Validation of a pseudo-3D phantom for radiobiological treatment plan verifications.

Performing realistic and reliable in vitro biological dose verification with good resolution for a complex treatment plan remains a challenge in particle beam therapy. Here, a new 3D bio-phantom consisting of 96-well plates containing cells embedded into Matrigel matrix was investigated as an alternative tool for biological dose verification. Feasibility tests include cell growth in the Matrigel as well as film dosimetric experiments that rule out the appearance of field inhomogeneities due to the presence of the well plate irregular structure. The response of CHO-K1 cells in Matrigel to radiation was studied by obtaining survival curves following x-ray and monoenergetic 12C ion irradiation, which showed increased radioresistance of 3D cell cultures in Matrigel as compared to a monolayer. Finally, as a proof of concept, a 12C treatment plan was optimized using in-house treatment planning system TRiP98 for uniform cell survival in a rectangular volume and employed to irradiate the 3D phantom. Cell survival distribution in the Matrigel-based phantom was analyzed and compared to cell survival in a reference setup using cell monolayers. Results of both methods were in good agreement and followed the TRiP98 calculation. Therefore, we conclude that this 3D bio-phantom can be a suitable, accurate alternative tool for verifying the biological effect calculated by treatment planning systems, which could be applied to test novel treatment planning approaches involving multiple fields, multiple ion modalities, complex geometries, or unconventional optimization strategies.

Oxygen beams for therapy: advanced biological treatment planning and experimental verification.

Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, [Formula: see text]O ions are being widely discussed due to their increased LET distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with [Formula: see text]O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from ≈20 up to ≈750 keV µ [Formula: see text], oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, [Formula: see text]O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to [Formula: see text]C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where [Formula: see text]O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of ≈0.15% or lower) and relatively low doses (≈4 Gy or lower) the choice of [Formula: see text]O over [Formula: see text]C or [Formula: see text]He may be justified.

No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission.

AIMS: Proof-of-concept evidence suggests that mechanical ischaemic post-conditioning (PostC) reduces infarct size when applied immediately after culprit coronary artery re-opening in ST-elevation myocardial infarction (STEMI) patients with thrombolysis in myocardial infarction 0-1 (TIMI 0-1) flow grade at admission. Whether PostC might also be protective in patients with a TIMI 2-3 flow grade on admission (corresponding to a delayed application of the post-conditioning algorithm) remains undetermined. METHODS AND RESULTS: In this multi-centre, randomized, single-blinded, controlled study, STEMI patients with a 2-3 TIMI coronary flow grade at admission underwent direct stenting of the culprit lesion, followed (PostC group) or not (control group) by four cycles of (1 min inflation/1 min deflation) of the angioplasty balloon to trigger post-conditioning. Infarct size was assessed both by cardiac magnetic resonance at Day 5 (primary endpoint) and cardiac enzymes release (secondary endpoint). Ninety-nine patients were prospectively enrolled. Baseline characteristics were comparable between control and PostC groups. Despite comparable size of area at risk (AAR) (38 ± 12 vs. 38 ± 13% of the LV circumference, respectively, P = 0.89) and similar time from onset to intervention (249 ± 148 vs. 263 ± 209 min, respectively, P = 0.93) in the two groups, PostC did not significantly reduce cardiac magnetic resonance infarct size (23 ± 17 and 21 ± 18 g in the treated vs. control group, respectively, P = 0.64). Similar results were found when using creatine kinase and troponin I release, even after adjustment for the size of the AAR. CONCLUSION: This study shows that infarct size reduction by mechanical ischaemic PostC is lost when applied to patients with a TIMI 2-3 flow grade at admission. This indicates that the timing of the protective intervention with respect to the onset of reperfusion is a key factor for preventing lethal reperfusion injury in STEMI patients. CLINICAL TRIAL NUMBER: NCT01483755.

[Prehospital treatment with bivalirudin in acute myocardial infarction referred for primary angioplasty. About 152 consecutive patients study]. / Traitement préhospitalier par bivalirudine de l'infarctus aigu du myocarde orienté vers une angioplastie primaire. À propos d'une série consécutive de 152 cas.

OBJECTIVE OF THE STUDY: Bivalirudin, a direct thrombin inhibitor, demonstrated an improvement in the prognosis of acute coronary syndromes by a decrease in major bleeding complications. This observational study evaluated inhospital outcome of patients with acute myocardial infarction treated by prehospital bivalirudin before primary angioplasty. PATIENTS AND METHODS: We included, from June 2010 to June 2012, all patients with acute myocardial infarction receiving prehospital bivalirudin with bolus of 0.75mg/kg followed by an infusion of 1.75mg/kg per hour until the arrival in the catheterization laboratory. Bivalirudin was possibly continued after primary angioplasty. RESULTS: We included 152 patients aged 57.6±11.6 years. A prehospital 60mg loading dose of prasugrel was given in 77% of patients. Coronary angiography with radial access (77.6%) was performed before a successful angioplasty in 97.3% of cases. The bivalirudin infusion was continued after the procedure in 81.6% of patients. Inhospital outcome showed two deaths (1.3%) and two re-infarctions (1.3%) of which one was related to the single acute stent thrombosis (0.6%). Major bleeding complications were limited irrespective of the Gusto (0.6%), Timi (0.6%) or Horizons-MI (4.6%) classification. Bleeding complications rate was similar when bivalirudin was followed or not after primary angioplasty. CONCLUSION: The use of bivalirudin in the prehospital setting for primary angioplasty seems to be effective and safe about ischemic and bleeding complications during the inhospital outcome.

Introducing a large animal model to create urethral stricture similar to human stricture disease: a comparative experimental microscopic study.

PURPOSE: In this tissue engineering study we investigated urethral stricture formation to evaluate different treatment modalities in the large animal model and validate the most current, comparable effect of human stricture development for successful human clinical application. MATERIALS AND METHODS: In 12 male minipigs stricture formation was evaluated by urethrography 1, 8 and 12 weeks after stricture induction by ligation, urethrotomy or thermocoagulation. Normal human urethral and scar tissue of 6 patients was harvested and compared to animal specimens. The effect of urethral damage was investigated for microvessel density and collagen I:III ratio. RESULTS: A week after urethrotomy urothelium covered the spongiosum tissue, showing minimal infiltration of lymphocytes and macrophages, and sporadic eosinophil granulocytes. However, increased connective tissue was observed with time as well as urethral luminal narrowing, vascular network loss (decreased microvessel density) and significantly increased collagen with a favorably revised collagen type I:III ratio. The 3 methods of stricture induction resulted in different stricture severity in the animal model (thermocoagulation >ligation >urethrotomy). Porcine urethral samples after thermocoagulation showed a significantly increased collagen I:III ratio (p <0.001), almost equal to that of human urethral stricture specimens. CONCLUSIONS: We successfully developed a large animal model in which to study urethral stricture formation by defined iatrogenic intervention. The established animal model advances investigation to evaluate new therapy modalities in a preclinical setting to treat urethral stricture and predict clinical outcome.

Development of a porcine animal model for urethral stricture repair using autologous urothelial cells.

OBJECTIVE: To present a versatile large animal model for endoscopic stricture repair using autologous urothelial cells. MATERIALS AND METHODS: 12 male minipigs were used. An artificial stricture model was established using suture-ligation, thermo-coagulation and internal urethrotomy. A vesicostomy served for urinary diversion. Stricture formation was confirmed radiologically and histologically. Autologous urothelial cells were harvested from bladder washings, cultivated and labeled. Internal urethrotomy was done in all, and the cultivated cells were injected into the urethrotomy wound. All animals were sacrificed after 4 or 8 weeks. Immunohistology was done to confirm the presence of autologous urothelial cells within the reconstituted urethra. RESULTS: Stricture formation was verified with all three methods. Histologically, no significant differences in the severity of stricture development could be observed with regard to the method used. The autologous urothelial cells in the area of the urethrotomy could be detected in the urothelium and the corpus spongiosum until 8 weeks after re-implantation. CONCLUSIONS: We created a reliable and reproducible porcine model for artificial urethral strictures. Autologous urothelial cells can be implanted into an artificial stricture after urethrotomy. These cells retain their epithelial phenotype and are integrated in the resident urothelium. Further comparative studies are needed to ultimately determine a superior efficacy of this novel approach.

[Non ST elevation acute coronary syndromes and normal coronary angiography: is it truly good news?]. / Coronarographie normale au cours des syndromes coronariens aigus non ST+: une fausse bonne nouvelle?

Among 10% of all patients presenting with non ST elevation acute coronary syndromes (ACS), coronary angiography do not show non lesions at all (50%) or mild atheromatous stenosis (50%). ACS without angiographic stenosis are more prevalent in female sex and young patients but can be seen in older ones and in men. Pathogenic mechanisms include acute evolution of vulnerable non-significant plaques and endothelial dysfunction. In hospital and mean term prognosis is not as benign as expected. Six months deaths and myocardial infarction incidence is around 6%. Numerous rehospitalizations due to ischemic recurrences are also very often seen. Therefore, such surprising coronary angiograms do not preclude a fair follow-up. These patients need a careful therapeutic strategy.

Discriminant responses of the catalytic unit and glucose 6-phosphate transporter components of the hepatic glucose-6-phosphatase system in Ehrlich ascites-tumor-bearing mice.

The effect of Ehrlich ascites tumor cells, in vivo, on the hepatic glucose-6-phosphatase (G6Pase) system was examined. The V(max) for glucose 6-phosphate hydrolysis by G6Pase was reduced by 40% and a greater than 15-fold decrease in mRNA encoding the catalytic unit of the G6Pase system was observed 8 days after injection with tumor cells. Blood glucose concentration was decreased from 169 +/- 17 to 105 +/- 9 mg/dl in tumor-bearing mice. There was no change in the G6P transporter (G6PT) mRNA level. However, there was a significant decrease in G6P accumulation into hepatic microsomal vesicles derived from tumor-bearing mice. Decreased G6P accumulation was also associated with a decrease in G6Pase hydrolytic activity in the presence of vanadate, a potent catalytic-unit inhibitor. In addition, G6P accumulation was nearly abolished in microsomes treated with N-bromoacetylethanolamine phosphate, an irreversible inhibitor of the G6PT. These results demonstrate that the catalytic unit and G6PT components of the G6Pase system can be discriminantly regulated, and that microsomal glucose 6-phosphate uptake is dependent on catalytic unit activity as well as G6PT action.

[Course and treatment of osteomyelitis in childhood (author's transl)]. / Zur Klinik und Therapie der kindlichen Osteomyelitis

In the years 1955-1972 132 children with osteomyelitis were treated in the Pediatric, Surgical and Orthopedic Department of the university of Kiel. There was no increase in the incidence of osteomyelitis during this period. Acute hematogenous osteomyelitis was diagnosed in 111 children, chronic hematogenous osteomyelitis in 11 children, traumatic and postoperative osteomyelitis in 10 children. Secondary chronic osteomyelitis occurred in 1 patient. Mainly staphylococci (in 90%) were the pathogenic bacteria, whereas haemophilus, pseudomonas, streptococci group A, E. coli and mixed infections occurred less frequently. In 17 of 111 patients with acute hematogenous osteomyelitis there were no roentgenological changes. Bacteriological investigations of blood and pus, and the antistaphylolysin reaction (repeated in the course of the disease) were helpful to establish the diagnosis in many cases. 107 of 111 patients with acute hematogenous osteomyelitis were cured (8 patients with defects). 4 children died in septic shock or because of complications (meningitis, pleural empyema, pneumonia). Bactericidal antibiotics in high dosage (penicillins, gentamicin) were superior to bacteriostatic antibiotics. Additional surgical treatment was necessary in 49 of 111 patients with acute hematogenous osteomyelitis. Recommendations for antibiotic therapy of osteomyelitis are given.