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Sample records for orthotopic neobladder replacement

  1. Endoscopic Treatment of Studer's Orthotopic Neobladder Lithiasis.

    PubMed

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

    2015-05-01

    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

  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. Intravesical OnabotulinumtoxinA Injection for Overactive Orthotopic Ileal Neobladder: Feasibility and Efficacy

    PubMed Central

    2016-01-01

    The efficacy of intravesical onabotulinumtoxinA (BTXA) in the treatment of overactive bladder (OAB) has been well documented. The use of BTXA injection in orthotopic neobladders is yet to be studied. We present 4 cases of patients injected with intravesical BTXA for overactive orthotopic ileal neobladder. We recorded patient demographics, presenting and follow-up symptoms, urodynamic profiles, and Patient Global Impression of Improvement (PGI-I) scores. The 4 patients reported varying degrees of subjective improvements in the symptoms, including urgency, urge incontinence, and pad usage. Mean follow-up duration was 8.3 months (range, 5–14 months). Average PGI-I score was 3 (“a little better”) (range, 2–4). To our knowledge, the current study is the first case series examining BTXA injection for orthotopic neobladder overactivity. BTXA injection yielded varying degrees of objective and subjective improvements, without significant complications. Intravesical BTXA injection is feasible and may be considered as a potential treatment alternative for OAB in orthotopic neobladders, although further study is warranted. PMID:27032562

  4. Comparison Between Ambulatory and Conventional Urodynamics of the Modified Orthotopic Hautmann Neobladder

    PubMed Central

    Georgios, Dimitriadis; Georgios, Gkotsos; Ioannis, Vakalopoulos; Stavros, Ioannidis; Konstantinos, Hatzimoutatidis; Dimitrios, Hatzichristou

    2015-01-01

    Purpose: The aim of the present study was to determine the diagnostic accuracy of conventional and ambulatory urodynamic studies (UDS) in estimating neobladder function. Methods: We evaluated 32 patients who underwent radical cystectomy and orthotopic Hautmann W neobladder with Abol-Enein-Ghoneim uretero-intestinal anastomosis for bladder cancer. The patients were initially examined by using both conventional and ambulatory UDS. Results: Conventional UDS detected a very high mean intravesical pressure at maximum capacity (53.7±17.5 cm H2O). By contrast, the mean intravesical pressure detected by using ambulatory UDS (which reflects the dominant pattern of pressure variation during filling) was significantly lower (34.4±5.2 cm H2O, P<0.001). The comparison between intravesical pressure at half of maximum capacity in conventional UDS and the mean value in ambulatory UDS did not show significant difference (P=0.152). The mean voided volume in conventional UDS was greater than both the mean voided volume (P<0.001) and the mean maximum voided volume in ambulatory UDS (P=0.001). However, this difference did not affect the postvoid residual urine volume measured in both studies (P=0.207). Moreover, incontinence episodes recorded in ambulatory UDS were more frequent but not statistically significantly different from those recorded in conventional UDS (P=0.332). Conclusions: The estimation of neobladder function by means of ambulatory UDS seems to provide interesting research data for the mode of lower urinary tract function in patients with orthotopic substitution after radical cystectomy. The great high value in ambulatory UDS, in cases in which conventional UDS had failed, is due to the exposure of daily and nocturnal incontinence episodes, confirming our patients’ complaints. PMID:26739181

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

    PubMed

    Wang, Dong; Li, Li-Jun; Liu, Jing; Qiu, Ming-Xing

    2014-09-01

    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

  6. Preperitoneal placement of an inflatable penile prosthesis reservoir for postoperative erectile dysfunction after radical cystoprostatectomy with orthotopic neobladder

    PubMed Central

    Kim, Jung Kwon; Cho, Min Chul; Ku, Ja Hyeon

    2016-01-01

    Purpose To describe a case of safe placement of an inflatable penile prosthesis reservoir for postoperative erectile dysfunction (ED) with a history of radical cystoprostatectomy with an orthotopic Studer neobladder. Materials and Methods A 55-year-old bladder cancer patient, who underwent radical cystoprostatectomy with orthotopic Studer neobladder 2 years prior, suffered from postoperative ED. A 3-piece inflatable penile prosthesis was implanted via a penoscrotal incision. The alternative reservoir placement began with a longitudinal 4-cm incision, which was 2 finger-breaths to the left and lateral to the umbilicus. Thereafter, the anterior and posterior rectus sheaths were dissected and incised. Then, the transversalis fascia entering into the preperitoneal space was incised, followed by circumferential sweeping using the forefinger, and, finally, placement of a 100 mL 'flat' reservoir. The reservoir was filled with 65 mL saline and then evaluated for back pressure. The reservoir tubing exited through the defect of the rectus sheaths and tunneled through the abdominal fat into the penoscrotal wound. Results Total operative time was 105 minutes, and the estimated blood loss was minimal. The patient was discharged at postoperative day 1 and experienced no perioperative complications. At the 6-month follow-up, there was no abdominal bulging from the preperitoneal reservoir, and the reservoir was not palpable. Conclusions The preperitoneal placement of the flat reservoir at the level of the umbilicus is a safe and acceptable surgical technique for postoperative ED after radical cystoprostatectomy with orthotopic neobladder.

  7. Technical steps of open radical cystectomy and orthotopic neobladder to achieve the goals of “minimally invasive surgery”?

    PubMed Central

    Mandhani, Anil; Dharaskar, Anand; Kapoor, Rakesh

    2010-01-01

    Technical modifications in open approach to radical cystectomy and orthotopic neobladder (ONB), that is, Pfannenstiel incision, single urethral catheter, internal splint, and extraperitonealization of the ONB were done in 36 patients. Median operative time was 300 (240–360) min. Median time to move the bowel and start of oral intake was 4 days (2–8) days. Major complications occurred in 3 (8.33%) patients. Mean postoperative pain score was 2 (1–4). These modifications in open radical cystectomy resulted in better cosmesis, less pain, and more comfort to the patients as they had to carry one urobag for 3 weeks. PMID:21116377

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

    PubMed Central

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

    2015-01-01

    Introduction: 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. Materials and Methods: 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. Results: 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). Conclusions: 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. PMID:26604445

  9. 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

  10. AB054. An improved technique for bladder cancer: pure laparoscopic radical cystectomy with orthotopic U-shape ileal neobladder using titanium staples

    PubMed Central

    Wang, Shuai; Qi, Xiaolong; Liu, Feng; Zheng, Min; Zhang, Dahong

    2015-01-01

    Objective To report our experience with an improved technique of laparoscopic radical cystectomy (LRC) and orthotopic ileal neobladder reconstruction, evaluating the perioperative and pathological outcomes. Methods We retrospectively reviewed the data of 56 cases who underwent radical cystoprostatectomy followed by construction of an orthotopic U-shaped ileal neobladder between August 2010 and December 2014. These data include intraoperative data, early and long-term postoperative complications, neobladder function, urinary continence and oncologic results. Also the key innovative procedure was introduced with details. Results The median time of the overall procedure was 212 min. The median estimated blood loss was 171 mL. The median hospitalization time after the operation was 21 days. Complications included two cases of unilateral ureter-pouch anastomotic strictures, one case of bilateral ureteral stricture, three cases of vesicourethral anastomotic strictures and three cases of vesicourethral leakage. The mean maximum pouch capacity was 446±32 mL, and pouch pressure at capacity was 18.1±2.6 cmH2O. The Qmax was 14±1.2 mL/s, and the mean post-void residual was 25±10 mL. There were nine cases of night-time incontinence at 3 months post-operatively. Negative surgical margins of the bladder specimens were achieved in all patients. During a follow-up period of 3 to 44 months (average 32.6 months), local recurrence was found in two patients and distant metastasis was occurred in another three patients. Conclusions Our preliminary experience showed that pure LRC with non-absorbable titanium staples assisted orthotopic U-shape ileal neobladder reconstruction is feasible based on perioperative data and oncologic features.

  11. Is frozen section analysis of the urethra at the time of radical cystectomy and orthotopic neobladder urinary diversion mandatory?

    PubMed Central

    Sureka, Sanjoy Kumar; Yadav, Abhishek; Arora, Sohrab; Kapoor, Rakesh; Mandhani, Anil

    2015-01-01

    Introduction: This study was aimed at analyzing the need for routine use of frozen section analysis (FSA) before performing orthotopic neobladder (ONB) after radical cystectomy for carcinoma urinary bladder. Materials and Methods: A total of 233 patients underwent radical cystectomy from January 2000 to June 2013. Of these, 151 (65.6%) patients were planned for ONB. In the initial 109 (72%) patients, FSA of urethral margin was performed, but, in the subsequent 42 (28%) patients, frozen section of urethral margin was not sent. Impact of hydroureteronephrosis, tumor size and location of tumor in relation to the bladder neck on the status of the urethral margin was analyzed. Results: Only three of the 109 (2.7%) patients had a positive urethral margin. Two of them had ileal conduit and one, after negative re-resection, had ONB. Although none of the factors was found to be significant, all three patients with a positive urethral margin had growth at the bladder neck and died of cancer at a mean follow up of 29.33 ± 18.3 months, without urethral recurrence. Among the negative FSA (106), two patients had recurrence in the penile urethra. The mean follow-up was 46.3 ± 25.1 months. None of the patients without FSA (42) had urethral recurrence at the mean follow-up of 36 ± 9.3 months. Of the 28 patients who had their growth located at the bladder neck, three had positive FSA, while none with growth away from the bladder neck had positive FSA. Conclusion: Routine FSA of the urethra before performing ONB can be avoided in those patients where the tumor does not reach the bladder neck. PMID:26604448

  12. [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. PMID:23995533

  13. Tubulovillous Adenoma in a Urethral Neobladder Anastomosis

    PubMed Central

    Morganstern, Bradley A.; Greenblatt, Logan B.; Yaskiv, Oksana; Steckel, Joph

    2015-01-01

    We present a case of a tubulovillous adenoma arising in a neobladder that was managed by cystoscopic resection. A 64 year-old male underwent a cystectomy with creation of an ileocolic neobladder urinary diversion for T2 urothelial carcinoma of the bladder. Nine years following his surgery, the patient noted several episodes of gross hematuria. Cystoscopic evaluation revealed the rare occurrence of a 3 cm tubulovillous adenoma with high-grade dysplasia at the neck of the neobladder. PMID:26793555

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

    PubMed Central

    2016-01-01

    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. PMID:27366009

  15. Medial thigh pain: An unusual presentation of giant calculi in sigmoid neobladder

    PubMed Central

    Abrol, Nitin; Gupta, Narmada; Kumar, Rajeev

    2011-01-01

    Calculi in a neobladder usually present with irritative lower urinary tract symptoms, flank pain, and haematuria. We report a case of giant stones in a sigmoid neobladder, who presented with medial thigh pain. PMID:21814323

  16. Robotic radical cystectomy with intracorporeal neobladder: Initial experience and outcomes

    PubMed Central

    Butt, Zulfiqar A.; Forbes, Ellen; Zorn, Jeff; Martin, Blair St

    2015-01-01

    Introduction: Total intra-corporeal robot-assisted radical cystectomy (RARC) with total intracorporeal neobladder formation is relatively new in the treatment of bladder cancer. We present our experience and believe it is the first Canadian reported series with this technique. Methods: This is a case series of 4 patients, who underwent total RARC, pelvic lymphadenectomy and creation of an intra-corporeal ileal neobladder. Surgical technique is described and perioperative variables, pathologic data, and complication rates are reported. Results: The mean patient age was 61.8 and the mean body mass index was 27.01 kg/m2. The mean operative time, estimated blood loss, time to full diet and length of stay were 522.8 minutes (standard deviation [SD] 74.5), 237.5 mL (SD 47.9), 9 days (range: 3–24) and 12.8 days (range: 6–31), respectively. All patients completed postoperative functional evaluation showing a mean neobladder capacity of 575 cc (range: 500–720). Surgical margins and pathological nodal status were negative in all patients with no evidence of disease recurrence or progression on follow-up. Three of the 4 patients suffered a complication within 90 days, with one occurring later in the first year. All early complications were Clavien grade I–II (grade I [n = 1]; grade II [n = 2]) and the later complication was grade IIIa. The mean follow-up was 632 days (range: 562–730). The limitation of our study is its small sample size with highly selected patients to compensate for the learning experience. The follow-up is short; however, the outcomes are comparable to early experiences reported at other institutions. Conclusions: In our initial experience, RARC with total intracorporeal neobladder formation is safe. We expect that with experience the expense of robotic surgery can be compensated with early ambulation and shorter stay. PMID:25844107

  17. Laparoscopic Radical Cystectomy and Ileal Neobladder for Muscle Invasive Bladder Cancer in Combination with One Stage Prophylactic Laparoscopic Sacrospinal Fixation to Avoid Future Pelvic Organ Prolapse

    PubMed Central

    Törzsök, Péter; Bauer, Sophina; Forstner, Rosemarie; Sievert, Karl-Dietrich; Janetschek, Günter

    2016-01-01

    Abstract Background: Women who undergo cystectomy with orthotopic ileal neobladder are more likely to have urinary retention and neocystocele mainly because of anatomical reasons than stress urinary incontinence. The risk is even higher in case of neurologic comorbidities, as in case of our patient. Case Presentation: We present a laparoscopic mesh insertion for sacrospinal colposuspension to prevent a neocystocele and pelvic organ prolapse in combination with laparoscopic radical cystectomy in a female patient suffering from bladder cancer and chronic episodic multiple sclerosis. After a 30-month follow-up, the patient is continent and voids without residual urine. A dynamic MR of the pelvis shows a minimal rectocele without any evidence of a cystocele. Conclusion: Laparoscopic cystectomy combined with sacrospinal mesh fixation is technically feasible and could be an option to prevent neocystocele for female patients.

  18. Ileal Neobladder With Mucous Plugs as a Cause of Obstructive Acute Kidney Injury Requiring Emergent Hemodialysis.

    PubMed

    Singla, Montish; Shikha, Deep; Lee, Sunggeun; Baumstein, Donald; Chaudhari, Ashok; Carbajal, Roger

    2016-01-01

    Ileal neobladder is the preferred technique in the management of urinary diversion postradical cystectomy for bladder malignancy. The common complications associated with this procedure are atrophied kidney, chronic pyelonephritis, decreased renal function, ureteroileal or urethral anastomotic site stricture, urinary tract stones, incontinence, and hyperchloremic metabolic acidosis. Mucous plugs are also seen in 2%-3% patients. We present a rare presentation of a patient who required hemodialysis for severe hyperkalemia and acute kidney injury caused by mucous plugging of ileal neobladder. PMID:25420078

  19. 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. PMID:12088194

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

    PubMed Central

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

    2016-01-01

    Purpose To investigate the serial changes of metabolic acidosis and identify associated risk factors in patients who underwent radical cystectomy and ileal neobladder. Material and Methods 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. Results 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. Conclusion 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. PMID:27384686

  1. 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. PMID:25782228

  2. 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

  3. Infections Following Orthotopic Liver Transplantation

    PubMed Central

    Arnow, Paul M.

    1991-01-01

    The epidemiology of infections associated with orthotopic liver transplantation is summarized herein, and approaches to prophylaxis are outlined. Infection is a major complication following orthotopic liver transplantation, and more than half of transplant recipients develop at least one infection. The risk of infection is highest in the first month after transplantation, and the most common pathogens are bacteria and cytomegalovirus (CMV). Bacterial infections usually occur in the first month, arise in the abdomen, and are caused by aerobes. The peak incidence of CMV infection is late in the first month and early in the second month after transplantationn. CMV syndromes include fever and neutropenia, hepatitis, pneumonitis, gut ulceration, and disseminated infection. Other significant problems are Candida intraabdominal infection, Herpes simplex mucocutaneous infection or hepatitis, adenovirus hepatitis, and Pneumocystis carinii pneumonia. Prophylaxis of infection in liver transplant recipients has not been well-studied. Several different regimens of parenteral, oral absorbable, and/or oral non-absorbable antibiotics active against bacteria and yeast have been used at various centers, but no randomized controlled trials have been conducted. Selective bowel decontamination appears to be a promising approach to the prevention of bacterial and Candida infections, while oral acyclovir may be a relatively convenient and effective agent for CMV prophylaxis. PMID:1650245

  4. Orthotopic Hind Limb Transplantation in the Mouse.

    PubMed

    Furtmüller, Georg J; Oh, Byoungchol; Grahammer, Johanna; Lin, Cheng-Hung; Sucher, Robert; Fryer, Madeline L; Raimondi, Giorgio; Lee, W P Andrew; Brandacher, Gerald

    2016-01-01

    In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and translational research in the field of transplantation medicine. A vast array of reagents is available exclusively in this setting, including mono- and polyclonal antibodies for both diagnostic and interventional applications. In addition, a vast number of genotyped, inbred, transgenic, and knock out strains allow detailed investigation of the individual contributions of humoral and cellular components to the complex interplay of an immune response and make the mouse the gold standard for immunological research. Vascularized Composite Allotransplantation (VCA) delineates a novel field of transplantation using allografts to replace "like with like" in patients suffering traumatic or congenital tissue loss. This surgical methodological protocol shows the use of a non-suture cuff technique for super-microvascular anastomosis in an orthotopic mouse hind limb transplantation model. The model specifically allows for comparison between established paradigms in solid organ transplantation with a novel form of transplants consisting of various different tissue components. Uniquely, this model allows for the transplantation of a viable vascularized bone marrow compartment and niche that have the potential to exert a beneficial effect on the balance of immune acceptance and rejection. This technique provides a tool to investigate alloantigen recognition and allograft rejection and acceptance, as well as enables the pursuit of functional nerve regeneration studies to further advance this novel field of transplantation. PMID:26967527

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

    PubMed

    Neumann, P A; Mehdorn, A S; Puehse, G; Senninger, N; Rijcken, E

    2016-04-01

    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. Comparison of postoperative acute kidney injury between ileal conduit and neobladder urinary diversions after radical cystectomy: A propensity score matching analysis.

    PubMed

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

    2016-09-01

    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. PMID:27603401

  7. Orthotopic Injection of Pancreatic Cancer Cells.

    PubMed

    Aiello, Nicole M; Rhim, Andrew D; Stanger, Ben Z

    2016-01-01

    Pancreatic ductal adenocarcinoma is an aggressive disease with a 5-yr survival rate of only 5%. The location of the pancreas in the abdomen, where it is obscured by other organs, makes it a difficult tissue to study and manipulate. This protocol describes in detail how to orthotopically inject cancer cells into the pancreas in mice. This technique is particularly useful when the cells must be manipulated in ways that cannot be modeled genetically. PMID:26729902

  8. Surgical techniques of orthotopic rat liver transplantation.

    PubMed

    Spiegel, H U; Palmes, D

    1998-01-01

    Liver transplantation in rats is frequently used as a transplantation model. Although liver transplantation in larger laboratory animals such as dogs and pigs is technically easier, the rat has become the most important subject for experimental liver transplantation because of the availability of genetically defined animals. Numerous surgical techniques have been developed that permit the investigator to carry out studies with high clinical relevance. In this article the principal models of orthotopic rat liver transplantation and their technical modifications of vessel anastomoses, rearterialization, and bile duct reconstruction techniques are reviewed. More than 20 transplantation models are described in detail and demonstrated with clear illustrations. Finally, the advantages and uses of all the surgical procedures (e.g., suture and cuff anastomoses, bile duct anastomoses, and rearterialization techniques), specific problems, and survival criteria are discussed and the experiences of investigators who applied these techniques are analyzed. In conclusion, an overview and critical evaluation of all surgical techniques of orthotopic rat liver transplantation are given, together with instructions for learning these techniques. PMID:9700616

  9. Complications of Radical Cystectomy and Orthotopic Reconstruction

    PubMed Central

    Tan, Wei Shen; Lamb, Benjamin W.; Kelly, John D.

    2015-01-01

    Radical cystectomy and orthotopic reconstruction significant morbidity and mortality despite advances in minimal invasive and robotic technology. In this review, we will discuss early and late complications, as well as describe efforts to minimize morbidity and mortality, with a focus on ileal orthotopic bladder substitute (OBS). We summarise efforts to minimize morbidity and mortality including enhanced recovery as well as early and late complications seen after radical cystectomy and OBS. Centralisation of complex cancer services in the UK has led to a fall in mortality and high volume institutions have a significantly lower rate of 30-day mortality compared to low volume institutions. Enhanced recovery pathways have resulted in shorter length of hospital stay and potentially a reduction in morbidity. Early complications of radical cystectomy occur as a direct result of the surgery itself while late complications, which can occur even after 10 years after surgery, are due to urinary diversion. OBS represents the ideal urinary diversion for patients without contraindications. However, all patients with OBS should have regular long term follow-up for oncological surveillance and to identify complications should they arise. PMID:26697063

  10. Regeneration and Experimental Orthotopic Transplantation of a Bioengineered Kidney

    PubMed Central

    Song, Jeremy J; Guyette, Jacques; Gilpin, Sarah; Gonzalez, Gabriel; Vacanti, Joseph P; Ott, Harald C

    2013-01-01

    Over 100,000 individuals in the United States currently await kidney transplantation, while 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney’s architecture and function, and permit perfusion, filtration, secretion, absorption, and drainage of urine. We decellularized rat, porcine, and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells, then perfused these cell-seeded constructs in a whole organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused via their intrinsic vascular bed. When transplanted in orthotopic position in rat, the grafts were perfused by the recipient’s circulation, and produced urine via the ureteral conduit in vivo. PMID:23584091

  11. Scedosporium apiosermum infection of the "Native" valve: Fungal endocarditis in an orthotopic heart transplant recipient.

    PubMed

    Clement, Meredith E; Maziarz, Eileen K; Schroder, Jacob N; Patel, Chetan B; Perfect, John R

    2015-09-01

    Scedosporium apiospermum is an increasingly appreciated pathogen in immunosuppressed patients. We present a case of S. apiospermum endocarditis in a 70-year-old male who had undergone orthotopic heart transplant. Echocardiogram demonstrated a 1.4 cm tricuspid valve vegetation. He underwent valve replacement, complicated by fatal massive post-operative haemorrhage. Valve cultures grew S. apiospermum. To our knowledge, our case is the first reported instance of endocarditis caused by S. apiospermum in a recipient of a cardiac transplant. PMID:26288748

  12. Aortic Balloon Valvuloplasty Prior to Orthotopic Liver Transplantation: A Novel Approach to Aortic Stenosis and End-Stage Liver Disease

    PubMed Central

    Coverstone, Edward; Korenblat, Kevin; Crippin, Jeffrey S.; Chapman, William C.; Kates, Andrew M.; Zajarias, Alan

    2014-01-01

    The combination of severe aortic stenosis and end-stage liver disease increases the morbidity and mortality of surgical aortic valve replacement or orthotopic liver transplantation resulting in a prohibitive operative risk. We propose a staged approach of balloon aortic valvuloplasty prior to orthotopic liver transplantation as a bridge to definitive aortic valve replacement. Between 2010 and 2012, four patients with severe aortic stenosis and end-stage liver disease underwent staged balloon aortic valvuloplasty followed by orthotopic liver transplantation. All patients had been deemed to be inappropriate candidates for liver transplantation or aortic valve surgery due to their comorbidity. One patient died of complications from a perivalvular abscess. Three patients went on to successful graft implantation and function and surgical recovery. Two of the three patients proceeded to definitive surgical aortic valve replacement with the remainder currently undergoing evaluation. In this case series, we present a novel approach of balloon aortic valvuloplasty prior to liver transplantation as a potential bridge to definitive treatment of severe aortic stenosis in the end-stage liver patient. PMID:25431682

  13. 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. PMID:20013242

  14. Intraoperative blood loss in orthotopic liver transplantation: The predictive factors

    PubMed Central

    Pandey, Chandra Kant; Singh, Anshuman; Kajal, Kamal; Dhankhar, Mandeep; Tandon, Manish; Pandey, Vijay Kant; Karna, Sunaina Tejpal

    2015-01-01

    Liver transplantation has been associated with massive blood loss and considerable transfusion requirements. Bleeding in orthotopic liver transplantation is multifactorial. Technical difficulties inherent to this complex surgical procedure and pre operative derangements of the primary and secondary coagulation system are thought to be the principal causes of perioperative hemorrhage. Intraoperative practices such as massive fluid resuscitation and resulting hypothermia and hypocalcemia secondary to citrate toxicity further aggravate the preexisting coagulopathy and worsen the perioperative bleeding. Excessive blood loss and transfusion during orthotopic liver transplant are correlated with diminished graft survival and increased septic episodes and prolonged ICU stay. With improvements in surgical skills, anesthetic technique, graft preservation, use of intraoperative cell savers and overall perioperative management, orthotopic liver transplant is now associated with decreased intra operative blood losses. The purpose of this review is to discuss the risk factors predictive of increased intra operative bleeding in patients undergoing orthotopic liver transplant. PMID:26131330

  15. A Novel Orthotopic Mouse Model of Human Anaplastic Thyroid Carcinoma

    PubMed Central

    Nucera, Carmelo; Nehs, Matthew A.; Mekel, Michal; Zhang, Xuefeng; Hodin, Richard; Lawler, Jack; Nose, Vânia

    2009-01-01

    Background Orthotopic mouse models of human cancer represent an important in vivo tool for drug testing and validation. Most of the human thyroid carcinoma cell lines used in orthotopic or subcutaneous models are likely of melanoma and colon cancer. Here, we report and characterize a novel orthotopic model of human thyroid carcinoma using a unique thyroid cancer cell line. Methods We used the cell line 8505c, originated from a thyroid tumor histologically characterized by anaplastic carcinoma cell features. We injected 8505c cells engineered using a green fluorescent protein–positive lentiviral vector orthotopically into the thyroid of severe combined immunodeficient mice. Results Orthotopic implantation with the 8505c cells produced thyroid tumors after 5 weeks, showing large neck masses, with histopathologic features of a high-grade neoplasm (anaplasia, necrosis, high mitotic and proliferative indexes, p53 positivity, extrathyroidal invasion, lymph node and distant metastases) and immunoprofile of follicular thyroid cell origin with positivity for thyroid transcription factor-1 and PAX8, and for cytokeratins. Conclusions Here we describe a novel orthotopic thyroid carcinoma model using 8505c cells. This model can prove to be a reliable and useful tool to investigate in vivo biological mechanisms determining thyroid cancer aggressiveness, and to test novel therapeutics for the treatment of refractory or advanced thyroid cancers. PMID:19772429

  16. 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

  17. Ankle replacement

    MedlinePlus

    Ankle arthroplasty - total; Total ankle arthroplasty; Endoprosthetic ankle replacement; Ankle surgery ... Ankle replacement surgery is most often done while you are under general anesthesia. This means you will ...

  18. 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

  19. 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

  20. Scedosporium apiosermum infection of the “Native” valve: Fungal endocarditis in an orthotopic heart transplant recipient

    PubMed Central

    Clement, Meredith E.; Maziarz, Eileen K.; Schroder, Jacob N.; Patel, Chetan B.; Perfect, John R.

    2015-01-01

    Scedosporium apiospermum is an increasingly appreciated pathogen in immunosuppressed patients. We present a case of S. apiospermum endocarditis in a 70-year-old male who had undergone orthotopic heart transplant. Echocardiogram demonstrated a 1.4 cm tricuspid valve vegetation. He underwent valve replacement, complicated by fatal massive post-operative haemorrhage. Valve cultures grew S. apiospermum. To our knowledge, our case is the first reported instance of endocarditis caused by S. apiospermum in a recipient of a cardiac transplant. PMID:26288748

  1. 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 ...

  2. Hip Replacement

    MedlinePlus

    ... surgeon removes damaged cartilage and bone from your hip joint and replaces them with new, man-made parts. A hip replacement can Relieve pain Help your hip joint work better Improve walking and other movements The ...

  3. 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 ( ...

  4. Knee Replacement

    MedlinePlus

    ... doctor may recommend it if you have knee pain and medicine and other treatments are not helping you anymore. When you have a total knee replacement, the surgeon removes damaged cartilage and bone ...

  5. Outcome of orthotopic liver transplantation in patients with haemophilia

    PubMed Central

    Gordon, F; Mistry, P; Sabin, C; Lee, C

    1998-01-01

    Background—Many patients with haemophilia have developed cirrhosis or hepatocellular carcinoma due to transfusion acquired chronic viral hepatitis. 
Aims—To assess the long term outcome of all haemophilic patients reported to have undergone orthotopic liver transplantation. 
Methods—Transplant centres of patients identified by medical database search were contacted and survival data assessed by Kaplan-Meier analysis. 
Results—Twenty six haemophilic men (median age 46 years, range 5-63 years) underwent orthotopic liver transplantation in 16centres between 1982 and 1996. Indications for transplantation were hepatitis C cirrhosis (69%), hepatitis B with or without C cirrhosis (15%), viral hepatitis related hepatocellular carcinoma (12%), and biliary atresia (4%). Six patients (23%) were infected with human immunodeficiency virus (HIV). Postoperatively, the median time to normal clotting factor levels was 24 hours (range 0-48 hours) and exogenous clotting factors were stopped at a median of 24 hours (range 0-480 hours). Four patients (15%) had bleeding complications. The one and three year survival of HIV positive recipients (67% and 23%) was significantly poorer (p=0.0003) than that of HIV negative recipients (90% and 83%). Coagulopathy was cured in all patients surviving more than 12 days post-transplant. Six of the 20 patients (30%) with hepatitis C cirrhosis pretransplant had evidence of disease recurrence at a mean of nine months post-transplant. 
Conclusions—Hepatitis C cirrhosis is the most common indication for orthotopic liver transplantation in patients with haemophilia. Transplantation results in long term cure of haemophilia but may be complicated by the effects of HIV infection or recurrent viral hepatitis. 

 Keywords: liver transplantation; haemophilia; hepatitis C; cirrhosis; HIV PMID:9659174

  6. Orthotopic non-metastatic and metastatic oral cancer mouse models.

    PubMed

    Bais, Manish V; Kukuruzinska, Maria; Trackman, Philip C

    2015-05-01

    Oral cancer is characterized by high morbidity and mortality with a predisposition to metastasize to different tissues, including lung, liver, and bone. Despite progress in the understanding of mutational profiles and deregulated pathways in oral cancer, patient survival has not significantly improved over the past decades. Therefore, there is a need to establish in vivo models that recapitulate human oral cancer metastasis to evaluate therapeutic potential of novel drugs. Here we report orthotopic tongue cancer nude mouse models to study oral cancer growth and metastasis using human metastatic (UMSCC2) and non-metastatic (CAL27) cell lines, respectively. Transduction of these cell lines with lentivirus expressing red fluorescent protein (DsRed) followed by injection into tongues of immunodeficient mice generated orthotopic tongue tumors that could be monitored for growth and metastasis by fluorescence measurement with an in vivo Imaging System (IVIS 200). The growth rates of CAL27-DsRed induced tumors were higher than UMSCC2-DsRed tumors after day 15, while UMSCC2-DsRed tumors revealed metastasis beginning on day 21. Importantly, UMSCC2 tumors metastasized to a number of tissues including the submandibular gland, lung, kidney, liver, and bone. Further, immunohistochemical analyses of tongue tumors induced by CAL27 and UMSCC2 cells revealed elevated expression of components of protumorigenic pathways deregulated in human cancers, including Cyclin D1, PCNA, Ki-67, LSD1, LOXL2, MT-MMP1, DPAGT1, E-cadherin, OCT4A, and H3K4me1/2. These orthotopic mouse models are likely to be useful tools for gaining insights into the activity and mechanisms of novel oral cancer drug candidates. PMID:25682387

  7. Multimodal Imaging of Orthotopic Mouse Model of Endometrial Carcinoma

    PubMed Central

    Haldorsen, Ingfrid S.; Brekke, Njål; Kopperud, Reidun; Visser, Nicole C.; Rygh, Cecilie B.; Pavlin, Tina; Salvesen, Helga B.; McCormack, Emmet; Krakstad, Camilla

    2015-01-01

    Background Orthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics in vivo, with potential relevance for monitoring response to therapy. Methods After orthotopic injection with luc-expressing endometrial cancer cells, eleven mice developed disease detected by weekly bioluminescence imaging (BLI). In parallel the same mice underwent positron emission tomography–computed tomography (PET-CT) and magnetic resonance imaging (MRI) employing 18F-fluorodeoxyglocose (18F-FDG) or 18F- fluorothymidine (18F-FLT) and contrast reagent, respectively. The mice were sacrificed when moribund, and post-mortem examination included macroscopic and microscopic examination for validation of growth of primary uterine tumours and metastases. PET-CT was also performed on a patient derived model (PDX) generated from a patient with grade 3 endometrioid endometrial cancer. Results Increased BLI signal during tumour growth was accompanied by increasing metabolic tumour volume (MTV) and increasing MTV x mean standard uptake value of the tumour (SUVmean) in 18F-FDG and 18F-FLT PET-CT, and MRI conspicuously depicted the uterine tumour. At necropsy 82% (9/11) of the mice developed metastases detected by the applied imaging methods. 18F-FDG PET proved to be a good imaging method for detection of patient derived tumour tissue. Conclusions We demonstrate that all imaging modalities enable monitoring of tumour growth and metastatic spread in an orthotopic mouse model of endometrial carcinoma. Both PET tracers, 18F-FDG and 18F-FLT, appear to be equally feasible for detecting tumour development and represent, together with MRI, promising imaging tools for monitoring of patient-derived xenograft (PDX) cancer models. PMID:26252891

  8. 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. PMID:27413274

  9. Ectopic goitrous submandibular thyroid with goitrous orthotopic thyroid gland

    PubMed Central

    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. PMID:27413274

  10. 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. PMID:26722664

  11. 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.

  12. 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

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

    PubMed Central

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

    2015-01-01

    ABSTRACT 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. PMID:26426173

  14. A Novel Bioluminescence Orthotopic Mouse Model for Advanced Lung Cancer

    PubMed Central

    Li, Bo; Torossian, Artour; Li, Wenyan; Schleicher, Stephen; Niu, Kathy; Giacalone, Nicholas J.; Kim, Sung June; Chen, Heidi; Gonzalez, Adriana; Moretti, Luigi; Lu, Bo

    2011-01-01

    Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model would allow easy monitoring of response to therapeutic interventions, tumors were treated with 30 mg/kg Paclitaxel or were irradiated with 5 fractions of 2 Gy, and tumor burden was monitored using bioluminescence imaging. Evidence of radiation-induced lung injury was assessed using immunohistochemical staining for phospho-Smad2/3 and cleaved caspase-3. We found that tumor implantation recapitulated advanced human lung cancer as evidenced by tumor establishment and proliferation within the mediastinum. The tumor responded to Paclitaxel or radiation as shown by decreased tumor bioluminescence and improved overall survival. Immunohistochemistry revealed increased phospho-Smad2/3 and cleaved caspase-3 in irradiated lungs, consistent with radiation-induced lung injury. This orthotopic lung cancer model may help provide a method to assess therapeutic interventions in a preclinical setting that recapitulates locally advanced lung cancer. PMID:21663394

  15. Development and characterization of a human orthotopic neuroblastoma xenograft

    PubMed Central

    Stewart, Elizabeth; Shelat, Anang; Bradley, Cori; Chen, Xiang; Federico, Sara; Thiagarajan, Suresh; Shirinifard, Abbas; Bahrami, Armita; Pappo, Alberto; Qu, Chunxu; Finkelstein, David; Sablauer, Andras; Dyer, Michael A.

    2016-01-01

    Neuroblastoma is a pediatric cancer of the developing sympathoadrenal lineage. The tumors are known to develop from the adrenal gland or paraspinal ganglia and have molecular and cellular features of sympathetic neurons such as dense core vesicles and catecholamine production. Here we present the detailed molecular, cellular, genetic and epigenetic characterization of an orthotopic xenograft derived from a high-risk stage 4 neuroblastoma patient. Overall, the xenografted tumor retained the high risk features of the primary tumor and showed aggressive growth and metastasis in the mouse. Also, the genome was preserved with no additional copy number variations, structural variations or aneuploidy. There were 13 missense mutations identified in the xenograft that were not present in the patient’s primary tumor and there were no new nonsense mutations. None of the missense mutations acquired in the xenograft were in known cancer genes. We also demonstrate the feasibility of using the orthotopic neuroblastoma xenograft to test standard of care chemotherapy and molecular targeted therapeutics. Finally, we optimized a new approach to produce primary cultures of the neuroblastoma xenografts for high-throughput drug screening which can be used to test new combinations of therapeutic agents for neuroblastoma. PMID:25863122

  16. Shoulder replacement - discharge

    MedlinePlus

    Total shoulder arthroplasty - discharge; Endoprosthetic shoulder replacement - discharge; Partial shoulder replacement - discharge; Partial shoulder arthroplasty - discharge; Replacement - shoulder - discharge; ...

  17. 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

  18. 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

  19. Establishment of reproducible osteosarcoma rat model using orthotopic implantation technique.

    PubMed

    Yu, Zhe; Sun, Honghui; Fan, Qingyu; Long, Hua; Yang, Tongtao; Ma, Bao'an

    2009-05-01

    In experimental musculoskeletal oncology, there remains a need for animal models that can be used to assess the efficacy of new and innovative treatment methodologies for bone tumors. Rat plays a very important role in the bone field especially in the evaluation of metabolic bone diseases. The objective of this study was to develop a rat osteosarcoma model for evaluation of new surgical and molecular methods of treatment for extremity sarcoma. One hundred male SD rats weighing 125.45+/-8.19 g were divided into 5 groups and anesthetized intraperitoneally with 10% chloral hydrate. Orthotopic implantation models of rat osteosarcoma were performed by injecting directly into the SD rat femur with a needle for inoculation with SD tumor cells. In the first step of the experiment, 2x10(5) to 1x10(6) UMR106 cells in 50 microl were injected intraosseously into median or distal part of the femoral shaft and the tumor take rate was determined. The second stage consisted of determining tumor volume, correlating findings from ultrasound with findings from necropsia and determining time of survival. In the third stage, the orthotopically implanted tumors and lung nodules were resected entirely, sectioned, and then counter stained with hematoxylin and eosin for histopathologic evaluation. The tumor take rate was 100% for implants with 8x10(5) tumor cells or more, which was much less than the amount required for subcutaneous implantation, with a high lung metastasis rate of 93.0%. Ultrasound and necropsia findings matched closely (r=0.942; p<0.01), which demonstrated that Doppler ultrasonography is a convenient and reliable technique for measuring cancer at any stage. Tumor growth curve showed that orthotopically implanted tumors expanded vigorously with time-lapse, especially in the first 3 weeks. The median time of survival was 38 days and surgical mortality was 0%. The UMR106 cell line has strong carcinogenic capability and high lung metastasis frequency. The present rat

  20. Molecular replacement.

    PubMed

    Toth, Eric A

    2007-01-01

    As more protein structures are solved, the likelihood that current structural investigations will involve proteins for which there exists no homologous structure continually decreases. The extraction of phase information from diffraction experiments is one of several great barriers that crystallographers must overcome on the path to structure solution. One means to overcome this obstacle, the technique of molecular replacement, uses the structural similarity between proteins with similar sequences to give a good first estimate of the phases for the diffraction data of the protein of interest. The programs that execute this technique currently come in many flavors, from traditional Patterson-based methods, to stochastic searches in greater than three dimensions, to maximum likelihood-enhanced molecular replacement, each possessing unique advantages that can shake loose a recalcitrant solution. As crystallographers aim to solve larger macromolecular complexes that more faithfully depict the actors in cellular events, having existing phase information for parts of those biological machines will reinforce the technological advancements in data collection and structure solution that have already produced mammoth structures like the ribosome, yielding an ever-clearer picture of the inner workings of biology. PMID:17172763

  1. Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer

    PubMed Central

    Rajput, Ashwani; Agarwal, Ekta; Leiphrakpam, Premila; Brattain, Michael G.

    2013-01-01

    Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient's specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.

  2. Regeneration and orthotopic transplantation of a bioartificial lung.

    PubMed

    Ott, Harald C; Clippinger, Ben; Conrad, Claudius; Schuetz, Christian; Pomerantseva, Irina; Ikonomou, Laertis; Kotton, Darrell; Vacanti, Joseph P

    2010-08-01

    About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation. PMID:20628374

  3. A New Rat Model for Orthotopic Abdominal Wall Allotransplantation

    PubMed Central

    Lao, William W.; Wang, Yen-Ling; Ramirez, Alejandro E.; Cheng, Hui-Yun

    2014-01-01

    Background: Abdominal wall, one of the most commonly transplanted composite tissues, is less researched and lacking animal models. Its clinical necessities were emphasized in multiple case series to reconstruct large abdominal defects. Previous animal models have only studied components of the abdominal wall transplant. We describe findings from a new model that more likely reflect clinical transplantation. Methods: Full-thickness hemiabdominal wall flap was procured from Brown Norway (BN) rats and transplanted to an orthotopic defect on Lewis rats. Three groups were studied: group 1: Lewis to Lewis syngeneic; group 2: BN to Lewis control; and group 3: BN to Lewis with postoperative cyclosporine. Vascular imaging and cross vessel section were performed along with full-thickness abdominal wall. Immune cell profiling with flow cytometry at different time points was studied in all groups. Results: Syngeneic group had no rejection. Control group consistently showed rejection around postoperative day 6. With cyclosporine treatment, however, transplant and recipient tissue integration was observed. Flow cytometry revealed that innate immunity is responsible for the initial inflammatory events following abdominal wall engraftment. Adaptive immunity cells, specifically interferon-γ-producing T helper (Th) 1 and interleukin-17-producing Th17 cells, dramatically and positively correlate with rejection progression of abdominal wall transplants. Conclusions: Technical, histological, and immunological aspects of a new rat model are described. These results give clues to what occurs in human abdominal wall transplantation. In addition, Th1, a proinflammatory cell, was found to be a potential biomarker for allograft rejection. PMID:25289329

  4. Hepatitis C Recurrence after Orthotopic Liver Transplantation: Mechanisms and Management

    PubMed Central

    Kakati, Bobby; Seetharam, Anil

    2014-01-01

    Chronic Hepatitis C (HCV) infection is the leading indication for orthotopic liver transplantation and recurrence is nearly universal. Chronic HCV infection is frequently established through evasion of the innate immune system. Priming of adaptive immune responses modulate the severity and rate of fibrosis progression. Those with demonstrable viremia entering the transplant period uniformly suffer recurrence post-transplant. Progression to cirrhosis is accelerated post-transplant secondary to systemic immunosuppression. In addition, a number of factors, including donor, host, and viral characteristics, influence severity and rate of fibrosis progression. Interferon-based therapy, the previous standard of care, in those with advanced cirrhosis or post-transplant has been limited by a number of issues. These include a relative lack of efficacy and poor tolerability with higher incidence of infection and anemia. Recently, approval of direct acting antivirals have ushered in a new era in HCV therapeutics and have applicability in these special populations. Their use immediately prior to or post-transplant is expected to improve both morbidity and mortality. PMID:26355427

  5. Utilization of Murine Colonoscopy for Orthotopic Implantation of Colorectal Cancer

    PubMed Central

    Zigmond, Ehud; Halpern, Zamir; Elinav, Eran; Brazowski, Eli; Jung, Steffen; Varol, Chen

    2011-01-01

    Background Colorectal-cancer (CRC) research has greatly benefited from the availability of small animal tumor models. Spontaneous and chemically-induced CRC models are widely used yet limited in their resemblance to human disease and are often prolonged, not accurately repetitive, and associated with inflammatory side effects. In-situ murine or human tumor implantation in the gastrointestinal tract of mice is extremely challenging, and limited by inter-animal variability and procedure-related complications and mortality. As a result, in frequent studies CRC is implanted in distal sites, most commonly the subcutaneous region, an approach that is greatly limited by the absence of normal gastrointestinal tumor milieu and has substantial effects on tumor development. Aims In this study we aimed to develop a well-tolerated repetitive tool to study CRC in small animals by adapting the murine colonoscopy system to serve as a platform for colonic sub-mucosal orthotopic implantation of human and murine CRC tumor cells. Results We report the establishment of a novel small-animal CRC model that is minimally invasive, rapid, well-tolerated, highly reproducible, and confers precise control of tumor number, location and growth rate. Moreover, we show that this model uniquely allows the side-by-side induction of distinct genetically manipulated tumors, enabling the mechanistic study of tumor interaction and cross-talk within the native intestinal microenvironment. Conclusions Employment of this new approach may represent a major technical advance for the in-vivo study of CRC. PMID:22174916

  6. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24651154

  8. Inorganic nanovehicle targets tumor in an orthotopic breast cancer model.

    PubMed

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

    2014-01-01

    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. PMID:24651154

  9. An Orthotopic Bladder Cancer Model for Gene Delivery Studies

    PubMed Central

    Kasman, Laura; Voelkel-Johnson, Christina

    2013-01-01

    Bladder cancer is the second most common cancer of the urogenital tract and novel therapeutic approaches that can reduce recurrence and progression are needed. The tumor microenvironment can significantly influence tumor development and therapy response. It is therefore often desirable to grow tumor cells in the organ from which they originated. This protocol describes an orthotopic model of bladder cancer, in which MB49 murine bladder carcinoma cells are instilled into the bladder via catheterization. Successful tumor cell implantation in this model requires disruption of the protective glycosaminoglycan layer, which can be accomplished by physical or chemical means. In our protocol the bladder is treated with trypsin prior to cell instillation. Catheterization of the bladder can also be used to deliver therapeutics once the tumors are established. This protocol describes the delivery of an adenoviral construct that expresses a luciferase reporter gene. While our protocol has been optimized for short-term studies and focuses on gene delivery, the methodology of mouse bladder catheterization has broad applications. PMID:24326612

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

    PubMed Central

    2013-01-01

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

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

    PubMed

    Paschall, Amy V; Liu, Kebin

    2016-01-01

    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. PMID:27584043

  12. Sequential and simultaneous revascularization in adult orthotopic piggyback liver transplantation.

    PubMed

    Polak, Wojciech G; Miyamoto, Shungo; Nemes, Balazs A; Peeters, Paul M J G; de Jong, Koert P; Porte, Robert J; Slooff, Maarten J H

    2005-08-01

    The aim of the study was to assess whether there is a difference in outcome after sequential or simultaneous revascularization during orthotopic liver transplantation (OLT) in terms of patient and graft survival, mortality, morbidity, and liver function. The study population consisted of 102 adult patients with primary full-size piggyback OLT transplanted between January 1998 and December 2001. In 71 patients (70%) the grafts were sequentially reperfused after completion of the portal vein anastomosis and subsequent arterial reconstruction was performed (sequential reperfusion [SeqR] group). In 31 patients (30%) the graft was reperfused simultaneously via the portal vein and hepatic artery (simultaneous reperfusion [SimR] group). Patient and graft survival at 1, 3, and 6 months and at 1 year did not differ between the SeqR group and the SimR group. The red blood cell (RBC) requirements were significantly higher in the SimR group (5.5 units; range 0-20) in comparison to the SeqR group (2 units; range 0-19) (P = 0.02). Apart from a higher number of biliary anastomotic complications and abdominal bleeding complications in the SimR group in comparison to the SeqR group (13% vs. 2% and 19% vs. 6%, respectively; P = 0.06), morbidity was not different between the groups. No differences between the groups were observed regarding the incidence of primary nonfunction (PNF), intensive care unit stay, and acute rejection. This was also true for the severity of rejections. Postoperative recuperation of liver function was not different between the groups. In conclusion, no advantage of either of the 2 reperfusion protocols could be observed in this analysis, especially with respect to the incidence of ischemic type biliary lesions (ITBL). PMID:16035059

  13. 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

  14. Current status of auxiliary partial orthotopic liver transplantation for acute liver failure.

    PubMed

    Rela, Mohamed; Kaliamoorthy, Ilankumaran; Reddy, Mettu Srinivas

    2016-09-01

    Auxiliary partial orthotopic liver transplantation (APOLT) is a technique of liver transplantation (LT) where a partial liver graft is implanted in an orthotopic position after leaving behind a part of the native liver. APOLT was previously considered technically challenging with results inferior to orthotopic liver transplantation. Results of this procedure have continued to improve with improving surgical techniques and a better understanding of the natural history of acute liver failure (ALF) and liver regeneration. The procedure is being increasingly accepted as a valid treatment option for ALF-especially in children. This article reviews the historical background to this operation, advances in the technique, and its current place in the management of ALF. Liver Transplantation 22 1265-1274 2016 AASLD. PMID:27357489

  15. Hip joint replacement

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/002975.htm Hip joint replacement To use the sharing features on this page, please enable JavaScript. Hip joint replacement is surgery to replace all or part ...

  16. Knee joint replacement

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/002974.htm Knee joint replacement To use the sharing features on this page, please enable JavaScript. Knee joint replacement is a surgery to replace a knee ...

  17. Diagnosis of rare association of orthotopic multicystic dysplasia with crossed fused renal ectopia.

    PubMed

    Tang, Linnan; Koshy, June; Spevak, Melissa R; Benson, Jane E; Bosemani, Thangamadhan

    2014-01-01

    Orthotopic multicystic dysplastic kidney with crossed fused ectopia is a rare congenital anomaly. This congenital anomaly may give an appearance of a solitary kidney morphology during the initial imaging evaluation. A solitary kidney should be carefully evaluated for the presence of duplication, horseshoe configuration, or crossed renal ectopy. Vesicoureteral reflux is a common finding associated with a multicystic dysplastic kidney. We present an infant with an orthotopic multicystic dysplastic kidney and an inferiorly placed crossed fused ectopic kidney. The presence of a complex congenital anomaly may warrant further evaluation with cross-sectional imaging to depict the anatomy and structure. PMID:24839577

  18. Diagnosis of Rare Association of Orthotopic Multicystic Dysplasia with Crossed Fused Renal Ectopia

    PubMed Central

    Tang, Linnan; Koshy, June; Spevak, Melissa R.; Benson, Jane E.; Bosemani, Thangamadhan

    2014-01-01

    Orthotopic multicystic dysplastic kidney with crossed fused ectopia is a rare congenital anomaly. This congenital anomaly may give an appearance of a solitary kidney morphology during the initial imaging evaluation. A solitary kidney should be carefully evaluated for the presence of duplication, horseshoe configuration, or crossed renal ectopy. Vesicoureteral reflux is a common finding associated with a multicystic dysplastic kidney. We present an infant with an orthotopic multicystic dysplastic kidney and an inferiorly placed crossed fused ectopic kidney. The presence of a complex congenital anomaly may warrant further evaluation with cross-sectional imaging to depict the anatomy and structure. PMID:24839577

  19. Severe obstruction of the left main coronary artery by mycotic aortic psuedoaneurysm following orthotopic heart transplantation.

    PubMed

    Kamineni, Raghunandan; Lui, Charles Y; Copeland, Jack G

    2004-04-01

    Mycotic aneurysm of the ascending aorta is a rare complication following orthotopic heart transplantation. This article describes a case of mycotic pseudoaneurysm caused by Candida albicans that developed shortly after orthotopic heart transplantation. The pseudoaneurysm compressed the left main coronary artery, which led to the development of congestive heart failure symptoms mimicking sub-acute transplant rejection. The heart failure signs and symptoms resolved completely with resection of the aneurysm. This case reiterates that early diagnosis and complete resection of the aneurysm is associated with good prognosis. PMID:15063413

  20. A case report of a completely vanished liver graft after auxiliary partial orthotopic liver transplantation

    PubMed Central

    Teomete, U; Dandin, O; Tekin, A; Sabuncuoglu, M Z; Chapman, J

    2015-01-01

    Background Auxiliary partial orthotopic liver transplantation is an alternative technique for the treatment of patients with fulminant hepatic failure and metabolic liver disease. It provides temporary support of liver function until sufficient regeneration of the native liver. Pediatric patients have a long life expectancy and are best candidates to benefit from the interruption of antirejection treatment. Description of case A 4-year-old boy underwent auxiliary partial orthotopic liver transplantation for fulminant hepatic failure using a cadaveric left lateral segment of liver. One year after auxiliary partial orthotopic liver transplantation, the patient’s native liver was determined to be completely normal and he was doing well. The patient was then gradually weaned from the immunosuppression over the course of one year. The graft was undetectable on follow-up computerized tomography performed before complete cessation of immunosuppression, leading to the diagnosis of “vanishing graft syndrome”. Conclusion Graft atrophy commonly occurs after auxiliary partial orthotopic liver transplantation due to cessation of antirejection therapy. But to our knowledge, complete graft disappearance is a rare occurrence reported in the English literature. Timing for withdrawal of the immunosuppression is an important decision to be made in this technique. Hippokratia 2015; 19 (3): 274-277.

  1. 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. PMID:27146063

  2. Elbow replacement - discharge

    MedlinePlus

    Total elbow arthroplasty - discharge; Endoprosthetic elbow replacement - discharge ... You had surgery to replace your elbow joint with artificial joint parts (prosthetics). The surgeon made a cut (incision) in the back of your upper or lower arm and ...

  3. Partial knee replacement - slideshow

    MedlinePlus

    ... page: //medlineplus.gov/ency/presentations/100225.htm Partial knee replacement - series To use the sharing features on ... A.M. Editorial team. Related MedlinePlus Health Topics Knee Replacement A.D.A.M., Inc. is accredited ...

  4. Nicotine replacement therapy

    MedlinePlus

    ... If wearing the patch at night causes odd dreams, try sleeping without the patch. People who smoke ... cessation - nicotine replacement; Tobacco - nicotine replacement therapy References American Cancer Society. Guide to quitting smoking. Last revised ...

  5. Partial knee replacement

    MedlinePlus

    Most people recover quickly and have much less pain than they did before surgery. People who have a partial knee replacement recover faster than those who have a total knee replacement. Many people are able to walk ...

  6. Transarterial Administration of Oncolytic Viruses for Locoregional Therapy of Orthotopic HCC in Rats.

    PubMed

    Altomonte, Jennifer; Muñoz-Álvarez, Kim A; Shinozaki, Katsunori; Baumgartner, Christine; Kaissis, Georgios; Braren, Rickmer; Ebert, Oliver

    2016-01-01

    Hepatocellular carcinoma (HCC) is a disease with limited treatment options and poor prognosis. In recent years, oncolytic virotherapies have proven themselves to be potentially powerful tools to fight malignancy. Due to the unique dual blood supply in the liver, it is possible to apply therapies locally to orthotopic liver tumors, which are predominantly fed by arterial blood flow. We have previously demonstrated that hepatic arterial delivery of oncolytic viruses results in safe and efficient transduction efficiency of multifocal HCC lesions, resulting in significant prolongation of survival in immune competent rats. This procedure closely mimics the application of transarterial embolization in patients, which is the standard palliative care provided to many HCC patients. The ability to administer tumor therapies through the hepatic artery in rats allows for a highly sophisticated preclinical model for evaluating novel viral vectors under development. Here we describe the detailed protocol for microdissection of the hepatic artery for infusion of oncolytic virus vectors to treat orthotopic HCC. PMID:27167921

  7. Orthotopic mouse liver transplantation to study liver biology and allograft tolerance.

    PubMed

    Yokota, Shinichiro; Ueki, Shinya; Ono, Yoshihiro; Kasahara, Naoya; Pérez-Gutiérrez, Angélica; Kimura, Shoko; Yoshida, Osamu; Murase, Noriko; Yasuda, Yoshikazu; Geller, David A; Thomson, Angus W

    2016-07-01

    Orthotopic liver transplantation in the mouse is a powerful research tool that has led to important mechanistic insights into the regulation of hepatic injury, liver immunopathology, and transplant tolerance. However, it is a technically demanding surgical procedure. Setup of the orthotopic liver transplantation model comprises three main stages: surgery on the donor mouse; back-table preparation of the liver graft; and transplant of the liver into the recipient mouse. In this protocol, we describe our procedure in stepwise detail to allow efficient completion of both the donor and recipient operations. The protocol can result in consistently high technical success rates when performed by personnel experienced in the protocol. The technique can be completed in ∼2-3 h when performed by an individual who is well practiced in performing mouse transplantation in accordance with this protocol. We have achieved a perioperative survival rate close to 100%. PMID:27254462

  8. 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. PMID:27091626

  9. Postoperative imaging findings in children with auxiliary partial orthotopic liver transplant (APOLT).

    PubMed

    Ayyala, Rama S; Martinez, Mercedes; Lobritto, Steven J; Kato, Tomoaki; Ruzal-Shapiro, Carrie

    2016-07-01

    Auxiliary partial orthotopic liver transplant (APOLT) is a treatment technique for people who have acute hepatic failure secondary to fulminant hepatic failure and might ultimately recover normal liver function. This surgical procedure is complicated, involving the placement of a liver graft while maintaining viability of the remaining native portion of the liver. This method allows the native liver to recover hepatic function, therefore eliminating the need for long-term immunosuppression, as is typically needed in post-transplant settings. Postoperative imaging in these cases can be challenging given the complex anatomy, specifically the vascular anastomosis. Therefore it is important for radiologists and clinicians to be aware of the anatomy as well as the variable imaging appearances of the liver. We review the imaging findings in children who have undergone auxiliary partial orthotopic liver transplant (APOLT). PMID:26867605

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

    PubMed

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

    2014-10-15

    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

  11. 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

  12. 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. PMID:26138695

  13. Role of hepatitis C virus in chronic liver disease occurring after orthotopic liver transplantation.

    PubMed Central

    Pastore, M; Willems, M; Cornu, C; Buts, J P; Reding, R; de Ville de Goyet, J; Rahier, J; Otte, J B; Yap, S H; Sokal, E M

    1995-01-01

    Paediatric orthotopic liver transplant recipients may develop chronic hepatitis after surgery. To investigate the role of hepatitis C virus in this pathology a cohort of 249 paediatric orthotopic liver transplant recipients was studied. Sixteen children (6.4%) were found to have chronic hepatitis C virus hepatitis after orthotopic liver transplantation. All but one of them had serum transaminase values which were persistently raised two to eight times the upper limit of normal. Thirteen were positive for both serology and serum hepatitis C virus RNA. Serum hepatitis C virus RNA detection occurred five to 33 months before hepatitis C virus antibodies. Liver tissue hepatitis C virus RNA and hepatitis C virus core antigen were detected in five. In one patient, tissue hepatitis C virus core antigen was detected when other tests for hepatitis C were negative. Two patients had positive human cytomegalovirus serum antibodies and RNA before transplantation. Although serum hepatitis C virus RNA was not detected after transplantation, serum enzyme immunosorbent assay and tissue core antigen were still detectable in both patients. In another child, serum hepatitis C virus RNA was positive and hepatitis C virus core antigen was found on a liver biopsy specimen but antihepatitis C virus antibodies were negative as well as liver hepatitis C virus RNA. No patient developed severe liver disease or cirrhosis during a follow up of up to 72 months. It is concluded that hepatitis C virus is a significant cause of morbidity after paediatric orthotopic liver transplantation. Diagnosis cannot rely on serological testing only. The patients remained stable on follow up, but longer prospective histological studies remain necessary to establish prognosis. PMID:7618905

  14. 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

  15. Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model.

    PubMed

    Weir, Chris J; Hudson, Amanda L; Peters, Lyndsay; Howell, Viive M

    2015-01-01

    The enormous upsurge of interest in immune-based treatments for cancer such as vaccines and immune checkpoint inhibitors, and increased understanding of the role of the tumor microenvironment in treatment response, collectively point to the need for immune-competent orthotopic models for pre-clinical testing of these new therapies. This paper demonstrates how to establish an orthotopic immune-competent rat model of pleural malignant mesothelioma. Monitoring disease progression in orthotopic models is confounded by the internal location of the tumors. To longitudinally monitor disease progression and its effect on circulating immune cells in this and other rat models of cancer, a single tube flow cytometry assay requiring only 25 µl whole blood is described. This provides accurate quantification of seven immune parameters: total lymphocytes, monocytes and neutrophils, as well as the T-cell subsets CD4 and CD8, B-cells and Natural Killer cells. Different subsets of these parameters are useful in different circumstances and models, with the neutrophil to lymphocyte ratio having the greatest utility for monitoring disease progression in the mesothelioma model. Analyzing circulating immune cell levels using this single tube method may also assist in monitoring the response to immune-based treatments and understanding the underlying mechanisms leading to success or failure of treatment. PMID:26485154

  16. Ion replacement electrorefining

    SciTech Connect

    Willit, J.L.; Tomczuk, Z.; Miller, W.E.; Laidler, J.J.

    1994-04-01

    We are developing a two-step electrochemical process for purifying and separating metals called ion replacement electrorefining. In each step, metal cations formed by oxidation at an electrode replace other metal cations that are reduced at another elecmae. Using this approach, we have separated or purified uranium, dysprosium, and lanthanum on a laboratory scale. This paper explains the ion replacement concept and presents results of these demonstration experiments.

  17. Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours

    PubMed Central

    Lunt, Sarah Jane; Kalliomaki, Tuula MK; Brown, Allison; Yang, Victor X; Milosevic, Michael; Hill, Richard P

    2008-01-01

    Background High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread. Methods KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically. Polyoma middle-T (MMTV-PyMT) transgenic spontaneous mammary tumours were studied either as spontaneous tumours or following orthotopic or i/m transplantation. IFP was measured in all tumours using the wick-in-needle method. Spontaneous metastasis formation in the lungs or lymph nodes was assessed in all models. An immunohistochemical analysis of tumour hypoxia, vascular density, lymphatic vascular density and proliferation was carried out in ME180 tumours grown both i/m and orthotopically. Blood flow was also assessed in the ME180 model using high-frequency micro-ultrasound functional imaging. Results Tumour IFP was heterogeneous in all the models irrespective of growth site: KHT-C i/m: 2–42 mmHg, s/c: 1–14 mmHg, ME180: i/m 5–68 mmHg, cervix 4–21 mmHg, SiHa: i/m 20–56 mmHg, cervix 2–26 mmHg, MMTV-PyMT: i/m: 13–45 mmHg, spontaneous 2–20 mmHg and transplanted 2–22 mmHg. Additionally, there was significant variation between individual tumours growing in the same mouse, and there was no correlation between donor and recipient tumour IFP values. Metastatic dissemination to the lungs or lymph nodes demonstrated no correlation with tumour IFP. Tumour hypoxia, proliferation, and lymphatic or blood vessel density also showed no relationship with tumour IFP. Speckle variance analysis of ultrasound images showed no differences in vascular perfusion between ME180 tumours grown

  18. Transcatheter neoaortic valve replacement utilizing the Melody Valve in hypoplastic left heart syndrome.

    PubMed

    Martin, Mary Hunt; Gruber, Peter J; Gray, Robert G

    2015-03-01

    Percutaneous transcatheter pulmonary valve replacement with the Melody Valve is fast becoming an important adjunct in the treatment of older children and adults with failing right ventricular outflow tract conduits. Recently, the Melody Valve has also been successfully implanted in the tricuspid, mitral, and aortic positions, typically within a failing bioprosthetic valve. We present a patient who underwent Fontan palliation for hypoplastic left heart syndrome variant and subsequently developed severe neoaortic regurgitation, which was successfully treated with a transcatheter neoaortic valve replacement. To our knowledge, this is the first successful use of the Melody Valve in the neoaortic position in a patient with single-ventricle physiology. Successful relief of neoaortic valve regurgitation using replacement with a transcatheter valve may allow avoidance of additional surgery, increase functional longevity of single-ventricle palliation, and postpone the need for orthotopic heart transplantation. PMID:24619505

  19. 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.

  20. Metastasis in an Orthotopic Murine Model of Melanoma is Independent of RAS/RAF Mutation

    PubMed Central

    Rozenberg, Gabriela I.; Monahan, Kimberly B.; Torrice, Chad; Bear, James E.; Sharpless, Norman E.

    2010-01-01

    Melanoma is the most lethal skin tumor, in large part because of a propensity for early metastasis. Good models of this most clinically relevant feature of melanoma are lacking. Here we report the development of an in vivo model of metastasis that relies on orthotopic injection of GFP-tagged lines in immunodeficient mice, serial intravital imaging of tumor progression and quantification of distant spread by 2-photon laser scanning microscopy, immunohistochemistry and real-time PCR analysis. Using this system, we report an assessment of the in vivo growth and metastatic properties of 11 well-characterized human melanoma cell lines. A subset of lines demonstrated rapid in vivo growth with invasion of host vasculature and distant seeding of viscera in this system. The ability to form metastasis in vivo did not correlate with 3D collagen invasion in vitro. Surprisingly, similar lines in terms of molecular genetic events differed markedly in their propensity to metastasize to distant organs such as brain and lung. In particular, two lines harboring B-RAF mutation and high levels of phosphorylated ERK and AKT (pERK and pAKT) were reproducibly unable to form tumors after orthotopic injection. Likewise, two previously identified RAS/RAF wild-type “epithelial-like” lines that do not have elevated pERK, pAKT or express TWIST1 mRNA still demonstrated a pronounced ability for orthotopic growth and metastatic spread. All the metastatic cell lines in this model showed increased NEDD9 expression, but NEDD9 lentiviral overexpression did not convey a metastatic phenotype on non-metastatic cells. These data suggest that melanoma metastasis is a molecularly heterogeneous process that may not require epidermal-to-mesenchymal transition or ERK activation, although both may facilitate the process. PMID:20679910

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

    PubMed

    Rao, Quan; You, Abin; Guo, Zhenglong; 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 0.5 cm (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

  2. 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. PMID:26647736

  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. Orthotopic non-metastatic and metastatic oral cancer mouse models ⋆

    PubMed Central

    Bais, Manish V.; Kukuruzinska, Maria; Trackman, Philip C.

    2015-01-01

    SUMMARY Oral cancer is characterized by high morbidity and mortality with a predisposition to metastasize to different tissues, including lung, liver, and bone. Despite progress in the understanding of mutational profiles and deregulated pathways in oral cancer, patient survival has not significantly improved over the past decades. Therefore, there is a need to establish in vivo models that recapitulate human oral cancer metastasis to evaluate therapeutic potential of novel drugs. Here we report orthotopic tongue cancer nude mouse models to study oral cancer growth and metastasis using human metastatic (UMSCC2) and non-metastatic (CAL27) cell lines, respectively. Transduction of these cell lines with lentivirus expressing red fluorescent protein (DsRed) followed by injection into tongues of immunodeficient mice generated orthotopic tongue tumors that could be monitored for growth and metastasis by fluorescence measurement with an in vivo Imaging System (IVIS 200). The growth rates of CAL27-DsRed induced tumors were higher than UMSCC2-DsRed tumors after day 15, while UMSCC2-DsRed tumors revealed metastasis beginning on day 21. Importantly, UMSCC2 tumors metastasized to a number of tissues including the submandibular gland, lung, kidney, liver, and bone. Further, immunohistochemical analyses of tongue tumors induced by CAL27 and UMSCC2 cells revealed elevated expression of components of protumorigenic pathways deregulated in human cancers, including Cyclin D1, PCNA, Ki-67, LSD1, LOXL2, MT-MMP1, DPAGT1, E-cadherin, OCT4A, and H3K4me1/2. These orthotopic mouse models are likely to be useful tools for gaining insights into the activity and mechanisms of novel oral cancer drug candidates. PMID:25682387

  5. 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. PMID:22604887

  6. Creation of a murine orthotopic hepatoma model with intra-abdominal metastasis

    PubMed Central

    Harris, Jamie; Kajdacsy-Balla, Andre; Chiu, Bill

    2016-01-01

    Aim: To create an orthotopic hepatoma model with local metastasis monitored with ultrasound could be created as a platform for testing new treatments. Background: Hepatoma accounts for 25% of liver tumors in children with poor overall survival. Intraabdominal metastasis are present in 35% of patients at time of diagnosis. We hypothesized that an orthotopic tumor model with local metastasis could be created as a platform for testing treatment modalities and could be monitored with ultrasound. Patients and methods: One million human hepatoma cells (Hep3B) were injected into the left lobe of the liver of immunocompromised mice. Tumor volume was monitored with high frequency-ultrasound until it reached 1,000mm3. At that time animals were sacrificed and examined for gross metastatic disease. Tumor sections were analyzed with hematoxylin and eosin (H&E) staining. Results: Tumor formed in 8/15 mice. The tumor was detected as small as 19.59mm3 on ultrasound. Of the forming tumors, tumor size was 145±177.93mm3 at 60 days post-injection, 665±650.39mm3 at 67 days, and reached >1000mm3 by 76.6±9.9 days. At necropsy, four mice (50%) had tumor only within the liver, four (50%) had additional tumors in omentum, pelvis and peritoneum. H&E showed tumor within the normal liver parenchyma, with multiple mitotic figures, small areas of necrosis, and hemorrhage within the tumor. Conclusion: We have successfully established an orthotopic hepatoma murine model, with a local metastatic rate of 50%. Non-invasive tumor monitoring is feasible via ultrasound. PMID:27458509

  7. 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

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

    PubMed Central

    Miller, Amy; Burson, Hannah; Söling, Ariane

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  10. Mitral valve dysfunction and repair following orthotopic heart transplantation: a case report.

    PubMed

    Wigfield, C H; Lewis, A; Parry, G; Dark, J H

    2008-06-01

    Mitral valve dysfunction after orthotopic heart transplantation may cause symptoms refractory to medical therapy. In this report, we present a patient who underwent mitral annuloplasty for severe symptomatic mitral valve insufficiency 9 years after heart transplantation, and we critically appraise the literature available for mitral valve dysfunction in this setting. Mitral valve repair, when feasible, should be considered for mitral insufficiency after transplantation to improve functional status and reduce the risk of retransplantation--this is particularly prudent in view of chronic donor shortage. PMID:18589200

  11. Auxiliary partial orthotopic liver transplant for Criggler-Najjar Syndrome: Report of 2 cases from Pakistan.

    PubMed

    Dar, Faisal Saud; Bhatti, Abu Bakar Hafeez; Hashmi, Syeda Shaheera; Zia, Haseeb; Malik, Munir Iqbal

    2016-05-01

    Auxiliary partial orthotopic liver transplant (APOLT) is a treatment option for certain liver disorders where liver structure is preserved. It includes Criggler Najjar syndrome (CNS), urea cycle defects and familial hypercholesterolaemia. Liver transplant as a treatment modality has only recently become available in Pakistan. Here we report two paediatric cases of CNS type 1 where auxiliary liver transplant was performed to correct jaundice and prevent inevitable brain damage. Both recipients and their respective living donors had successful surgery and are doing well. PMID:27183949

  12. Hip joint replacement - slideshow

    MedlinePlus

    ... this page: //medlineplus.gov/ency/presentations/100006.htm Hip joint replacement - series—Normal anatomy To use the sharing ... to slide 5 out of 5 Overview The hip joint is made up of two major parts: the ...

  13. Replacing a Missing Tooth

    MedlinePlus

    ... majority of patients with clefts will require full orthodontic treatment, especially if the cleft has passed through ... later replacement of the missing lateral incisor. During orthodontic treatment, an artificial tooth may be attached to ...

  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. Hip replacement - discharge

    MedlinePlus

    ... a hip replacement and need antibiotics before any dental work. When to Call Your Doctor Call your health care provider if you have: A sudden increase in pain Chest pain or shortness of breath Frequent urination ...

  16. Replacing Arizona's Roofs.

    ERIC Educational Resources Information Center

    Fickes, Michael

    2000-01-01

    Discusses the Arizona statewide mandate to spend $500 million to repair or replace roofs in its public school system. Data from the state's evaluation process are provided, including how the state will fund the project. (GR)

  17. Knee joint replacement

    MedlinePlus

    The results of a total knee replacement are often excellent. The operation relieves pain for most people. Most people do not need help walking after they fully recover. Most artificial knee joints last 10 ...

  18. Knee joint replacement - slideshow

    MedlinePlus

    ... page: //medlineplus.gov/ency/presentations/100088.htm Knee joint replacement - series—Normal anatomy To use the sharing ... of 4 Overview The knee is a complex joint. It contains the distal end of the femur ( ...

  19. Kidney Replacement Therapy

    MedlinePlus

    ... their function with either dialysis or a transplant. Dialysis Dialysis, the more common form of kidney-replacement ... the result of diabetes, not of hemodialysis. Peritoneal dialysis Another form of dialysis is called peritoneal dialysis. ...

  20. 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 ...

  1. 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

  2. Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.

    PubMed

    Kim, Juhyun; Won, Ranhui; Ban, Guyee; Ju, Mi Ha; Cho, Kyung Sook; Young Han, Sang; Jeong, Jin-Sook; Lee, Seong-Wook

    2015-01-01

    Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment. PMID:26189916

  3. Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation

    PubMed Central

    Kim, Juhyun; Won, Ranhui; Ban, Guyee; Ha Ju, Mi; Sook Cho, Kyung; Young Han, Sang; Jeong, Jin-Sook; Lee, Seong-Wook

    2015-01-01

    Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment. PMID:26189916

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

    PubMed Central

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

    2015-01-01

    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. PMID:26169357

  5. The long-term fate of fresh and frozen orthotopic bone allografts in genetically defined rats.

    PubMed

    Bos, G D; Goldberg, V M; Gordon, N H; Dollinger, B M; Zika, J M; Powell, A E; Heiple, K G

    1985-01-01

    Fresh and frozen orthotopic iliac crest bone grafts in rats were studied histologically for determination of the long-term effects of histocompatibility matching and the freezing process on orthotopic bone graft incorporation. Grafts exchanged between groups of inbred rats, syngeneic or differing with respect to major or minor histocompatibility loci, were studied histologically at 20, 30, 40, 50, and 150 days after bone transplantation. A numerical histologic scoring system was developed and used by three observers for evaluation of coded hematoxylin and eosin sections. All frozen graft groups had the same fate regardless of histocompatibility relations between donors and recipients, and all grafts were inferior to fresh syngeneic grafts. Both fresh allograft groups received similar scores and initially at 20 and 30 days had scores similar to those of the fresh syngeneic groups. In the later intervals, however, the fresh allografts were inferior to the fresh syngeneic grafts and similar to the frozen groups. This is consistent with an older model describing two distinct phases of osteogenesis. In the long term, frozen syngeneic and fresh and frozen allografts across major and minor histocompatibility barriers were comparable, but all were significantly inferior to fresh syngeneic bone grafts. PMID:3893828

  6. 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.

  7. 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

  8. An improved intrafemoral injection with minimized leakage as an orthotopic mouse model of osteosarcoma.

    PubMed

    Sasaki, Hiromi; Iyer, Swathi V; Sasaki, Ken; Tawfik, Ossama W; Iwakuma, Tomoo

    2015-10-01

    Osteosarcoma, the most common type of primary bone cancer, is the second highest cause of cancer-related death in pediatric patients. To understand the mechanisms behind osteosarcoma progression and to discover novel therapeutic strategies for this disease, a reliable and appropriate mouse model is essential. For this purpose, osteosarcoma cells need to be injected into the bone marrow. Previously, the intratibial and intrafemoral injection methods were reported; however, the major drawback of these methods is the potential leakage of tumor cells from the injection site during or after these procedures. To overcome this, we have established an improved method to minimize leakage in an orthotopic mouse model of osteosarcoma. By taking advantage of the anatomical benefits of the femur with less bowing and larger medullary cavity than those of the tibia, osteosarcoma cells are injected directly into the femoral cavity following reaming of its intramedullary space. To prevent potential leakage of tumor cells during and after the surgery, the injection site is sealed with bone wax. This method requires a minor surgery of approximately 15min under anesthesia. Our established orthotopic osteosarcoma model could serve as a valuable and reliable tool for examining progression of various types of bone tumors. PMID:26142221

  9. 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. PMID:27000989

  10. 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

  11. Python import replacement

    Energy Science and Technology Software Center (ESTSC)

    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.

  12. 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…

  13. 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

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

    PubMed Central

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

    2015-01-01

    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. What's new? Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease have a poor outcome. Here, the authors established neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high-risk neuroblastoma into immunodeficient mice

  15. Comparison of Survival and Osteogenic Ability of Human Mesenchymal Stem Cells in Orthotopic and Ectopic Sites in Mice.

    PubMed

    Manassero, Mathieu; Paquet, Joseph; Deschepper, Mickael; Viateau, Véronique; Retortillo, Jose; Bensidhoum, Morad; Logeart-Avramoglou, Delphine; Petite, Hervé

    2016-03-01

    Tissue constructs containing mesenchymal stem cells (MSCs) are appealing strategies for repairing large segmental bone defects, but they do not allow consistent bone healing and early cell death was identified as a cause of failure. However, little is known about cell survival in the clinical microenvironment encountered during bone healing process. Osteoconductive coral scaffold with or without luciferase-labeled human MSCs were implanted either in a critical segmental femoral bone defect stabilized by plate or subcutaneously in 44 mice. Cell survival was evaluated by serial bioluminescence imaging (BLI) and osteogenic capabilities by histology and microcomputed tomography. Comparisons between groups were performed with two-way analysis of variance test. Twenty mice were sacrificed 2 weeks after surgery for short-term evaluation and 24 mice at 10 weeks for long-term evaluation. BLI provided evidence of fast and continuous cell death: 85% decrease of the BLI signal over the first 2 weeks in both locations; in fact, less than 2% of the initial cell number was present in all constructs analyzed 4 weeks postimplantation and less than 1% of the initial cell number by 8 weeks postimplantation. By 2 weeks postimplantation, the amount of newly formed bone was self-limited and was similar to ectopic and orthotopic groups. By 10 weeks postimplantation, bone formation was significantly enhanced in the presence of MSCs in orthotopic site and the amount of newly formed bone in cell-containing constructs implanted in orthotopic locations was significantly higher than that observed in the ectopic group. Our results indicated that hMSCs promote bone formation despite early and massive cell death when loaded on coral scaffolds. Interestingly, bone formation was higher in orthotopic than ectopic site despite the same survival pattern. Ectopic implantation of cell-containing constructs is suitable to evaluate cell survival, but assessment of bone formation ability requires

  16. Surface coil localization of /sup 31/P NMR signals from orthotopic human kidney and liver

    SciTech Connect

    Jue, T.; Rothman, D.L.; Lohman, J.A.B.; Hughes, E.W.; Hanstock, C.C.; Shulman, R.G.

    1988-02-01

    By incorporating the hyperbolic secant inversion pulses with the image-selected in vivo spectroscopy localization technique and by applying a gradient-echo imaging method, the authors have selected only the /sup 31/P NMR signals from orthotopic human kidney and liver, using a single concentric /sup 1/H//sup 31/P surface coil. Corresponding to the experimental results on animal studies, the phosphocreatine signal is dramatically reduced in the localized spectra. The localization strategy also allows them to shim easily on the well-defined volume of interest and leads to high-resolution spectra that exhibit multiplet structure. The results indicate that they can obtain localized signals from deep small organs and point the way for other human metabolism studies.

  17. 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. PMID:26548537

  18. Prolonged Intraoperative Cardiac Resuscitation Complicated by Intracardiac Thrombus in a Patient Undergoing Orthotopic Liver Transplantation.

    PubMed

    Kim, Sang; DeMaria, Samuel; Cohen, Edmond; Silvay, George; Zerillo, Jeron

    2016-09-01

    We report the case of successful resuscitation after prolonged cardiac arrest during orthotopic liver transplantation. After reperfusion, the patient developed ventricular tachycardia, complicated by intracardiac clot formation and massive hemorrhage. Transesophageal echocardiography demonstrated stunned and nonfunctioning right and left ventricles, with developing intracardiac clots. Treatment with heparin, massive transfusion and prolonged cardiopulmonary resuscitation ensued for 51 minutes. Serial arterial blood gases demonstrated adequate oxygenation and ventilation during cardiopulmonary resuscitation. Cardiothoracic surgery was consulted for potential use of extracorporeal membrane oxygenation, however, the myocardial function improved and the surgery was completed without further intervention. On postoperative day 6, the patient was extubated without neurologic or cardiac impairment. The patient continues to do well 2 years posttransplant, able to perform independent daily activities of living and his previous job. This case underscores the potential for positive outcomes with profoundly prolonged, effective advanced cardiovascular life support in patients who experience postreperfusion syndrome. PMID:27233818

  19. Orthotopic Heart Transplantation and Mechanical Circulatory Support in Cancer Survivors: Challenges and Outcomes

    PubMed Central

    Ghosh, Nina; Hilton, John

    2015-01-01

    Chemotherapy-induced cardiomyopathy (CCMP) is a significant cause of morbidity and mortality. Compared to cardiomyopathy due to other causes, anthracycline-induced cardiomyopathy is associated with a worse survival. As cancer survival improves, patients with CCMP can be expected to comprise a significant proportion of patients who may require advanced therapies such as inotropic support, cardiac transplantation, or left ventricular assist device (LVAD). Distinct outcomes related to advanced therapies for end-stage heart failure in this patient population may arise due to unique demographic characteristics and comorbidities. We review recent literature regarding the characteristics of patients who have survived cancer undergoing orthotopic heart transplantation and mechanical circulatory support for end-stage heart failure. The challenges and outcomes of advanced therapies for heart failure related specifically to anthracycline-induced cardiomyopathy are emphasized. PMID:26339241

  20. Distribution of Gemcitabine Is Nearly Homogenous in Two Orthotopic Murine Models of Pancreatic Cancer.

    PubMed

    Kramer, Robin M; Russell, James; Humm, John L

    2015-09-01

    Pancreatic cancer is one of the leading causes of cancer-related death in the United States. Gemcitabine is a common treatment, but response rates are low, perhaps due in part to tumor hypoxia. We utilized (14)C-labeled gemcitabine to map distribution of the drug with respect to perfused and hypoxic regions of the tumor microenvironment in two orthotopic xenograft models of pancreatic cancer. There was only a slight reduction in gemcitabine in hypoxic areas, with ∼78% of the drug present in hypoxic compared to perfused areas. In addition, only a 4% reduction in gemcitabine was measured at >100 μm from perfused blood vessels. Thus, despite significant areas of hypoxia in these tumors, gemcitabine distribution is relatively homogenous. Ours is the first study to directly measure gemcitabine distribution within tumor tissue, demonstrating that in these models, tumor tissue does not represent a barrier to gemcitabine penetration. PMID:26203552

  1. Pharmacologic Strategies to Prevent Blood Loss and Transfusion in Orthotopic Liver Transplantation.

    PubMed

    Tischer, Sarah; Miller, James T

    2016-01-01

    Patients undergoing orthotopic liver transplantation are at risk of both life-threatening blood loss and thrombosis due to preexisting liver dysfunction and major intra- and postoperative coagulopathy. Traditional laboratory markers of hemostasis and coagulopathy are often inadequate to describe the alterations. Whole blood global viscoelastic tests, thromboelastography, and thromboelastometry may provide more complete pictures of the hematologic derangements and allow for more targeted therapy to prevent blood loss and massive transfusion. Antifibrinolytic medications such as aprotinin, tranexamic acid, and [Latin Small Letter Open E]-aminocaproic acid have been used successfully to reduce blood loss and the need for transfusion, although most published data are from small prospective trials or larger retrospective cohorts. Recombinant factor VIIa has not been shown to improve outcomes. Although transfusion needs have been associated with adverse outcomes, no studied medications for prevention of blood loss and transfusion have been associated with improved mortality or graft survival post-liver transplant. PMID:27254642

  2. 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

  3. 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. PMID:24901248

  4. SERPINI1 regulates epithelial-mesenchymal transition in an orthotopic implantation model of colorectal cancer.

    PubMed

    Matsuda, Yasufumi; Miura, Koh; Yamane, Junko; Shima, Hiroshi; Fujibuchi, Wataru; Ishida, Kazuyuki; Fujishima, Fumiyoshi; Ohnuma, Shinobu; Sasaki, Hiroyuki; Nagao, Munenori; Tanaka, Naoki; Satoh, Kennichi; Naitoh, Takeshi; Unno, Michiaki

    2016-05-01

    An increasingly accepted concept is that the progression of colorectal cancer is accompanied by epithelial-mesenchymal transition (EMT). In our study, in order to characterize the properties of EMT in 16 colorectal cancer cell lines, the cells were first orthotopically implanted into nude mice, and the tumors in vivo, as well as cells cultured in vitro, were immunostained for EMT markers. The immunostaining revealed that seven of the cells had an epithelial phenotype with a high expression of E-cadherin, whereas other cells showed opposite patterns, such as a high expression of vimentin (CX-1, COLO205, CloneA, HCT116, and SW48). Among the cells expressing vimentin, some expressed vimentin in the orthotopic tumors but not in the cultured cells (SW480, SW620, and COLO320). We evaluated these findings in combination with microarray analyses, and selected five genes: CHST11, SERPINI1, AGR2, FBP1, and FOXA1. Next, we downregulated the expression of SERPINI1 with siRNA in the cells, the results of which showed reverse-EMT changes at the protein level and in the cellular morphology. Along with immunohistochemical analyses, we confirmed the effect of the intracellular and secreted SERPINI1 protein of SW620 cells, which supported the importance of SERPINI1 in EMT. The development of therapeutic strategies targeting EMT is ongoing, including methods targeting the transforming growth factor-β signaling pathway as well as the Wnt pathway. SERPINI1 is an important regulator of EMT. Our findings help to elucidate the signaling pathways of EMT, hopefully clarifying therapeutic pathways as well. PMID:26892864

  5. Real-time Imaging of Tumor Progression in a Fluorescent Orthotopic Mouse Model of Thyroid Cancer

    PubMed Central

    TRAN CAO, HOP S.; KAUSHAL, SHARMEELA; SNYDER, CYNTHIA S.; ONGKEKO, WEG M.; HOFFMAN, ROBERT M.; BOUVET, MICHAEL

    2015-01-01

    There is a need for a clinically relevant mouse model of thyroid cancer that enables real-time, non-invasive monitoring of tumor growth, progression, and drug response over time. Human thyroid cancer cell lines NPA (papillary) and KAK-1 (anaplastic) were stably transfected to express either red or green fluorescent protein. Cancer cells were injected into the thyroid glands of 8-week-old athymic mice. The animals were imaged with whole-body fluorescence imaging weekly and sacrificed when premorbid. At necropsy, the primary tumor was resected en bloc with the respiratory system for processing and analysis. Histology was performed on fixed tissue specimens for review of morphologic findings. Both anaplastic and papillary thyroid cancer cell lines led to robust development of orthotopic fluorescent tumors in nude mice. Injection of 5×105 cancer cells was sufficient for tumor development. Tumors were visualized for both cell lines via non-invasive imaging as early as 3 weeks post-implantation and were monitored over time. Time to premorbid condition varied between mice and was associated with a primary tumor growth pattern (early local compression of the esophagus vs. late metastatic disease) rather than tumor size. At necropsy, tumor fluorescence demonstrated metastases in the lungs, lymph nodes and vessels that were not visible under white light. Thus an orthotopic mouse model of thyroid cancer has been developed that replicates the major clinical features of thyroid cancer and enables real-time, non-invasive monitoring of tumor progression. This model should permit preclinical evaluation of novel thyroid cancer therapeutics. PMID:21115887

  6. Prognostic Value of Preoperatively Obtained Clinical and Laboratory Data in Predicting Survival Following Orthotopic Liver Transplantation

    PubMed Central

    Cuervas-Mons, Valentin; Millan, Isabel; Gavaler, Judith S.; Starzl, Thomas E.; Van Thiel, David H.

    2010-01-01

    Twenty-seven clinical and laboratory data and the subsequent clinical course of 93 consecutive adult patients who underwent orthotopic liver transplantation for various chronic advanced liver diseases were analyzed retrospectively to assess the risk factors of early major bacterial infection and death after the procedure. Forty-one patients (44%) had early major bacterial infection during hospitalization for orthotopic liver transplantation. The mortality rate was 70.7% in patients with early major bacterial infection and was 7.7% in patients without early major bacterial infection (p < 0.001). Total serum bilirubin, total white blood cell count and polymorphonuclear cell count, IgG (all p < 0.05) and plasma creatinine level (p < 0.001) were higher in patients that developed early major bacterial infection than in those who did not. By step-wise discriminant analysis, the strongest risk factor for early major bacterial infection was the serum creatinine level, which achieved an accuracy of 69% for a creatinine level greater than 1.58 mg per dl. Seven variables (ascites, hepatic encephalopathy, elevated white blood and polymorphonuclear cell count, decreased helper to suppressor T cell ratio and elevated plasma creatinine and bilirubin levels) were associated with a significant increased risk for death. A step-wise discriminant analysis of these seven factors resulted in the demonstration of serum creatinine as the greatest risk factor for mortality. A preoperative serum creatinine either less than or greater than 1.72 mg per dl accurately predicts survival or death, respectively, in 79% of cases. These data suggest that the baseline preoperative serum creatinine level provides the best indication of the short-term prognosis after liver transplantation than does any other preoperatively obtained index of the patient’s status. PMID:3530947

  7. Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer.

    PubMed

    Schölch, Sebastian; García, Sebastián A; Iwata, Naoki; Niemietz, Thomas; Betzler, Alexander M; Nanduri, Lahiri K; Bork, Ulrich; Kahlert, Christoph; Thepkaysone, May-Linn; Swiersy, Anka; Büchler, Markus W; Reissfelder, Christoph; Weitz, Jürgen; Rahbari, Nuh N

    2016-05-10

    The prognosis of colorectal cancer (CRC) is closely linked to the occurrence of distant metastases, which putatively develop from circulating tumor cells (CTCs) shed into circulation by the tumor. As far more CTCs are shed than eventually metastases develop, only a small subfraction of CTCs harbor full tumorigenic potential. The aim of this study was to further characterize CRC-derived CTCs to eventually identify the clinically relevant subfraction of CTCs.We established an orthotopic mouse model of CRC which reliably develops metastases and CTCs. We were able to culture the resulting CTCs in vitro, and demonstrated their tumor-forming capacity when re-injected into mice. The CTCs were then subjected to qPCR expression profiling, revealing downregulation of epithelial and proliferation markers. Genes associated with cell-cell adhesion (claudin-7, CD166) were significantly downregulated, indicating a more metastatic phenotype of CTCs compared to bulk tumor cells derived from hepatic metastases. The stem cell markers DLG7 and BMI1 were significantly upregulated in CTC, indicating a stem cell-like phenotype and increased capacity of tumor formation and self-renewal. In concert with their in vitro and in vivo tumorigenicity, these findings indicate stem cell properties of mouse-derived CTCs.In conclusion, we developed an orthotopic mouse model of CRC recapitulating the process of CRC dissemination. CTCs derived from this model exhibit stem-cell like characteristics and are able to form colonies in vitro and tumors in vivo. Our results provide new insight into the biology of CRC-derived CTCs and may provide new therapeutic targets in the metastatic cascade of CRC. PMID:27029058

  8. Differential responses of scirrhous and well-differentiated gastric cancer cells to orthotopic fibroblasts.

    PubMed Central

    Yashiro, M.; Chung, Y. S.; Kubo, T.; Hato, F.; Sowa, M.

    1996-01-01

    Scirrhous gastric cancer cells proliferate rapidly with fibrosis, when the cancer cells invade into the submucosa of the stomach. To investigate the mechanisms responsible for the rapid proliferation, the growth interaction between gastric cancer cells and fibroblasts was examined. Human gastric cancer cell lines established from scirrhous carcinoma or well-differentiated adenocarcinoma were used. Human fibroblast cell lines were obtained from various organs. The growth interaction between gastric cancer cells and fibroblasts was examined by calculating the number of cancer cells or by measuring [3H]thymidine incorporation of cancer cells. Gastric fibroblasts specifically stimulated the growth of scirrhous gastric cancer cells, but not that of well-differentiated adenocarcinoma cells. The growth factor(s) produced from gastric fibroblasts were then partially purified and characterised. The growth-promoting factor(s) had apparent molecular weights of 10000 dalton and was sensitive both to heat and proteinase treatment. No inhibition for the factor(s) was achieved with defined anti-growth factor antibodies. In this study, differential responses of scirrhous and well-differentiated gastric cancer cells to orthotopic fibroblasts were shown. Rapid proliferation of scirrhous gastric carcinoma should be partly controlled by orthotopic fibroblasts. The growth factor(s) from gastric fibroblasts, which was distinct from various defined growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (b-FGF), transforming growth factor-alpha (TGF-alpha), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), insulin-like growth factor I (IGF-I), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGF-beta 1) may play an important role in the progression of scirrhous gastric cancer cells. PMID:8855981

  9. 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

  10. 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. PMID:26650066

  11. 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. PMID:26718447

  12. 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

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. Renal Replacement Therapy.

    PubMed

    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

  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. Thyroid hormone replacement therapy.

    PubMed

    Wiersinga, W M

    2001-01-01

    Thyroid hormone replacement has been used for more than 100 years in the treatment of hypothyroidism, and there is no doubt about its overall efficacy. Desiccated thyroid contains both thyroxine (T(4)) and triiodothyronine (T(3)); serum T(3) frequently rises to supranormal values in the absorption phase, associated with palpitations. Liothyronine (T(3)) has the same drawback and requires twice-daily administration in view of its short half-life. Synthetic levothyroxine (L-T(4)) has many advantages: in view of its long half-life, once-daily administration suffices, the occasional missing of a tablet causes no harm, and the extrathyroidal conversion of T(4) into T(3) (normally providing 80% of the daily T(3) production rate) remains fully operative, which may have some protective value during illness. Consequently, L-T(4) is nowadays preferred, and its long-term use is not associated with excess mortality. The mean T(4) dose required to normalize serum thyroid stimulating hormone (TSH) is 1.6 microg/kg per day, giving rise to serum free T(4) (fT(4)) concentrations that are slightly elevated or in the upper half of the normal reference range. The higher fT(4) values are probably due to the need to generate from T(4) the 20% of the daily T(3) production rate that otherwise is derived from the thyroid gland itself. The daily maintenance dose of T(4) varies widely between 75 and 250 microg. Assessment of the appropriate T(4) dose is by assay of TSH and fT(4), preferably in a blood sample taken before ingestion of the subsequent T(4) tablet. Dose adjustments can be necessary in pregnancy and when medications are used that are known to interfere with the absorption or metabolism of T(4). A new equilibrium is reached after approximately 6 weeks, implying that laboratory tests should not be done earlier. With a stable maintenance dose, an annual check-up usually suffices. Accumulated experience with L-T(4) replacement has identified some areas of concern. First, the

  1. 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. PMID:11913258

  2. Renal Replacement Therapy.

    PubMed

    Villa, Gianluca; Ricci, Zaccaria; Ronco, Claudio

    2015-10-01

    Renal replacement therapy (RRT) is a cornerstone in the clinical management of patients with acute kidney injury. Results from different studies agree that early renal support therapy (aimed to support the residual kidney function during early phases of organ dysfunction) may reduce mortality with respect to late RRT (aimed to substitute the complete loss of function during the advanced kidney insufficiency). Although it seems plausible that a timely initiation of RRT may be associated with improved renal and nonrenal outcomes in these patients, there is scarce evidence in literature to exactly identify the most adequate onset timing for RRT. PMID:26410148

  3. Real-Time GFP Intravital Imaging of the Differences in Cellular and Angiogenic Behavior of Subcutaneous and Orthotopic Nude-Mouse Models of Human PC-3 Prostate Cancer.

    PubMed

    Zhang, Yong; Toneri, Makoto; Ma, Huaiyu; Yang, Zhijian; Bouvet, Michael; Goto, Yusuke; Seki, Naohiko; Hoffman, Robert M

    2016-11-01

    There are two major types of mouse xenograft models of cancer: subcutaneous implantation and orthotopic implantation. Subcutaneous transplant models are widely used with both cancer cell lines and human-tumor specimens. Recently, subcutaneous models of patient tumors, termed patient-derived xenographs (PDX) have become highly popular and have acquired such names as "Avatar" and "Xenopatients." However, such s.c. models rarely metastasize and are therefore not patient-like. In contrast, orthotopic models have the capability to metastasize. If intact fragments of tumor tissue are implanted by surgical orthotopic implantation (SOI), the metastatic potential can match that of the donor patient. The present study images in real time, using green fluorescent protein (GFP) expression, the very different tumor behavior at the orthotopic and subcutaneous sites of human prostate cancer PC-3 in athymic nude mice. By day-2 after tumor implantation, the orthotopic tumor is already highly vascularized and the cancer cells have begun to migrate out of the tumor. In contrast, the subcutaneous tumor only begins to be vascularized by day-3 and cells do not migrate from the tumor. Angiogenesis is much more extensive in the orthotopic tumor throughout the 2-week observation period. The orthotopic PC-3-GFP tumor progresses very rapidly and distinct metastasis have appeared in lymph nodes by day-3 which rapidly appear in many areas of the abdominal cavity including portal lymph nodes by day-7. At day-14, no invasion or metastasis was observed with the s.c. tumor even when the animal was extensively explored. These results explain why orthotopic tumors mimimc clinical metastatic tumors in nude mice and why subcutaneous tumors do not. J. Cell. Biochem. 117: 2546-2551, 2016. © 2016 Wiley Periodicals, Inc. PMID:27012365

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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. PMID:24412045

  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. Knee joint replacement prosthesis (image)

    MedlinePlus

    A prosthesis is a device designed to replace a missing part of the body, or to make a part of the body work better. The metal prosthetic device in knee joint replacement surgery replaces cartilage and bone which is damaged from disease or aging.

  12. Successful management of hemolysis in ABO-nonidentical orthotopic liver transplantation by steroid therapy: a case report.

    PubMed

    Auwerda, J J; Bac, D J; van't Veer, M B; de Rave, S; Yzermans, J N

    1996-01-01

    Hemolysis due to donor-derived B lymphocytes has been reported in patients who have undergone ABO-nonidentical orthotopic liver transplantation (OLT). Yet, until now, little was known about the management of this transplantation-induced hemolysis. In this report we describe our experience with hemolysis in a patient after OLT. In addition, based on theoretical assumption, we hypothesize that corticosteroids can be helpful in the management of ABO-nonidentical OLT-induced hemolysis. PMID:8875796

  13. Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial

    PubMed Central

    2013-01-01

    Background In patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload. In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements. Methods/Design This is a double blind, multicenter, placebo-controlled randomized trial. Cirrhotic patients with a prolonged INR (≥1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements. Discussion Patients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and

  14. 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

  15. 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

  16. Targeted Non-invasive Imaging of EGFR-expressing Orthotopic Pancreatic Cancer using Multispectral Optoacoustic Tomography (MSOT)

    PubMed Central

    Hudson, Shanice V.; Huang, Justin S.; Yin, Wenyuan; Albeituni, Sabrin; Rush, Jamie; Khanal, Anil; Yan, Jun; Ceresa, Brian P.; Frieboes, Hermann B.; McNally, Lacey R.

    2014-01-01

    Detection of orthotopic xenograft tumors is difficult due to poor spatial resolution and reduced image fidelity with traditional optical imaging modalities. In particular, light scattering and attenuation in tissue at depths beyond subcutaneous implantation hinder adequate visualization. We evaluate the use of multispectral optoacoustic tomography (MSOT) to detect upregulated epidermal growth factor (EGF) receptor in orthotopic pancreatic xenografts using a near-infrared (NIR) EGF-conjugated CF-750 fluorescent probe. MSOT is based on the photoacoustic effect and thus not limited by photon scattering, resulting in high-resolution tomographic images. Pancreatic tumor-bearing mice with luciferase-transduced S2VP10L tumors were intravenously injected with EGF-750 probe prior to MSOT imaging. We characterized probe specificity and bioactivity via immunoblotting, immunocytochemistry, and flow cytometric analysis. In vitro data along with optical bioluminescence/fluorescence imaging were used to validate acquired MSOT in vivo images of probe biodistribution. Indocyanine green dye was used as a non-specific control to define specificity of EGF-probe accumulation. Maximum accumulation occurred at six hours post-injection, demonstrating specific intra-tumoral probe uptake and minimal liver and kidney off-target accumulation. Optical bioluminescence and fluorescence imaging confirmed tumor-specific probe accumulation consistent with MSOT images. These studies demonstrate the utility of MSOT to obtain volumetric images of ligand probe biodistribution in vivo to detect orthotopic pancreatic tumor lesions through active targeting of EGF receptor. PMID:25217521

  17. NRL attacks halon replacement

    SciTech Connect

    Baturin, D.

    1994-07-01

    In November 1992, as a result of the International Montreal Protocol Treaty and its addenda, it was announced that worldwide production of halons would halt by January 1994. Research has shown that halons, with the component bromine, would likely be more damaging to the ozone layer than chlorofluorocarbons. Today, while other researchers are looking at ways to limit the use of or to recycle halogenated fire suppressants, the Naval Research Laboratory (NRL) is conducting active programs aimed at developing replacement agents. The program includes laboratory-scale screening of candidate agents, intermediate-scale chamber tests, and full-scale shipboard discharge fire tests. A substantial research effort is underway on the measurement of the effectiveness of alternate, nonhalogen-containing suppressants; the elucidation of the chemical and physical mechanisms by which they suppress fires; and the development of theory and models on the relationship of chemical structures to suppressive behavior.

  18. 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.

  19. 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.

  20. Short stem shoulder replacement

    PubMed Central

    Bell, Simon N.; Coghlan, Jennifer A.

    2014-01-01

    Context: It is agreed that it is important to anatomically reproduce the proximal humeral anatomy when performing a prosthetic shoulder replacement. This can be difficult with a long stemmed prosthesis, in particular if there is little relationship of the metaphysis to the humeral shaft. The ‘short stem’ prosthesis can deal with this problem. Aims: A prospective study assessed the results of total shoulder arthroplasty using a short stem humeral prosthesis, a ceramic humeral head, and a pegged cemented polyethylene glenoid. Materials and methods: Patients with primary shoulder osteoarthritis were recruited into this prospective trial and pre-operatively had the ASES, Constant, SPADI, and DASH scores recorded. The patients were clinically reviewed at the two weeks, eight weeks, one year, and two year mark with completion of a data form. Radiological evaluation was at the eight week, one year and two year follow-up. At the one and two year follow-up the satisfaction rating, the range of passive and active motion, Constant, ASES, SPADI, DASH and pain results were recorded and analysed with SPPS 20. Results: During the study period 97 short stem, ceramic head total shoulder replacements were carried out. At the time of follow-up 12 were two years from operation and 38 one year from operation. Active elevation was overall mean 160 degrees. Constant scores were 76 at 1 year, and 86 at 2 years, ASES 88 and 93, and satisfaction 96% and 98% respectively at one and 2 year follow up. There were no problems during insertion of the humeral prosthesis, or any radiolucent lines or movement of the prosthesis on later radiographs. Conclusion: The short stem prosthesis had no complications, and on follow up radiographs good bone fixation. These fairly short term clinical results were overall good. PMID:25258497

  1. Establishment of an Orthotopic Xenograft Mice Model of Retinoblastoma Suitable for Preclinical Testing

    PubMed Central

    Cassoux, Nathalie; Thuleau, Aurélie; Assayag, Franck; Aerts, Isabelle; Decaudin, Didier

    2015-01-01

    Retinoblastoma is a rare cancer that occurs during childhood. The goal of current and future therapeutic strategies is to conserve the eye and visual function without using external beam radiotherapy, which is known to increase the risk of secondary cancers in genetically predisposed patients. Multimodality therapy (usually intravenous but also intra-arterial and intravitreal chemotherapy, transpupillary thermotherapy, cryotherapy, or brachytherapy) has recently improved the eye salvage rate in retinoblastoma and has led to a decreased need for external beam radiotherapy. However, the treatment of advanced intraocular retinoblastoma remains a real challenge, especially in cases of vitreous and subretinal seeding. There is a need for alternative and less toxic therapies as well as for better ways to administer the drugs. Animal models are an integral part of preclinical research in the field of oncology. This paper describes the different xenograft rodent models published in the literature so far. We will also describe a new orthotopic xenografted retinoblastoma model in immunodeficient mice, which is suitable for preclinical assays. The xenograft model was established from tumor tissue obtained directly from surgical samples and closely mimics human retinoblastoma. PMID:27171982

  2. Real Time Metastatic Route Tracking of Orthotopic PC-3-GFP Human Prostate Cancer Using Intravital Imaging.

    PubMed

    Zhang, Yong; Wang, Xiaoen; Hoffman, Robert M; Seki, Naohiko

    2016-04-01

    The cellular basis of metastasis is poorly understood. An important step to understanding this process is to be able to visualize the routes by which cancer cells migrate from the primary tumor to various distant sites to eventually form metastasis. Our laboratory previously developed single-cell in vivo imaging using fluorescent proteins to label cancer cells. In the present study, using PC-3 human prostate cancer cells labeled with green fluorescent protein (GFP) and orthotopic tumor transplantation, we have imaged in live mice various highly diverse routes by which PC-3 cells metastasize superiorly and inferiorly to distant sites, including in the portal area, stomach area, and urogenital system. Imaging began at day 9, at which time distant metastasis had already occurred, and increased at each imaging point at days 10, 13, 14, and 16. Metastatic cells were observed migrating superiorly and inferiorly from the primary tumor as well as in lymphatic channels and trafficking in various organ systems demonstrating that PC-3 has multiple metastatic routes similar to hormone-independent advanced-stage prostate cancer in the clinic. PMID:26515240

  3. Incidence of and risk factors for ischemic-type biliary lesions following orthotopic liver transplantation.

    PubMed

    Heidenhain, Christoph; Pratschke, Johann; Puhl, Gero; Neumann, Ulf; Pascher, Andreas; Veltzke-Schlieker, Winfried; Neuhaus, Peter

    2010-01-01

    Ischemic-type biliary lesions (ITBL) account for a major part of patients' morbidity and mortality after orthotopic liver transplantation (OLT). The exact origin of this type of biliary complication remains unknown. This study retrospectively evaluated 1843 patients. Patients with primary sclerosing cholangitis were excluded from this study. The diagnosis of ITBL was established only when all other causes of destruction of the biliary tree were ruled out. Donor age (P = 0.028) and cold ischemic time (CIT) (P = 0.002) were found to be significant risk factors for the development of ITBL. Organs that were perfused with University of Wisconsin (UW) solution developed ITBL significantly more often than Histidine-Tryptophan-Ketoglutarate (HTK)-perfused organs (P = 0.036). The same applied to organs harvested externally and shipped to our center versus those that were procured locally by our harvest teams (P < 0.001). Pressure perfusion via the hepatic artery significantly reduced the risk of ITBL (P = 0.001). The only recipient factor that showed a significant influence was Child-Pugh score status C (P = 0.021). Immunologic factors had no significant impact on ITBL. The clinical consequences of this study for our institution have been the strict limitation of CIT to <10 h and the exclusive use of HTK solution. We further advocate that all organ procurement teams perform pressure perfusion on harvested organs. PMID:19691661

  4. 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.

  5. 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.

  6. Use of multiphoton microscopy to diagnose liver cancer and lung metastasis in an orthotopic rat model.

    PubMed

    Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Tan, Changjun; Zhu, Weifeng; Lu, Jianping; Fan, Jia; Chen, Jianxin; Zhou, Jian

    2012-01-01

    Liver or lung biopsy for suspicious lesions has several disadvantages such as bleeding, bile leak or pneumothorax, needle track seeding, and time-consuming histopathological procedure. The ability to directly observe cellular and subcellular details and then perform "optical biopsy" is a major goal in the development of new interventional techniques. Multiphoton microscopy (MPM) enables real-time noninvasive visualization of tissue architecture and cell morphology in live tissue. We performed a study to evaluate whether MPMcan make real-time optical diagnosis for liver cancer and lung metastasis using an orthotopic rat model with Morris hepatoma. We found that real-time high-resolution MPMimaging could clearly show tissue architecture and cell morphology. In the normal liver tissue, MPMimaging clearly revealed the blood-filled sinusoids and cords of hepatocytes. In the cancerous tissue, MPMimaging clearly illustrated that cancer cells displayed marked cellular and nuclear pleomorphism. MPMimages were comparable to golden standard hematoxylin-eosin staining images. Moreover, MPMimaging had deep penetration with the capability of optical sectioning. In short, MPMcan make real-time optical diagnosis for liver cancer and lung metastasis. This study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive "optical biopsy" for liver cancer and lung metastasis in the near future. PMID:22331704

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

    PubMed

    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

    2015-08-01

    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(-/-)Stk3(F/-) (also known as Mst1(-/-)Mst2(F/-); F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis. PMID:26203823

  8. Establishment of an Orthotopic Xenograft Mice Model of Retinoblastoma Suitable for Preclinical Testing.

    PubMed

    Cassoux, Nathalie; Thuleau, Aurélie; Assayag, Franck; Aerts, Isabelle; Decaudin, Didier

    2015-04-01

    Retinoblastoma is a rare cancer that occurs during childhood. The goal of current and future therapeutic strategies is to conserve the eye and visual function without using external beam radiotherapy, which is known to increase the risk of secondary cancers in genetically predisposed patients. Multimodality therapy (usually intravenous but also intra-arterial and intravitreal chemotherapy, transpupillary thermotherapy, cryotherapy, or brachytherapy) has recently improved the eye salvage rate in retinoblastoma and has led to a decreased need for external beam radiotherapy. However, the treatment of advanced intraocular retinoblastoma remains a real challenge, especially in cases of vitreous and subretinal seeding. There is a need for alternative and less toxic therapies as well as for better ways to administer the drugs. Animal models are an integral part of preclinical research in the field of oncology. This paper describes the different xenograft rodent models published in the literature so far. We will also describe a new orthotopic xenografted retinoblastoma model in immunodeficient mice, which is suitable for preclinical assays. The xenograft model was established from tumor tissue obtained directly from surgical samples and closely mimics human retinoblastoma. PMID:27171982

  9. A novel mucosal orthotopic murine model of human papillomavirus-associated genital cancers.

    PubMed

    Decrausaz, Loane; Gonçalves, Ana-Rita; Domingos-Pereira, Sonia; Pythoud, Christelle; Stehle, Jean-Christophe; Schiller, John; Jichlinski, Patrice; Nardelli-Haefliger, Denise

    2011-05-01

    Cervical cancer results from infection with high-risk type human papillomaviruses (HPV). Therapeutic vaccines aiming at controlling existing genital HPV infections and associated lesions are usually tested in mice with HPV-expressing tumor cells subcutaneously implanted into their flank. However, effective vaccine-induced regression of these ectopic tumors strongly contrasts with the poor clinical results of these vaccines produced in patients with HPV-associated genital neoplasia. To assess HPV therapeutic vaccines in a more relevant setting, we have, here, established an orthotopic mouse model where tumors in the genital mucosa (GM) develop after an intravaginal instillation of HPV16 E6/E7-expressing tumor cells transduced with a luciferase-encoding lentiviral vector for in vivo imaging of tumor growth. Tumor take was 80-90% after nonoxynol-9 induced damage of the epithelium. Tumors remained localized in the genital tract, and histological analysis showed that most tumors grew within the squamous epithelium of the vaginal wall. Those tumors induced (i) E7-specific CD8 T cells restricted to the GM and draining lymph nodes, in agreement with their mucosal location and (ii) high Foxp3+ CD4+ infiltrates, similarly to those found in natural non-regressing HPV lesions. This novel genital HPV-tumor model by requiring GM homing of vaccine-induced immune responses able to overcome local immuno-suppression may be more representative of the situation occurring in patients upon therapeutic vaccination. PMID:20635385

  10. N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation.

    PubMed

    Taut, F J; Schmidt, H; Zapletal, C M; Thies, J C; Grube, C; Motsch, J; Klar, E; Martin, E

    2001-05-01

    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 < or = 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

  11. 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

  12. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis.

    PubMed

    Gore, Jesse; Craven, Kelly E; Wilson, Julie L; Cote, Gregory A; Cheng, Monica; Nguyen, Hai V; Cramer, Harvey M; Sherman, Stuart; Korc, Murray

    2015-04-10

    Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1-2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1-2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature. PMID:25762644

  13. 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. PMID:26840261

  14. Effectively Screening for Coronary Artery Disease in Patients Undergoing Orthotopic Liver Transplant Evaluation

    PubMed Central

    Li, Feng; Hanje, Adam J.; Mumtaz, Khalid; Boudoulas, Konstantinos D.; Lilly, Scott M.

    2016-01-01

    Coronary artery disease (CAD) is prevalent in patients with end-stage liver disease and associated with poor outcomes when undergoing orthotopic liver transplantation (OLT); however, noninvasive screening for CAD in this population is less sensitive. In an attempt to identify redundancy, we reviewed our experience among patients undergoing CAD screening as part of their OLT evaluation between May 2009 and February 2014. Demographic, clinical, and procedural characteristics were analyzed. Of the total number of screened patients (n = 132), initial screening was more common via stress testing (n = 100; 75.8%) than coronary angiography (n = 32; 24.2%). Most with initial stress testing underwent angiography (n = 52; 39.4%). Among those undergoing angiography, CAD was common (n = 31; 23.5%). Across the entire cohort the number of traditional risk factors was linearly associated with CAD, and those with two or more risk factors were found to have CAD by angiography 50% of the time (OR 1.92; CI 1.07–3.44, p = 0.026). Our data supports that CAD is prevalent among pre-OLT patients, especially among those with 2 or more risk factors. Moreover, we identified a lack of uniformity in practice and the need for evidence-based and standardized screening protocols. PMID:27418975

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

    PubMed

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

    2010-08-01

    Impaired hepatic arterial perfusion after orthotopic liver transplantation (OLT) may lead to ischemic biliary tract lesions and graft-loss. Hampered hepatic arterial blood flow is observed in patients with hypersplenism, often described as arterial steal syndrome (ASS). However, arterial and portal perfusions are directly linked via the hepatic arterial buffer response (HABR). Recently, the term 'splenic artery syndrome' (SAS) was coined to describe the effect of portal hyperperfusion leading to diminished hepatic arterial blood flow. We retrospectively analyzed 650 transplantations in 585 patients. According to preoperative imaging, 78 patients underwent prophylactic intraoperative ligation of the splenic artery. In case of postoperative SAS, coil-embolization of the splenic artery was performed. After exclusion of 14 2nd and 3rd retransplantations and 83 procedures with arterial interposition grafts, SAS was diagnosed in 28 of 553 transplantations (5.1%). Twenty-six patients were treated with coil-embolization, leading to improved liver function, but requiring postinterventional splenectomy in two patients. Additionally, two patients with SAS underwent splenectomy or retransplantation without preceding embolization. Prophylactic ligation could not prevent SAS entirely (n = 2), but resulted in a significantly lower rate of complications than postoperative coil-embolization. We recommend prophylactic ligation of the splenic artery for patients at risk of developing SAS. Post-transplant coil-embolization of the splenic artery corrected hemodynamic changes of SAS, but was associated with a significant morbidity. PMID:20180930

  16. Generation of Noninvasive, Quantifiable, Orthotopic Animal Models for NF2-Associated Schwannoma and Meningioma.

    PubMed

    Burns, Sarah S; Chang, Long-Sheng

    2016-01-01

    Schwannomas and meningiomas are nervous system tumors that can occur sporadically or in patients with neurofibromatosis type 2 (NF2). Mutations of the Neurofibromatosis 2 (NF2) gene are frequently observed in these tumors. Schwannomas and meningiomas cause significant morbidities, and an FDA-approved medical therapy is currently not available. The development of preclinical animal models that accurately capture the clinical characteristics of these tumors will facilitate the evaluation of novel therapeutic agents for the treatment of these tumors, ultimately leading to more productive clinical trials. Here, we describe the generation of luciferase-expressing NF2-deficient schwannoma and meningioma cells and the use of these cells to establish orthotopic tumor models in immunodeficient mice. The growth of these tumors and their response to treatment can be measured effectively by bioluminescence imaging (BLI) and confirmed by small-animal magnetic resonance imaging (MRI). These and other animal models, such as genetically-engineered models, should substantially advance the investigation of promising therapies for schwannomas and meningiomas. PMID:27259921

  17. 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

  18. Prolonged Delirium With Catatonia Following Orthotopic Liver Transplant Responsive to Memantine.

    PubMed

    Brown, Gregory D; Muzyk, Andrew J; Preud'homme, Xavier A

    2016-03-01

    A 59-year-old man with nonalcoholic steatohepatitis cirrhosis underwent an orthotopic liver transplant and experienced a complicated postoperative course, including a prolonged delirium. After discharge to rehabilitation, he had 2 subsequent admissions for delirium. On the first readmission, the transplant team started the patient on risperidone and resumed treatment with sertraline. On his second readmission, neurology and psychiatry were consulted. On evaluation, the patient demonstrated signs of catatonia. On the basis of recommendations from psychiatry, the risperidone and sertraline were stopped, and the patient was started on mirtazapine. He failed to demonstrate improvement within the next 48 hours. Extensive work-up demonstrated a multifactorial etiology for his delirium, including calcineurin-related neuropsychiatric toxicity from tacrolimus leading to possible posterior reversible encephalopathy syndrome. However, after the initiation of memantine on hospital day 3-before the cessation of tacrolimus-the patient demonstrated marked improvement in mental status and motor symptoms. His magnetic resonance imaging, in addition to findings that raised concerns about posterior reversible encephalopathy syndrome, had demonstrated bilateral basal ganglia abnormalities on T1 imaging of uncertain origin. It is postulated that these findings served as predisposing factors for the patient's catatonic symptoms. Although it has been described in case reports following liver transplant, catatonia remains an underrecognized neuropsychiatric complication following liver transplant. This case demonstrates the effectiveness of memantine, an N-methyl-D-aspartic acid antagonist that decreases glutamine excitotoxicity, as a potential treatment for catatonia in postliver transplant patients. PMID:27138082

  19. Dexmedetomidine Pretreatment Attenuates Kidney Injury and Oxidative Stress during Orthotopic Autologous Liver Transplantation in Rats

    PubMed Central

    Wu, Shan; Jin, Yi; Wang, Yiheng; Cai, Jun

    2016-01-01

    This paper aims to explore whether pretreatment with dexmedetomidine (Dex) has antioxidative and renal protective effects during orthotopic autologous liver transplantation (OALT) and its impact on nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Sprague-Dawley rats were randomized into groups that include sham-operated (group S), model (group M), low dose Dex (group D1), high dose Dex (group D2), atipamezole (a nonspecific α2 receptor blocker) + high dose Dex (group B1), ARC239 (a specific α2B/c receptor blocker) + high dose Dex (group B2), and BRL-44408 (a specific α2A receptor blocker) + high dose Dex (group B3). Then histopathologic examination of the kidneys and measurement of renal function, the renal Nrf2 protein expression, and oxidants and antioxidants were performed 8 hours after OALT. We found that pretreatment with Dex activated Nrf2 in glomerular cells and upregulated antioxidants but reduced oxidants (all P < 0.01, group D2 versus group M). Atipamezole and BRL-44408, but not ARC239, reversed these protective effects. In conclusion, pretreatment with Dex activates Nrf2 through α2A receptor, increases the antioxidant levels, and attenuates renal injury during OALT. PMID:26682005

  20. 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

  1. TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis

    PubMed Central

    Gore, Jesse; Craven, Kelly E.; Wilson, Julie L.; Cote, Gregory A.; Cheng, Monica; Nguyen, Hai V.; Cramer, Harvey M.; Sherman, Stuart; Korc, Murray

    2015-01-01

    Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1–2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1–2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature. PMID:25762644

  2. Temozolomide/PLGA microparticles plus vatalanib inhibits tumor growth and angiogenesis in an orthotopic glioma model.

    PubMed

    Zhang, Yu-Hui; Yue, Zhi-Jian; Zhang, He; Tang, Gu-Sheng; Wang, Yang; Liu, Jian-Min

    2010-11-01

    Temozolomide (TM) has anti-tumor activity in patients with malignant glioma. Implantable poly (D,L-lactide-co-glycolide) (PLGA) microparticles of TM (TM-MS) have been developed, enhancing the cytotoxicity of TM to Glioma C6 cells. Vatalanib, as anti-angiogenic agent, has also shown anti-tumor activity with malignant gliomas. We examined the combined effects of TM-MS and vatalanib in a rat orthotopic glioma model and found TM-MS offered a greater tumor inhibition than TM, and combination treatment with both of them improved the survival time versus single agent therapy. The combination treatment also demonstrated an inhibition to rat glioma tumors, a significant decrease in cell proliferation, an increase in apoptosis, and a lower microvessel density within the glioma tumors. The results suggest that TM-MS can more effectively inhibit tumor than TM, and combination treatment with TM-MS and vatalanib inhibits tumor growth and angiogenesis and may prove to be a promising therapy for malignant gliomas. PMID:20816959

  3. 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

  4. A pseudo-outbreak of disseminated cryptococcal disease after orthotopic heart transplantation.

    PubMed

    Kennedy, E; Vanichanan, J; Rajapreyar, I; Gonzalez, B; Nathan, S; Gregoric, I; Kar, B; Loyalka, P; Weeks, P; Chavez, V; Wanger, A; Ostrosky Zeichner, L

    2016-02-01

    Cryptococcal infection is the third most common invasive fungal infection (IFI) among solid-organ transplant (SOT) recipients and is considered an important opportunistic infection due to its significant morbidity and mortality. To determine whether a cluster of cryptococcosis in heart transplant patients was of nosocomial nature, three cases of orthotopic heart transplant recipients with postoperative disseminated cryptococcal infection were investigated and paired with an environmental survey in a tertiary care hospital. The infection prevention department conducted a multidisciplinary investigation, which did not demonstrate any evidence of health care-associated environmental exposure. Moreover, multilocus sequence typing showed that one isolate was unique and the two others, although identical, were not temporally related and belong to the most common type seen in the Southern US. Additionally, all three patients had preexisting abnormalities of the CT chest scan and various degrees of acute and chronic rejection. Reactivation was suggested in all three patients. Screening methods may be useful to identify at risk patients and trigger a prophylactic or preemptive approach. However, more data is needed. PMID:26627342

  5. 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.

  6. Graft complications following orthotopic liver transplantation: Role of non-invasive cross-sectional imaging techniques.

    PubMed

    Boraschi, Piero; Della Pina, Maria Clotilde; Donati, Francescamaria

    2016-07-01

    Orthotopic liver transplantation is the treatment of choice in adult patients with endstage liver disease. Survival of both graft and patient has progressively improved over time due to improvements in surgical and medical treatment. However, post-transplant complications still have a significant impact on morbidity and mortality associated with transplant surgery. The most common adverse events of the graft include vascular (arterial and venous stenosis and thrombosis), biliary (leakage, strictures, stones) and parenchymal complications (hepatitis virus C infection, HCC recurrence, liver abscesses). The diagnosis of these adverse events is often challenging because of the low specificity of clinical and biologic findings. Different diagnostic algorithms have been proposed for the detection of graft complications and, in this setting, radiological evaluation plays a key role in differential diagnosis of graft complications and the exclusion of other adverse events. Ultrasound examination is established the first-line method of identifying adverse events in liver transplant recipients but a normal or a technically unsatisfactory study cannot exclude the presence of biliary, vascular and/or parenchymal complications. In these circumstances, before planning any treatment, multi-detector CT and/or MR imaging and MR cholangiography should be performed for the evaluation of vascular structures, biliary system, liver parenchyma and fluid collections. The aim of this review is to illustrate the role and state-of-the-art of non-invasive cross-sectional imaging techniques in the diagnosis and management of complications which primarily affect the graft in patients after liver transplantation. PMID:27235874

  7. Postoperative left ventricular apical ballooning: Transient Takotsubo cardiomyopathy following orthotopic liver transplantation

    PubMed Central

    Bedanova, Helena; Orban, Marek; Nemec, Petr

    2013-01-01

    Patient: Female, 51 Final Diagnosis: Takotsubo cardiomyopathy Symptoms: — Medication: — Clinical Procedure: — Specialty: Cardiology • Transplantology Objective: Rare disease Background: Left ventricular apical ballooning syndrome (LVAB), also known as Takotsubo cardiomyopathy, is a cardiac syndrome characterized by transient left ventricular dysfunction in the absence of obstructive atherosclerotic coronary artery disease. An episode of emotional stress, typically in female patients, is believed to precede and trigger the development of this syndrome. Case Report: We report a case of Takotsubo cardiomyopathy that developed after orthotopic liver transplantation in a 51-year-old woman. On D2 (day 2) the patient had severe hemodynamic compromise. Echocardiography showed systolic dysfunction of the left ventricle (LV), with ejection fraction (EF) of 20% and anteroapical akinesis and ballooning of the apical 2/3 of the LV. Troponin T was elevated but other markers of myocardial necrosis were negative, as was coronary angiography. From D7 onward, there was an improvement in the hemodynamics in conjunction with a gradual increase of LV EF. The patient was dismissed from the hospital on D30 with signs of normal cardiac function and LV motion and EF of 50%. Liver function was also excellent. Conclusions: Every major operation, including liver transplantation, is associated with emotional stress for the patient. Therefore, it is necessary to consider Takotsubo cardiomyopathy in the differential diagnosis of heart failure developing early after LT, and clinicians should subsequently use adequate diagnostic and therapeutic measures. PMID:24298303

  8. Orthotopic transplantation of LH receptor knockout and wild-type ovaries.

    PubMed

    Chudgar, Daksha; Lei, Zhenmin; Rao, Ch V

    2005-10-01

    Luteinizing hormone (LH) receptor knockout animals have an ovarian failure due to an arrest in folliculogenesis at the antral stage. As a result, the animals have an infertility phenotype. The present study was undertaken to determine whether this phenotype could be reversed by orthotopic transplantation of wild-type ovaries. The results revealed that transplanting wild-type ovaries into null animals did not result in resumption of estrus cycles. Although the number of different types of follicles increased, none progressed to ovulation. The serum hormone profiles improved, reflecting the ovarian changes. The wild-type animals with null ovaries also failed to cycle and their ovaries and serum hormone levels were more like null animals with their own ovaries. Although the lack of rescue of null ovaries placed into wild-type animals was predicted, the failure of wild-type ovaries placed in null animals was not, which could be due to chronic exposure of transplanted tissue to high circulating LH levels and also possibly due to altered internal milieu in null animals. These findings may have implications for potential future considerations of grafting normal donor ovaries into women who have an ovarian failure resulting from inactivating LH receptor mutations. PMID:15964032

  9. 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 . PMID:25200444

  10. Technique of Porcine Liver Procurement and Orthotopic Transplantation using an Active Porto-Caval Shunt

    PubMed Central

    Spetzler, Vinzent N.; Goldaracena, Nicolas; Knaak, Jan M.; Louis, Kristine S.; Selzner, Nazia; Selzner, Markus

    2015-01-01

    The success of liver transplantation has resulted in a dramatic organ shortage. Each year, a considerable number of patients on the liver transplantation waiting list die without receiving an organ transplant or are delisted due to disease progression. Even after a successful transplantation, rejection and side effects of immunosuppression remain major concerns for graft survival and patient morbidity. Experimental animal research has been essential to the success of liver transplantation and still plays a pivotal role in the development of clinical transplantation practice. In particular, the porcine orthotopic liver transplantation model (OLTx) is optimal for clinically oriented research for its close resemblance to human size, anatomy, and physiology. Decompression of intestinal congestion during the anhepatic phase of porcine OLTx is important to guarantee reliable animal survival. The use of an active porto-caval-jugular shunt achieves excellent intestinal decompression. The system can be used for short-term as well as long-term survival experiments. The following protocol contains all technical information for a stable and reproducible liver transplantation model in pigs including post-operative animal care. PMID:25992583

  11. 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.

  12. 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.

  13. Replacement, reduction and refinement.

    PubMed

    Flecknell, Paul

    2002-01-01

    In 1959, William Russell and Rex Burch published "The Principles of Humane Experimental Technique". They proposed that if animals were to be used in experiments, every effort should be made to Replace them with non-sentient alternatives, to Reduce to a minimum the number of animals used, and to Refine experiments which used animals so that they caused the minimum pain and distress. These guiding principles, the "3 Rs" of animal research, were initially given little attention. Gradually, however, they have become established as essential considerations when animals are used in research. They have influenced new legislation aimed at controlling the use of experimental animals, and in the United Kingdom they have become formally incorporated into the Animal (Scientific) Procedures Act. The three principles, of Replacement, Reduction and Refinement, have also proven to be an area of common ground for research workers who use animals, and those who oppose their use. Scientists, who accept the need to use animals in some experiments, would also agree that it would be preferable not to use animals. If animals were to be used, as few as possible should be used and they should experience a minimum of pain or distress. Many of those who oppose animal experimentation, would also agree that until animal experimentation is stopped, Russell and Burch's 3Rs provide a means to improve animal welfare. It has also been recognised that adoption of the 3Rs can improve the quality of science. Appropriately designed experiments that minimise variation, provide standardised optimum conditions of animals care and minimise unnecessary stress or pain, often yield better more reliable data. Despite the progress made as a result of attention to these principles, several major problems have been identified. When replacing animals with alternative methods, it has often proven difficult to formally validate the alternative. This has proven a particular problem in regulatory toxicology

  14. 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

  15. Assessment of the Early Effects of 5,6-Dimethylxanthenone-4-Acetic Acid Using Macromolecular Contrast Media-Enhanced Magnetic Resonance Imaging: Ectopic Versus Orthotopic Tumors

    SciTech Connect

    Seshadri, Mukund Bellnier, David A.; Cheney, Richard T.

    2008-11-15

    Purpose: To investigate the early effects of a vascular disrupting agent (VDA) in ectopic and orthotopic tumors by using macromolecular contrast media (MMCM)-enhanced magnetic resonance imaging (MMCM-MRI). Methods and Materials: The MMCM-MRI of ectopic and orthotopic MCA205 murine fibrosarcomas was performed using the intravascular contrast agent albumin-(gadopentetate dimeglumine){sub 35}. Change in longitudinal relaxation rate ({delta}R1) was measured 24 hours after treatment with 5,6-dimethylxanthenone-4-acetic acid (DMXAA; 30 mg/kg) and used to compute tumor vascular volume and permeability. Correlative histologic and immunohistochemical evaluation was carried out, along with measurement of tumor necrosis factor {alpha} and vascular endothelial growth factor levels in whole tumor extracts using the enzyme-linked immunosorbent assay. Results: Orthotopic tumors showed higher vascular volume (p < 0.05) than ectopic tumors before treatment. Twenty-four hours after DMXAA treatment, a significant (p < 0.0001), but differential, decrease in {delta}R1 (70% in ectopic and 50% in orthotopic tumors) was observed compared with baseline estimates. Consistent with this observation, greater levels of tumor necrosis factor {alpha}, an important mediator of the antivascular activity of DMXAA, were measured in ectopic tumors 3 hours posttreatment compared with orthotopic tumors (p < 0.05). Immunohistochemical (CD31) and histologic (hematoxylin and eosin) sections of ectopic and orthotopic tumors showed highly tumor-selective vascular damage after treatment with the presence of viable surrounding normal tissue. Conclusions: The MMCM-MRI provided early quantitative estimates of change in tumor perfusion after VDA treatment that showed good correlation with cytokine induction. Differences in the response of ectopic and orthotopic tumors highlight the influence of the host microenvironment in modulating the activity of VDAs.

  16. 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

  17. Leukocyte populations and IL-6 in the tumor microenvironment of an orthotopic colorectal cancer model.

    PubMed

    Miller, Sarah; Senior, Paul V; Prakash, Monica; Apostolopoulos, Vasso; Sakkal, Samy; Nurgali, Kulmira

    2016-04-01

    Colorectal cancer (CRC) is a major health problem worldwide. It is often diagnosed late due to its asymptomatic nature. As with all cancers, an immune reaction is involved; however, in CRC, it is unknown if this immune response is favorable or unfavorable for disease progression. In this study, the immune response in mesenteric lymph nodes (MLNs) and Peyer's patches was investigated during development of CRC in an orthotopic mouse model. CRC was induced by injecting CT26 cells into the cecum wall of BALB/c mice. Flow cytometry was used to analyze leukocyte populations involved in tumor immunity in MLNs and Peyer's patches. Cryostat sections for immunohistochemistry were prepared from the caecum and colon from CRC-induced and sham-operated animals. Cytokines produced by mouse CT26 cell line were measuredin vitroandin vivo Significant increases in the number of CD8(+)/TCR(+)and CD49b(+)/TCR(-)(natural killer) cells were found in MLNs and Peyer's patches in the CRC group. In addition, γδT cells were present in the lamina propria of the colon tissues from sham-operated mice, but absent in the colon tissues from mice with CRC. Immunohistochemical analysis of tumorous tissues showed eosinophil, CD69(+)T cell, and CD11b(+)cell infiltration. Bothin vitroandin vivoCT26 tumor cells were interleukin (IL)-6 positive. In addition, tumor-infiltrating CD45(+)cells were also IL-6 positive. In summary, the kinetics of the immune response to CRC and the key effector lymphocytes that are implicated in tumor immunity are demonstrated. Furthermore, IL-6 is a key cytokine present within the tumor microenvironment. PMID:26893144

  18. A protective effect after clearance of orthotopic rat hepatocellular carcinoma by nanosecond pulsed electric fields.

    PubMed

    Chen, Ru; Sain, Nova M; Harlow, K Tyler; Chen, Yeong-Jer; Shires, Peter K; Heller, Richard; Beebe, Stephen J

    2014-10-01

    Strategies for treating liver cancer using radiation, chemotherapy combinations and tyrosine kinase inhibitors targeting specific mutations have provided longer survival times, yet multiple treatments are often needed and recurrences with new malignant phenotypes are not uncommon. New and innovative treatments are undoubtedly needed to successfully treat liver cancer. Over the last decade, nanosecond pulsed electric fields (nsPEFs) have shown promise in pre-clinical studies; however, these have been limited to treatment of skin cancers or xenographs in mice. In the present report, an orthotopic hepatocellular carcinoma (HCC) model is established in rats using N1-S1 HCC cells. Data demonstrate a response rate of 80-90% when 1000 pulses are delivered with 100ns durations, electric field strengths of 50kV/cm and repetition rates of 1Hz. N1-S1 tumours treated with nsPEFs expressed significant number of cells with active caspase-3 and caspase-9, but not caspase-8, indicating an intrinsic apoptosis mechanism(s) as well as caspase-independent mechanisms. Most remarkably, rats with successfully ablated tumours failed to re-grow tumours when challenged with a second injection of N1-S1 cells when implanted in the same or different liver lobe that harboured the original tumour. Given this protective effect, infiltration of immune cells and the presence of granzyme B expressing cells within days of treatment suggest the possibility of an anti-tumour adaptive immune response. In conclusion, NsPEFs not only eliminate N1-S1 HCC tumours, but also may induce an immuno-protective effect that defends animals against recurrences of the same cancer. PMID:25081978

  19. Endoscopic retrograde cholangiopancreatography in patients with biliary complications after orthotopic liver transplantation: outcomes and complications.

    PubMed

    Sanna, C; Saracco, G M; Reggio, D; Moro, F; Ricchiuti, A; Strignano, P; Mirabella, S; Ciccone, G; Salizzoni, M

    2009-05-01

    Biliary complications after orthotopic liver transplantation (OLT) still remain a major cause of morbidity and mortality. The most frequent complications are strictures and leakages in OLT cases with duct-to-duct biliary reconstruction (D-D), which can be treated with dilatation or stent placement during endoscopic retrograde cholangiopancreatography (ERCP), although this procedure is burdened with potentially severe complications, such as retroperitoneal perforation, acute pancreatitis, septic cholangitis, bleeding, recurrence of stones, strictures due to healing process. The aim of the study was to analyze the outcome of this treatment and the complications related to the procedure. Among 1634 adult OLTs, we compared postprocedural complications and mortality rates with a group of 5852 nontransplanted patients (n-OLTs) who underwent ERCP. Of 472 (28,8%) post-OLT biliary complications, 319 (67.6%) occurred in D-D biliary anstomosis cases and 94 (29.5%) patients underwent 150 ERCP sessions. Among 49/80 patients (61.2%) who completed the procedure, ERCP treatment was successful. Overall complication rate was 10.7% in OLT and 12.8% in n-OLT (P = NS). Compared with the n-OLT group, post-ERCP bleeding was more frequent in OLT (5.3% vs 1.3%, P = .0001), while the incidence of pancreatitis was lower (4.7% vs 9.6%, P = .04). Procedure-related mortality rate was 0% in OLT and 0.1% in n-OLT (P = NS). ERCP is a safe procedure for post-OLT biliary complications in the presence of a D-D anastomosis. Morbidity and mortality related with this procedure are acceptable and similar to those among nontransplanted population. PMID:19460551

  20. Regression of Established Hepatocellular Carcinoma Is Induced by Chemo-immunotherapy in an Orthotopic Murine Model

    PubMed Central

    Avella, Diego M.; Li, Guangfu; Schell, Todd D.; Liu, Dai; Zhang, Samuel Shao-Min; Lou, Xi; Berg, Arthur; Kimchi, Eric T.; Tagaram, Hephzibah Rani S.; Yang, Qing; Shereef, Serene; Garcia, Luis S.; Kester, Mark; Isom, Harriet C.; Rountree, C. Bart; Staveley-O’Carroll, Kevin F.

    2011-01-01

    The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this report, we evaluated the efficacy of a novel chemo-immunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen specific immune-directed therapy in an immunocompetent murine model. Using this model, we tested the efficacy of a combination of oral sunitinib, a small molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8+ T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8+ T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T cell tolerance. Conclusion These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8+ T cell tolerance, thus defining a synergistic chemo-immunotherapeutic approach for HCC. PMID:21898502

  1. Aerosol Azacytidine Inhibits Orthotopic Lung Cancers in Mice through Its DNA Demethylation and Gene Reactivation Effects

    PubMed Central

    Qiu, Xuan; Liang, Yuanxin; Sellers, Rani S.; Perez-Soler, Roman; Zou, Yiyu

    2014-01-01

    We devised an aerosol based demethylation therapy to achieve therapeutic efficacy in premalignant or in situ lesions of lung cancer, without systemic toxicity. Optimum regimens of aerosolized azacytidine (Aza) were designed and used in orthotopic human non-small cell lung cancer xenograft models. The therapeutic efficacy and toxicity of aerosol Aza were compared with intravenously administered Aza. We observed that 80% of the droplets of the aerosol Aza measured ∼0.1–5 microns, which resulted in deposition in the lower bronchial airways. An animal model that phenocopies field carcinogeneisis in humans was developed by intratracheal inoculation of the human lung cancer cells in mice, thus resulting in their distribution throughout the entire airway space. Aerosolized Aza significantly prolonged the survival of mice bearing endo-bronchial lung tumors. The aerosol treatment did not cause any detectable lung toxicity or systemic toxicity. A pre-pharmacokinetic study in mice demonstrated that lung deposition of aerosolized Aza was significantly higher than the intravenous route. Lung tumors were resected after aerosol treatment and the methylation levels of 24 promoters of tumor-suppresser genes related to lung cancer were analyzed. Aerosol Aza significantly reduced the methylation level in 9 of these promoters and reexpressed several genes tested. In conclusion, aerosol Aza at non-cytotoxic doses appears to be effective and results in DNA demethylation and tumor suppressor gene re-expression. The therapeutic index of aerosol Aza is >100-fold higher than that of intravenous Aza. These results provide a preclinical rationale for a phase I clinical trial of aerosol Aza to be initiated at our Institution. PMID:25347303

  2. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.

    PubMed

    Reardon, David A; Gokhale, Prafulla C; Klein, Sarah R; Ligon, Keith L; Rodig, Scott J; Ramkissoon, Shakti H; Jones, Kristen L; Conway, Amy Saur; Liao, Xiaoyun; Zhou, Jun; Wen, Patrick Y; Van Den Abbeele, Annick D; Hodi, F Stephen; Qin, Lei; Kohl, Nancy E; Sharpe, Arlene H; Dranoff, Glenn; Freeman, Gordon J

    2016-02-01

    Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma. PMID:26546453

  3. Orthotopic Human Choroidal Melanoma Xenografts in Nude Rats with Aggressive and Nonaggressive PAS Staining Patterns

    PubMed Central

    Braun, Rod D.; Abbas, Asad

    2007-01-01

    PURPOSE Choroidal melanoma is the most common primary ocular cancer among the adult population. Patient survival has been linked to the periodic acid-Schiff base (PAS)–positive vascular patterns in the tumors. The presence of PAS-positive loops or cross-linking parallel channels is a marker of an aggressive tumor. The purpose of this study was to develop new xenograft models of human choroidal melanoma that predictably demonstrate the PAS staining patterns associated with nonaggressive and aggressive tumors in humans. METHODS Three human choroidal melanoma cell lines (C918, M619, and OCM-1) were used. C918 and M619 are considered aggressive, based on their ability to form PAS-positive channels in vitro. The nonaggressive OCM-1 cells do not form these channels. C918, M619, and OCM-1 spheroids were grown and implanted in the suprachoroidal space of 20, 17, and 16 WAG/RijHs-rnu nude rats, respectively. Tumors were grown for 1 to >4 weeks, and histology was performed to evaluate tumor growth and determine PAS labeling patterns. RESULTS Growth of C918, M619, and OCM-1 xenografts were histologically verified in 20/20, 15/17, and 16/16 rats, respectively. PAS staining revealed loops and cross-linking parallel channels, typical of aggressive tumors in patients, in 90% of C918 and 100% of M619 xenografts. Only 4 of 16 OCM-1 xenografts showed PAS-positive loops. The rest showed no PAS staining or only perivascular staining, indicative of nonaggressive tumors. CONCLUSIONS It is possible to grow human choroidal melanoma orthotopic xenografts in nude rats that reproduce the PAS staining patterns associated with aggressive and nonaggressive choroidal melanomas in patients. PMID:16384938

  4. 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

  5. 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.

  6. Standardized orthotopic xenografts in zebrafish reveal glioma cell-line-specific characteristics and tumor cell heterogeneity

    PubMed Central

    Welker, Alessandra M.; Jaros, Brian D.; Puduvalli, Vinay K.; Imitola, Jaime; Kaur, Balveen; Beattie, Christine E.

    2016-01-01

    ABSTRACT Glioblastoma (GBM) is a deadly brain cancer, for which few effective drug treatments are available. Several studies have used zebrafish models to study GBM, but a standardized approach to modeling GBM in zebrafish was lacking to date, preventing comparison of data across studies. Here, we describe a new, standardized orthotopic xenotransplant model of GBM in zebrafish. Dose-response survival assays were used to define the optimal number of cells for tumor formation. Techniques to measure tumor burden and cell spread within the brain over real time were optimized using mouse neural stem cells as control transplants. Applying this standardized approach, we transplanted two patient-derived GBM cell lines, serum-grown adherent cells and neurospheres, into the midbrain region of embryonic zebrafish and analyzed transplanted larvae over time. Progressive brain tumor growth and premature larval death were observed using both cell lines; however, fewer transplanted neurosphere cells were needed for tumor growth and lethality. Tumors were heterogeneous, containing both cells expressing stem cell markers and cells expressing markers of differentiation. A small proportion of transplanted neurosphere cells expressed glial fibrillary acidic protein (GFAP) or vimentin, markers of more differentiated cells, but this number increased significantly during tumor growth, indicating that these cells undergo differentiation in vivo. By contrast, most serum-grown adherent cells expressed GFAP and vimentin at the earliest times examined post-transplant. Both cell types produced brain tumors that contained Sox2+ cells, indicative of tumor stem cells. Transplanted larvae were treated with currently used GBM therapeutics, temozolomide or bortezomib, and this resulted in a reduction in tumor volume in vivo and an increase in survival. The standardized model reported here facilitates robust and reproducible analysis of glioblastoma tumor cells in real time and provides a platform for

  7. 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.

  8. 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 ...

  9. On total disc replacement.

    PubMed

    Berg, Svante

    2011-02-01

    Low back pain consumes a large part of the community's resources dedicated to health care and sick leave. Back disorders also negatively affect the individual leading to pain suffering, decreased quality-of-life and disability. Chronic low back pain (CLBP) due to degenerative disc disease (DDD) is today often treated with fusion when conservative treatment has failed and symptoms are severe. This treatment is as successful as arthroplasty is for hip arthritis in restoring the patient's quality of life and reducing disability. Even so, there are some problems with this treatment, one of these being recurrent CLBP from an adjacent segment (ASD) after primarily successful surgery. This has led to the development of alternative surgical treatments and devices that maintain or restore mobility, in order to reduce the risk for ASD. Of these new devices, the most frequently used are the disc prostheses used in Total Disc Replacement (TDR). This thesis is based on four studies comparing total disc replacement with posterior fusion. The studies are all based on a material of 152 patients with DDD in one or two segments, aged 20-55 years that were randomly treated with either posterior fusion or TDR. The first study concerned clinical outcome and complications. Follow-up was 100% at both one and two years. It revealed that both treatment groups had a clear benefit from treatment and that patients with TDR were better in almost all outcome scores at one-year follow-up. Fusion patients continued to improve during the second year. At two-year follow-up there was a remaining difference in favour of TDR for back pain. 73% in the TDR group and 63% in the fusion group were much better or totally pain-free (n.s.), while twice as many patients in the TDR group were totally pain free (30%) compared to the fusion group (15%). Time of surgery and total time in hospital were shorter in the TDR group. There was no difference in complications and reoperations, except that seventeen of the

  10. Replacement Cost of Domestic Crude

    Energy Science and Technology Software Center (ESTSC)

    1994-12-01

    The DEEPWATER model forecasts the replacement cost of domestic crude oil for 13 offshore regions in the lower 48 states. The replacement cost of domestic crude oil is the constant or levelized selling price that will recover the full expense of exploration, development, and productions with a reasonable return on capital.

  11. Biomaterials in total joint replacement.

    PubMed

    Katti, Kalpana S

    2004-12-10

    The current state of materials systems used in total hip replacement is presented in this paper. An overview of the various material systems used in total hip replacement reported in literature is presented in this paper. Metals, polymers, ceramics and composites are used in the design of the different components of hip replacement implants. The merits and demerits of these material systems are evaluated in the context of mechanical properties most suitable for total joint replacement such as a hip implant. Current research on advanced polymeric nanocomposites and biomimetic composites as novel materials systems for bone replacement is also discussed. This paper examines the current research in the materials science and the critical issues and challenges in these materials systems that require further research before application in biomedical industry. PMID:15556342

  12. Monitoring Prostate Tumor Growth in an Orthotopic Mouse Model Using Three-Dimensional Ultrasound Imaging Technique12

    PubMed Central

    Ni, Jie; Cozzi, Paul; Hung, Tzong-Tyng; Hao, Jingli; Graham, Peter; Li, Yong

    2016-01-01

    Prostate cancer (CaP) is the most commonly diagnosed and the second leading cause of death from cancer in males in USA. Prostate orthotopic mouse model has been widely used to study human CaP in preclinical settings. Measurement of changes in tumor size obtained from noninvasive diagnostic images is a standard method for monitoring responses to anticancer modalities. This article reports for the first time the usage of a three-dimensional (3D) ultrasound system equipped with photoacoustic (PA) imaging in monitoring longitudinal prostate tumor growth in a PC-3 orthotopic NODSCID mouse model (n = 8). Two-dimensional and 3D modes of ultrasound show great ability in accurately depicting the size and shape of prostate tumors. PA function on two-dimensional and 3D images showed average oxygen saturation and average hemoglobin concentration of the tumor. Results showed a good fit in representative exponential tumor growth curves (n = 3; r2 = 0.948, 0.955, and 0.953, respectively) and a good correlation of tumor volume measurements performed in vivo with autopsy (n = 8, r = 0.95, P < .001). The application of 3D ultrasound imaging proved to be a useful imaging modality in monitoring tumor growth in an orthotopic mouse model, with advantages such as high contrast, uncomplicated protocols, economical equipment, and nonharmfulness to animals. PA mode also enabled display of blood oxygenation surrounding the tumor and tumor vasculature and angiogenesis, making 3D ultrasound imaging an ideal tool for preclinical cancer research. PMID:26947880

  13. 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.

  14. Enhanced bone morphogenetic protein-2-induced ectopic and orthotopic bone formation by intermittent parathyroid hormone (1-34) administration.

    PubMed

    Kempen, Diederik H R; Lu, Lichun; Hefferan, Theresa E; Creemers, Laura B; Heijink, Andras; Maran, Avudaiappan; Dhert, Wouter J A; Yaszemski, Michael J

    2010-12-01

    Bone morphogenetic proteins (BMPs) play a central role in local bone regeneration strategies, whereas the anabolic features of parathyroid hormone (PTH) are particularly appealing for the systemic treatment of generalized bone loss. The aim of the current study was to investigate whether local BMP-2-induced bone regeneration could be enhanced by systemic administration of PTH (1-34). Empty or BMP-2-loaded poly(lactic-co glycolic acid)/poly(propylene fumarate)/gelatin composites were implanted subcutaneously and in femoral defects in rats (n = 9). For the orthotopic site, empty defects were also tested. Each of the conditions was investigated in combination with daily administered subcutaneous PTH (1-34) injections in the neck. After 8 weeks of implantation, bone mineral density (BMD) and bone volume were analyzed using microcomputed tomography and histology. Ectopic bone formation and almost complete healing of the femoral defect were only seen in rats that received BMP-2-loaded composites. Additional treatment of the rats with PTH (1-34) resulted in significantly (p < 0.05) enhanced BMD and bone volume in the BMP-2 composites at both implantation sites. Despite its effect on BMD in the humerus and vertebra, PTH (1-34) treatment had no significant effect on BMD and bone volume in the empty femoral defects and the ectopically or orthotopically implanted empty composites. Histological analysis showed that the newly formed bone had a normal woven and trabecular appearance. Overall, this study suggests that intermittent administration of a low PTH dose alone has limited potential to enhance local bone regeneration in a critical-sized defect in rats. However, when combined with local BMP-2-releasing scaffolds, PTH administration significantly enhanced osteogenesis in both ectopic and orthotopic sites. PMID:20666615

  15. The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer

    PubMed Central

    Helland, Øystein; Popa, Mihaela; Bischof, Katharina; Gjertsen, Bjørn Tore; McCormack, Emmet; Bjørge, Line

    2016-01-01

    Background In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC. Methods The effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured. Results Panobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment. Conclusions Panobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was

  16. 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.

  17. Imaging the microenvironment of pancreatic cancer patient-derived orthotopic xenografts (PDOX) growing in transgenic nude mice expressing GFP, RFP, or CFP.

    PubMed

    Hoffman, Robert M; Bouvet, Michael

    2016-09-28

    We have developed a multi-color, imageable, orthotopic mouse model for individual patients with pancreatic cancer. The tumors are labeled by first passaging them orthotopically through transgenic nude mice expressing green fluorescent protein (GFP), red fluorescent protein (RFP), or cyan fluorescent protein (CFP). Passage of the tumors in these colored transgenic mice labels the stromal cells of the tumor. The cancer cells in the PDOX are labeled in situ with GFP by telomerase-dependent adenovirus OBP-401. The models are termed imageable patient-derived orthotopic xenografts (iPDOX). The tumors acquired brightly-fluorescent stromal cells from the transgenic host mice, which were stably associated with the tumors through multiple passages. The colored fluorescent protein-expressing stromal cells included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This model enables powerful color-coded imaging of the interaction of cancer and stromal cells during tumor progression and treatment. PMID:26742463

  18. [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. PMID:8767813

  19. Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model

    PubMed Central

    Kuroda, Shinji; Kubota, Tetsushi; Aoyama, Katsuyuki; Kikuchi, Satoru; Tazawa, Hiroshi; Nishizaki, Masahiko; Kagawa, Shunsuke; Fujiwara, Toshiyoshi

    2014-01-01

    Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n = 5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n = 5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n = 8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies. PMID:25493557

  20. 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

  1. 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

  2. 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

  3. 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 ...

  4. When to Replace a Prosthesis

    MedlinePlus

    Donate Fundraise Connect Contact Us Materiales en español Amputee Coalition Navigation HOME WHO WE ARE About Us ... Advisory Committee Connect With Us! STORE CALENDAR SEARCH Amputee Coalition > Limb Loss Resource Center > When to Replace ...

  5. 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.

  6. Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3

    PubMed Central

    Subramaniam, Aruljothi; Shanmugam, Muthu K; Ong, Tina H; Li, Feng; Perumal, Ekambaram; Chen, Luxi; Vali, Shireen; Abbasi, Taher; Kapoor, Shweta; Ahn, Kwang Seok; Kumar, Alan Prem; Hui, Kam M; Sethi, Gautam

    2013-01-01

    BACKGROUND AND PURPOSE Aberrant activation of STAT3 is frequently encountered and promotes proliferation, survival, metastasis and angiogenesis in hepatocellular carcinoma (HCC). Here, we have investigated whether emodin mediates its effect through interference with the STAT3 activation pathway in HCC. EXPERIMENTAL APPROACH The effect of emodin on STAT3 activation, associated protein kinases and apoptosis was investigated using various HCC cell lines. Additionally, we also used a predictive tumour technology to analyse the effects of emodin. The in vivo effects of emodin were assessed in an orthotopic mouse model of HCC. KEY RESULTS Emodin suppressed STAT3 activation in a dose- and time-dependent manner in HCC cells, mediated by the modulation of activation of upstream kinases c-Src, JAK1 and JAK2. Vanadate treatment reversed emodin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase and emodin induced the expression of the tyrosine phosphatase SHP-1 that correlated with the down-regulation of constitutive STAT3 activation. Interestingly, silencing of the SHP-1 gene by siRNA abolished the ability of emodin to inhibit STAT3 activation. Finally, when administered i.p., emodin inhibited the growth of human HCC orthotopic tumours in male athymic nu/nu mice and STAT3 activation in tumour tissues. CONCLUSIONS AND IMPLICATIONS Emodin mediated its effects predominantly through inhibition of the STAT3 signalling cascade and thus has a particular potential for the treatment of cancers expressing constitutively activated STAT3. PMID:23848338

  7. 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

  8. 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.

  9. 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

  10. High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology

    PubMed Central

    Sobilo, Julien; Le Mée, Marilyne; Rétif, Stéphanie; Natkunarajah, Sharuja; Lerondel, Stéphanie; Le Pape, Alain

    2016-01-01

    Objectives We have developed a relevant preclinical model associated with a specific imaging protocol dedicated to onco-pharmacology studies in mice. Materials and Methods We optimized both the animal model and an ultrasound imaging procedure to follow up longitudinally the lung tumor growth in mice. Moreover we proposed to measure by photoacoustic imaging the intratumoral hypoxia, which is a crucial parameter responsible for resistance to therapies. Finally, we compared ultrasound data to x-ray micro computed tomography and volumetric measurements to validate the relevance of this approach on the NCI-H460 human orthotopic lung tumor. Results This study demonstrates the ability of ultrasound imaging to detect and monitor the in vivo orthotopic lung tumor growth by high resolution ultrasound imaging. This approach enabled us to characterize key biological parameters such as oxygenation, perfusion status and vascularization of tumors. Conclusion Such an experimental approach has never been reported previously and it would provide a nonradiative tool for assessment of anticancer therapeutic efficacy in mice. Considering the absence of ultrasound propagation through the lung parenchyma, this strategy requires the implantation of tumors strictly located in the superficial posterior part of the lung. PMID:27070548