Fusion of Magnetic Resonance Imaging and Real-Time Elastography to Visualize Prostate Cancer: A Prospective Analysis using Whole Mount Sections after Radical Prostatectomy.

PURPOSE: To determine whether the fusion of multiparametric magnetic resonance imaging (MRI) with transrectal real-time elastography (RTE) improves the visualization of PCa lesions compared to MRI alone. MATERIALS AND METHODS: In a prospective setting, 45 patients with biopsy-proven PCa received prostate MRI prior to radical prostatectomy (RP). T2 and diffusion-weighted imaging (T2WI/DW-MRI) and, if applicable, dynamic contrast-enhanced sequences (T2WI/DW/DCE-MRI) were used to perform MRI/RTE fusion. The probability of PCa on MRI was graded according to the PI-RADS score for 12 different prostate sectors per patient. MRI images were fused with RTE to stratify suspicious from non-suspicious sectors. Imaging results were compared to whole mount sections using nonparametrical receiver operating characteristic curves and the area under these curves (AUC). RESULTS: 41 of 45 patients were eligible for final analyses. Histopathology confirmed PCa in 261 (53%) of 492 prostate sectors. MRI alone provided an AUC of 0.62 (T2WI/DW-MRI) and 0.65 (T2WI/DW/DCE-MRI) to predict PCa and was meaningfully enhanced to 0.75 (T2WI/DW-MRI) and 0.74 (T2WI/DW/DCE-MRI) using MRI/RTE fusion. Sole MRI showed a sensitivity and specificity of 57.9% and 61% with the best results for ventral prostate sectors whereas RTE was superior in dorsal and apical sectors. MRI/RTE fusion improved sensitivity and specificity to 65.9% and 75.3%, respectively. Additional use of DCE sequences showed a sensitivity and specificity of 65% and 55.7% for MRI and 72.1% and 66% for MRI/RTE fusion. CONCLUSION: MRI/RTE fusion provides improved PCa visualization by combining the strength of both imaging techniques in regard to prostate zonal anatomy and thereby might improve future biopsy-guided PCa detection.

Integration and evaluation of automated Monte Carlo simulations in the clinical practice of scanned proton and carbon ion beam therapy.

Monte Carlo (MC) simulations of beam interaction and transport in matter are increasingly considered as essential tools to support several aspects of radiation therapy. Despite the vast application of MC to photon therapy and scattered proton therapy, clinical experience in scanned ion beam therapy is still scarce. This is especially the case for ions heavier than protons, which pose additional issues like nuclear fragmentation and varying biological effectiveness. In this work, we present the evaluation of a dedicated framework which has been developed at the Heidelberg Ion Beam Therapy Center to provide automated FLUKA MC simulations of clinical patient treatments with scanned proton and carbon ion beams. Investigations on the number of transported primaries and the dimension of the geometry and scoring grids have been performed for a representative class of patient cases in order to provide recommendations on the simulation settings, showing that recommendations derived from the experience in proton therapy cannot be directly translated to the case of carbon ion beams. The MC results with the optimized settings have been compared to the calculations of the analytical treatment planning system (TPS), showing that regardless of the consistency of the two systems (in terms of beam model in water and range calculation in different materials) relevant differences can be found in dosimetric quantities and range, especially in the case of heterogeneous and deep seated treatment sites depending on the ion beam species and energies, homogeneity of the traversed tissue and size of the treated volume. The analysis of typical TPS speed-up approximations highlighted effects which deserve accurate treatment, in contrast to adequate beam model simplifications for scanned ion beam therapy. In terms of biological dose calculations, the investigation of the mixed field components in realistic anatomical situations confirmed the findings of previous groups so far reported only in homogenous water targets. This work can thus be useful to other centers commencing clinical experience in scanned ion beam therapy.

Monte Carlo simulations to support start-up and treatment planning of scanned proton and carbon ion therapy at a synchrotron-based facility.

Reliable treatment planning of highly conformal scanned ion beam therapy demands accurate tools for the determination and characterization of the individual pencil-like beams building up the integral dose delivery and related mixed radiation field. At present, clinically practicable inverse treatment planning systems (TPSs) can only rely on fast-performing analytical algorithms. However, the rapidly emerging though more computationally intensive Monte Carlo (MC) methods can be employed to complement analytical TPS, e.g., via accurate calculations of the input beam-model data, together with a considerable reduction of the measuring time. Here we present the work done for the application of the FLUKA MC code to support several aspects of scanned ion beam delivery and treatment planning at the Heidelberg Ion Beam Therapy Center (HIT). Emphasis is given to the generation of the accelerator library and of experimentally validated TPS input basic data which are now in clinical use for proton and carbon ion therapy. Additionally, MC dose calculations of planned treatments in water are shown to represent a valuable tool for supporting treatment plan verification in comparison to dosimetric measurements. This paper can thus provide useful information and guidelines for the start-up and clinical operation of forthcoming ion beam therapy facilities similar to HIT.

Inverse association of p16 INK4a and p14 ARF methylation of the CDKN2a locus in different Gleason scores of prostate cancer.

BACKGROUND: Promoter hypermethylation is an important epigenetic mechanism in the regulation of several key modulators of prostate carcinoma progression. Recent studies suggest that the polycomb-group (PcG) protein BMI1 may have an impact on epigenetic regulation of several targets, including the CDKN2a locus. METHODS: In this study, we investigated the association of BMI1 expression, promoter methylation of CDKN2a (p16(INK4a) and p14(ARF)) and TMS1 with pathological variables (Gleason score, TNM stage, perineural invasion) in prostate cancer (PCa). RESULTS: Methylation of p16(INK4a) and p14(ARF) revealed an inverse association with Gleason score 7b and Gleason score 6. No significant association could be demonstrated for BMI1 -overexpression and promoter methylation of p16(INK4a), p14(ARF) and TMS1 as well as pT category. CONCLUSIONS: Our data suggest that the CDKN2a locus is a switch in PCa with methylation of p16(INK4a) being a marker for more aggressive tumours of Gleason score 7b, but no association with BMI overexpression was observed.

The influence of lateral beam profile modifications in scanned proton and carbon ion therapy: a Monte Carlo study.

Scanned ion beam delivery promises superior flexibility and accuracy for highly conformal tumour therapy in comparison to the usage of passive beam shaping systems. The attainable precision demands correct overlapping of the pencil-like beams which build up the entire dose distribution in the treatment field. In particular, improper dose application due to deviations of the lateral beam profiles from the nominal planning conditions must be prevented via appropriate beam monitoring in the beamline, prior to the entrance in the patient. To assess the necessary tolerance thresholds of the beam monitoring system at the Heidelberg Ion Beam Therapy Center, Germany, this study has investigated several worst-case scenarios for a sensitive treatment plan, namely scanned proton and carbon ion delivery to a small target volume at a shallow depth. Deviations from the nominal lateral beam profiles were simulated, which may occur because of misaligned elements or changes of the beam optic in the beamline. Data have been analysed with respect to the lateral penumbra, homogeneity and coverage of the dose deposition in the target volume. The results indicate that homogeneity is not seriously compromised by extremely narrow profiles for the standard planning choices of the lateral raster scan stepping and dose grid. Differently, broad beam distributions can significantly deteriorate the conformality of the dose delivery and too large increases (above approximately 150-200% of the nominal spotsize) must be prevented.

The FLUKA Monte Carlo code coupled with the local effect model for biological calculations in carbon ion therapy.

Clinical Monte Carlo (MC) calculations for carbon ion therapy have to provide absorbed and RBE-weighted dose. The latter is defined as the product of the dose and the relative biological effectiveness (RBE). At the GSI Helmholtzzentrum für Schwerionenforschung as well as at the Heidelberg Ion Therapy Center (HIT), the RBE values are calculated according to the local effect model (LEM). In this paper, we describe the approach followed for coupling the FLUKA MC code with the LEM and its application to dose and RBE-weighted dose calculations for a superimposition of two opposed (12)C ion fields as applied in therapeutic irradiations. The obtained results are compared with the available experimental data of CHO (Chinese hamster ovary) cell survival and the outcomes of the GSI analytical treatment planning code TRiP98. Some discrepancies have been observed between the analytical and MC calculations of absorbed physical dose profiles, which can be explained by the differences between the laterally integrated depth-dose distributions in water used as input basic data in TRiP98 and the FLUKA recalculated ones. On the other hand, taking into account the differences in the physical beam modeling, the FLUKA-based biological calculations of the CHO cell survival profiles are found in good agreement with the experimental data as well with the TRiP98 predictions. The developed approach that combines the MC transport/interaction capability with the same biological model as in the treatment planning system (TPS) will be used at HIT to support validation/improvement of both dose and RBE-weighted dose calculations performed by the analytical TPS.

In-beam PET monitoring of mono-energetic (16)O and (12)C beams: experiments and FLUKA simulations for homogeneous targets.

(16)O and (12)C ion beams will be used-besides lighter ions-for cancer treatment at the Heidelberg Ion Therapy Center (HIT), Germany. It is planned to monitor the treatment by means of in-beam positron emission tomography (PET) as it is done for therapy with (12)C beams at the experimental facility at the Gesellschaft für Schwerionenforschung (GSI), Darmstadt, Germany. To enable PET also for (16)O beams, experimental data of the beta(+)-activity created by these beams are needed. Therefore, in-beam PET measurements of the activity created by (16)O beams of various energies on targets of PMMA, water and graphite were performed at GSI for the first time. Additionally reference measurements of (12)C beams on the same target materials were done. The results of the measurements are presented. The deduction of clinically relevant results from in-beam PET data requires reliable simulations of the beta(+)-activity production, which is done presently by a dedicated code limited to (12)C beams. Because this code is not extendable to other ions in an easy way, a new code, capable of simulating the production of the beta(+)-activity by all ions of interest, is needed. Our choice is the general purpose Monte Carlo code FLUKA which was used to simulate the ion transport, the beta(+)-active isotope production, the decay, the positron annihilation and the transport of the annihilation photons. The detector response was simulated with an established software that gives the output in the same list-mode data format as in the experiment. This allows us to use the same software to reconstruct measured and simulated data, which makes comparisons easier and more reliable. The calculated activity distribution shows general good agreement with the measurements.

[Ductal Adenocarcinoma of the prostate with infiltration of the bladder. Can radical cystectomy and antiandrogen therapy cure the disease?]. / Das duktale Adenokarzinom der Prostata mit Blasenhalsinfiltration. Heilung durch radikale Zystektomie und antiandrogene Therapie?

Ductal adenocarcinoma of the prostate is a rare entity. The lack of correlation between the prostate-specific antigen value and the tumor stage, as well as early dissemination, are major differences from acinar cancer. Due to a lack of early symptoms, the tumor is often found in an advanced stage. Urinary obstruction and hematuria lead to clinical assessment. The characteristic tumor growth near the seminal colliculus can yield a negative digital rectal examination. Despite a lack of treatment guidelines, authors recommend an aggressive surgical concept. First approaches include radical prostatectomy, transurethral resection, and high-dose radiotherapy. Subsequent androgen deprivation is recommended. We report the case of a 64-year-old man with ductal prostate cancer who underwent radical cystectomy followed by androgen deprivation therapy. This is the first such case reported in both the German and the English literature.

Expression of purinergic P2X2-receptors in neurogenic bladder dysfunction due to spinal cord injury: a preliminary immunohistochemical study.

STUDY DESIGN: Retrospective descriptive study. OBJECTIVE: Although muscarinic receptors are the main targets for the treatment of detrusor overactivity today, anticholinergic therapy is not satisfying in a substantial percentage of patients. Recently, overexpression of P(2)X(2) receptors in patients with idiopathic overactive bladder was demonstrated, indicating that purinergic innervation may play an important role in the pathophysiology of detrusor overactivity. We evaluated the expression of P(2)X(2) receptors in patients with spinal cord lesions. SETTING: German university hospital. METHODS: By immunohistochemical staining, the frequency and intensity of P(2)X(2) expression in bladder specimens from 15 patients with suprasacral spinal cord lesion were compared to those from 11 patients with bladder disorders not related to spinal cord injury (overactive bladder: n=6; chronic non-obstructive retention: n=2; bladder tumour: n=3). RESULTS: Specimens (12/15) from patients with spinal cord lesions and specimens (8/11) without spinal cord lesions demonstrated staining for P(2)X(2) receptors in the detrusor muscle and the urothelium. There was a tendency towards a stronger staining in specimens from patients with spinal cord lesion. CONCLUSION: Our pilot study gives a first hint that the P(2)X(2) expression in patients with suprasacral spinal cord injury seems to be comparable to the expression in patients with idiopathic overactive bladder. Therefore, P(2)X(2) receptors in detrusor tissue may be a future target for the treatment of detrusor overactivity.

[Case reports of operative management of very large, benign phylloid tumors--is a safety margin necessary?]. / Fallberichte über operatives Management bei sehr grossen, benignen Phylloidtumoren--Ist ein Sicherheitssaum notwendig?

The phylloid tumor (PT, formerly called cystosarcoma phylloides) is a rare neoplasia of the female breast. Usually the PT is treated with breast-conserving surgery. In spite of progress in early diagnosis, PTs recur frequently--independently of tumor's degree of malignancy. Especially in cases of malignant PT, complete resection with tumor-free margins is seen as the only predictive marker for tumor recurrence or metastases. Benign PT is also often resected with wide tumor-free margins. Because of the tumor's occasionally enormous dimensions, this therapy concept makes breast-conserving surgery almost impossible. A simple enucleation of benign PT is an option to facilitate the preservation of breast tissue and a cosmetically satisfactory breast reconstruction. In the case of particularly large benign PT, enucleation even without wide margins prevents tumor recurrence.

In-beam PET measurement of 7Li3+ irradiation induced beta+-activity.

At present positron emission tomography (PET) is the only feasible method of an in situ and non-invasive monitoring of patient irradiation with ions. At the experimental carbon ion treatment facility of the Gesellschaft für Schwerionenforschung (GSI) Darmstadt an in-beam PET scanner has been integrated into the treatment site and lead to a considerable quality improvement of the therapy. Since ions other than carbon are expected to come into operation in future patient treatment facilities, it is highly desirable to extend in-beam PET also to other therapeutic relevant ions, e.g. (7)Li. Therefore, by means of the in-beam PET scanner at GSI the beta(+)-activity induced by (7)Li(3+) ions has been investigated for the first time. Targets of PMMA, water, graphite and polyethylene were irradiated with monoenergetic, pencil-like beams of (7)Li(3+) with energies between 129.1 A MeV and 205.3 A MeV and intensities ranging from 3.0 x 10(7) to 1.9 x 10(8) ions s(-1). This paper presents the measured beta(+)-activity profiles as well as depth dependent thick target yields which have been deduced from the experimental data. The beta(+)-activity induced by (7)Li ions was found to be a factor of 1.76 higher than the one induced by (12)C ions at the same physical dose and particle range.

[Effectiveness of radiofrequency ablation of lung tumours ]. / Radiofrequenzablation von Lungentumoren : Eine wirklich effektive Therapiemassnahme?

BACKGROUND: There has been great success in the treatment of primary and secondary tumours of the liver using radiofrequency ablation (RFA) therapy, resulting in this method being used for other solid tumours such as in the lung. However, concerning lung cancer only few data are available about the histomorphological effects of this method. The aim of this study was to analyse the effects of RFA therapy in tumours of the lung. PATIENTS AND METHODS: Eleven patients with non-small-cell lung cancer and one with a lung metastasis (primary tumour identified as urothelial carcinoma) underwent RFA therapy followed by resection of the affected lobe. One patient with a metastasis of the liver was included for comparison of treatment effects. Histomorphological analysis of the collected material was used to measure the amount of necrosis. RESULTS: None of the treated tumours of the lung showed complete necrosis after applying RFA therapy. In contrast, this method with the control metastasis of the liver resulted in complete thermal destruction. CONCLUSION: Our results indicate that RFA therapy is not adequate for successful induction of necrosis in tumours of the lung. Therefore the use of this method has to be considered extremely carefully as a palliative treatment option in tumours of the lung.

A lightweight, partially absorbable mesh (Ultrapro) for endoscopic hernia repair: experimental biocompatibility results obtained with a porcine model.

BACKGROUND: A meticulous surgical technique, a mesh of adequate dimensions, and use of a mesh with good biocompatibility properties are decisively important for minimizing the development of recurrences after endoscopic hernia repair surgery. Mesh "shrinkage" is a function of the mesh's biocompatibility, that is, the properties of the mesh. Large-pore, lightweight polypropylene meshes possess the best biocompatibility, and the newly developed meshes meet these requirements. METHODS: Using a totally extraperitoneal technique in an experimental animal model, 10 domestic pigs were implanted with a lightweight, large-pore polypropylene mesh containing an absorbable component consisting of poliglecaprone (Ultrapro). After a period of 91 days, diagnostic laparoscopy followed by explantation of the specimens for macroscopic, histologic, and immunohistochemical evaluation was performed. RESULTS: The mean mesh shrinkage was a mere 1.9%. The partial volume of the inflammatory cells was a low 15.8%. The markers of cell turnover, namely Ki67 and the apoptosis index, were, at 5.8 and 2.1, respectively, also very low. The extracellular matrix showed a low value of transforming growth factor-beta (TGF-beta) (50.8). The mean value of collagen 1 was 136.9. CONCLUSIONS: As a result of its good biocompatibility and elastic properties, the lightweight, large-pore Ultrapo mesh showed only a very slight tendency to "shrink." This renders it extremely well suited for clinical use in hernia repair surgery, and its minimal shrinkage characteristic should help in achieving low complication and recurrence rates.

Clinical CT-based calculations of dose and positron emitter distributions in proton therapy using the FLUKA Monte Carlo code.

Clinical investigations on post-irradiation PET/CT (positron emission tomography/computed tomography) imaging for in vivo verification of treatment delivery and, in particular, beam range in proton therapy are underway at Massachusetts General Hospital (MGH). Within this project, we have developed a Monte Carlo framework for CT-based calculation of dose and irradiation-induced positron emitter distributions. Initial proton beam information is provided by a separate Geant4 Monte Carlo simulation modelling the treatment head. Particle transport in the patient is performed in the CT voxel geometry using the FLUKA Monte Carlo code. The implementation uses a discrete number of different tissue types with composition and mean density deduced from the CT scan. Scaling factors are introduced to account for the continuous Hounsfield unit dependence of the mass density and of the relative stopping power ratio to water used by the treatment planning system (XiO (Computerized Medical Systems Inc.)). Resulting Monte Carlo dose distributions are generally found in good correspondence with calculations of the treatment planning program, except a few cases (e.g. in the presence of air/tissue interfaces). Whereas dose is computed using standard FLUKA utilities, positron emitter distributions are calculated by internally combining proton fluence with experimental and evaluated cross-sections yielding 11C, 15O, 14O, 13N, 38K and 30P. Simulated positron emitter distributions yield PET images in good agreement with measurements. In this paper, we describe in detail the specific implementation of the FLUKA calculation framework, which may be easily adapted to handle arbitrary phase spaces of proton beams delivered by other facilities or include more reaction channels based on additional cross-section data. Further, we demonstrate the effects of different acquisition time regimes (e.g., PET imaging during or after irradiation) on the intensity and spatial distribution of the irradiation-induced beta+-activity signal for the cases of head and neck and para-spinal tumour sites.

The FLUKA code: new developments and application to 1 GeV/n iron beams.

The modeling of ion transport and interactions in matter is a subject of growing interest, driven by the continuous increase of possible application fields. These include hadron therapy, dosimetry, and space missions, but there are also several issues involving fundamental research, accelerator physics, and cosmic ray physics, where a reliable description of heavy ion induced cascades is important. In the present work, the capabilities of the FLUKA code for ion beams will be briefly recalled and some recent developments presented. Applications of the code to the simulation of therapeutic carbon, nitrogen and oxygen ion beams, and of iron beams, which are of direct interest for space mission related experiments, will be also presented together with interesting consideration relative to the evaluation of dosimetric quantities. Both applications involve ion beams in the AGeV range.

Eosinophilia in nasal polyposis: its objective quantification and clinical relevance.

BACKGROUND: Eosinophilia within nasal polyps is often taken as a criterion for adjuvant medical treatment postoperatively such as topical steroids. OBJECTIVE: This study was performed in order to validate a new technique for objective quantification of eosinophilia by using laser scanning cytometry (LSC), to compare these results with manual scoring and routine histopathology, and to correlate them with the history of allergy or recurrence. METHODS: LSC was used for semi-automated analysis of single-cell preparations from representative ethmoidal polyps obtained during routine paranasal sinus surgery (n=41). This microscope-based instrument scans the cells after immobilization of cells on a glass slide and after triple staining of cytokeratin, eosinophilic granula, and DNA. The location of each cell is stored with the fluorescence data. Therefore, the morphology of every cell can be documented by re-staining with haemotoxylin and eosin and re-localization on the slide. Subsequently, slides were subjected to manual scoring. The remaining polyps were analysed by routine histopathology. RESULTS: Data from LSC and manual scoring showed good correlation (r=0.81, P<0.001), whereas there were discrepancies with histopathology. Eosinophilia scored by LSC and histopathology was neither correlated with the history of allergy nor with recurrence as determined by Fisher's exact test independent of the definition of eosinophilia (> or =2%, > or =3%, or > or =5% of all cells). CONCLUSION: Scoring eosinophilia by LSC in comparison with histopathology does not contribute to a more reliable basis for adjuvant medical therapy in nasal polyposis. Instead, functional parameters (cytokine production, apoptosis) may serve better.

Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.

BACKGROUND: The Raf/MEK/ERK (mitogen activated protein kinase-MAPK) signal transduction cascade is an important mediator of a number of cellular fates, including growth, proliferation, and survival. The BRAF gene, one of the human isoforms of RAF, is activated by oncogenic Ras, leading to cooperative effects in cells responding to growth factor signals. AIMS: The aim of this study was to elucidate a possible function of BRAF in liver tumours. METHODS: Mutations of BRAF and KRAS were evaluated in 25 hepatocellular carcinomas (HCC) and in 69 cholangiocarcinomas (CC) by direct DNA sequencing analyses after microdissection. The presence of active intermediates of the MAPK pathway was assessed immunohistochemically. The results obtained were correlated with histopathological variables and patient survival. RESULTS: Activating BRAF missense mutations were identified in 15/69 CC (22%) and in one case of tumour surrounding liver. KRAS mutations were found in 31 of 69 (45%) CC examined and in two cases of tumour surrounding non-neoplastic liver tissue. In HCC, neither BRAF nor KRAS mutations were detected. All 31 CC with KRAS mutations had an intact BRAF gene. We failed to observe a correlation between BRAF or KRAS mutations and histopathological factors or prognosis of patients. CONCLUSIONS: Our data indicate that BRAF gene mutations are a relatively common event in CC but not in HCC. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway, either by RAS or BRAF mutation, was detected in approximately 62% of all CC and is therefore one of the most frequent defects in cholangiocellular carcinogenesis.