image processing, the template matching algorithm is used for multispectral image fusion. For the application of tumor detection, the mouse breast cancer cell line 4T1-luc, which shows highly metastasis, was used for tumor model establishment and a model of matrix metalloproteinase (MMP) expressing breast cancer. The tumor-bearing nude mice were given tail vein injection of MMP 750FAST (PerkinElmer, Inc. USA) probe and imaged with both bioluminescence and fluorescence to assess in vivo binding of the probe to the tumor and metastases sites. Hematoxylin and eosin (H&E) staining was performed to confirm the presence of tumor and metastasis. As a result, one tumor can be observed visually in vivo. However liver metastasis has been detected under surgical navigation system and all were confirmed by histology. This approach helps surgeons to find orthotopic tumors and metastasis during intraoperative resection and visualize tumor borders for precise positioning. Further investigation is needed for future application in clinics.

  6. Induction of Apoptosis in Tumor-Associated Endothelial Cells and Therapy of Orthotopic Human Pancreatic Carcinoma in Nude Mice1

    PubMed Central

    Yokoi, Kenji; Kim, Sun-Jin; Thaker, Premal; Yazici, Sertac; Nam, Do-Hyun; He, Junqin; Sasaki, Takamitsu; Chiao, Paul J; Sclabas, Guido M; Abbruzzese, James L; Hamilton, Stanley R; Fidler, Isaiah J

    2005-01-01

    Abstract Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice. PMID:16026649

  7. [Estimation of the healing process of denatured orthotopic bone implants in an animal model. I. Measurements with polarization microscopy].

    PubMed

    Keller, F; Wolff, W; Bocher, R

    1990-01-01

    The paper gives in a series of 3 parts a survey, quantitative statements and conclusions on the healing process of denatured orthotopic osteoresections with the initial bone obtained by, polarization optical measurements (this first part), morphological evaluation method (part II), (in these cases the collagen polymorphism served as indicator for the regeneration course) and, semiquantitative method of observation