Changes in Bladder Volume During Radiotherapy for Prostate Cancer.

BACKGROUND/AIM: Patients irradiated for prostate cancer may experience urinary toxicity, particularly if the bladder volume is small. A mobile application (app) that reminds the patients to drink water prior to each radiation fraction may help avoid small volumes. This study investigating bladder volumes during a radiotherapy course is a prerequisite for a prospective trial testing such a reminder app. PATIENTS AND METHODS: Frequency of bladder volumes <200 ml and seven potential risk factors were retrospectively evaluated in 72 patients receiving external beam radiotherapy for non-metastatic prostate cancer. RESULTS: The mean and median values of the numbers of radiation fractions with bladder volumes <200 ml were 17.8 (standard deviation=12.0) and 16.5 (interquartile range Q1-Q3=7.5-29.5) fractions, respectively. Higher numbers of fractions with volumes <200 ml were significantly associated with pre-radiotherapy bladder volumes <200 ml (p<0.001) and high-risk prostate cancer (p=0.014). CONCLUSION: The proportion of bladder volumes <200 ml during the radiotherapy course was high and needs to be decreased. Pre-radiotherapy bladder volume and risk level of prostate cancer were significant risk factors for higher numbers of fractions with volumes <200 ml. These results are important for designing a prospective trial.

Therapy Intensity Outweighs the Prognostic Importance of the Timing of Chemoradiotherapy in Newly Diagnosed Glioblastoma Patients.

BACKGROUND/AIM: To investigate the significance of the timing of chemoradiotherapy together with clinical and laboratory features in newly diagnosed glioblastoma. PATIENTS AND METHODS: Clinical and laboratory parameters of 209 patients with glioblastoma potentially influencing overall (OS) and progression-free (PFS) survival were analyzed in univariable and multivariable models. RESULTS: On univariable analyses, Karnofsky performance status (p<0.001), recursive partitioning analysis (RPA) class (p<0.001), O6-methylguanine-DNA methyltransferase (MGMT)-status (p<0.001), extent of resection (p<0.001), radiotherapy dose (p=0.01), and the number of adjuvant temozolomide (TMZ) cycles (p<0.001) were significantly associated with OS. Additionally, MGMT-status (p<0.001), extent of resection (p=0.03), surgical site infections (p=0.02), and the number of adjuvant TMZ cycles (p<0.001) were significantly associated with PFS. Multivariable analysis identified radiotherapy dose as the only independent predictor (p=0.049) of OS. MGMT-status (p=0.02) and the number of adjuvant TMZ cycles (p<0.001) were independent predictors of PFS. CONCLUSION: The timing of chemoradiotherapy did not play a prognostic role. For OS, the radiotherapy dose, and for PFS, MGMT-status and the number of adjuvant TMZ cycles were identified as independent prognostic factors.

Novel hybrid treatment planning approach for irradiation a pediatric craniospinal axis.

This study presents a new treatment planning approach merging 3D-CRT and VMAT fields into a hybrid treatment plan (HybTP), in order to achieve an optimum dose coverage of the planning target volume (PTV) and protection of OAR. Craniospinal axis irradiation (CSI) treated with 3D conformal radiotherapy (3D-CRT) is associated with high doses to the heart and eye lenses but provides better sparing of lungs and kidneys compared to volumetric modulated arc therapy (VMAT). VMAT treatment spares eye lenses and the heart, but lungs and kidneys are not as effective as 3D-CRT. Thus, a combination of both techniques (HybTP) may be optimal in sparing all these organs at risk (OAR). The results of HybTP are compared with helical tomotherapy (HT), intensity modulated radio therapy (IMRT), VMAT, and 3D-CRT plans. Hybrid, HT, VMAT, IMRT, and 3D-CRT treatment plans for a male child (age 6 years) with medulloblastoma were created and compared. A total dose of 35.2 Gy (PTV) with a dose per fraction of 1.6 Gy was prescribed. The following dose acceptance criteria were defined: The plans were compared regarding dose homogeneity index (HI) and conformity index (CI), PTV coverage, (particularly at cribriform plate) and doses at OARs. Best conformity was achieved with HT (CI = 0.98) followed by VMAT (CI = 0.96), IMRT (CI = 0.91), HybTP (CI = 0.86), and 3D-CRT (CI = 0.83). The homogeneity index varied marginally. For both HT and IMRT the HI was 0.07, and for 3D-CRT, VMAT and HybTP the HI was between 0.13 and 0.15. The cribriform plate was sufficiently covered by HybTP, VMAT, and 3D-CRT. The dose acceptance criteria for OARs were met by HT and HybTP. VMAT did not meet the criteria for lung (Dmean = right 10.4 Gy/left 10.2 Gy), 3D-CRT did not meet the criteria for eye lenses (Dmax = right 32.3 Gy/left 33.1), and heart (V25≈44%) and IMRT did not meet the criteria for lung (Dmean = right 11.1 Gy/left 11.2 Gy) and eye lenses (Dmax = right 12.2 Gy/left 13.1). HybTP meets all defined acceptance criteria and has proved to be a reasonable alternative for CSI. With HybTP that combines VMAT at the brain and heart with 3D-CRT posterior spinal fields (to spare lungs and kidneys), both appropriate coverage of the PTV and sparing of OAR can be achieved.

A New Phantom for Individual Verification of the Dose Distribution in Precision Radiotherapy for Head-and-Neck Cancer.

BACKGROUND/AIM: Many patients with head-and-neck cancers receive radiotherapy. Treatment planning can be very complex in case of dental fillings or implants that cause metal artefacts. Verification of dose distributions may be performed using specific phantoms. This study aimed to develop a 3D-printed phantom that can be produced easily and cost-effectively. PATIENTS AND METHODS: The phantom was designed to allow fast adaption to a patient's individual situation with a particular focus on metal artefacts due to dental fillings. Bone and soft-tissue shells were 3D-printed and filled with tissue-equivalent materials. RESULTS: Attenuation properties of the tissue-equivalent structures in the phantom corresponded well to the structures of real human anatomy. In magnetic resonance (MR)-imaging, useful signals of the materials in the phantom were obtained. CONCLUSION: The phantom met the requirements including equivalence with human tissues and can be useful for highly individual treatment planning in precision-radiotherapy of head-and-neck cancers. It can be also used for scientific issues related to MR-imaging.

Intra-arterial EmboCept S® and DC Bead® effectively inhibit tumor growth of colorectal rat liver metastases.

BACKGROUND: Intra-arterial therapy with embolics is established for the treatment of malignancies of the liver. However, there are no studies comparing the different effects of various embolics used in clinical practice. Herein, we analyzed the effect of 3 different embolics on tumor growth in a rat model of colorectal liver metastases. METHODS: Eight days after subcapsular implantation of 5 × 105 colorectal cancer cells (CC531) in the left liver lobe of WAG/Rij rats were randomized into 4 groups (n = 8) and underwent intra-arterial hepatic therapy. Animals received either EmboCept S®, DC Bead® or Lipiodol® Ultra-Fluid. Animals of the control group received a comparable amount of saline. Tumor growth was measured on day 8 and 11 using a three-dimensional 40 MHz ultrasound device. On day 11 tumor and liver tissue were removed for histological and immunohistochemical analyses. RESULTS: On day 11 animals of the control group showed a tumor growth of ~ 60% compared to day 8. Application of Lipiodol Ultra-Fluid® did not significantly influence tumor growth (~ 40%). In contrast, treatment with EmboCept S® or DC Bead® completely inhibited tumor growth. Of interest, application of EmboCept S® did not only completely inhibit tumor growth but even decreased tumor size. Immunohistochemical analysis showed a significant increase of necrotic areas within the tumors after application of EmboCept S® and DC Bead® compared to Lipiodol® Ultra-Fluid. CONCLUSION: The present study demonstrates that an intra-arterial therapy with EmboCept S® and DC Bead®, but not Lipiodol® Ultra-Fluid, results in a complete inhibition of rat colorectal liver metastatic growth.

Improvement of dose calculation in radiation therapy due to metal artifact correction using the augmented likelihood image reconstruction.

BACKGROUND: Metal artifacts caused by high-density implants lead to incorrectly reconstructed Hounsfield units in computed tomography images. This can result in a loss of accuracy in dose calculation in radiation therapy. This study investigates the potential of the metal artifact reduction algorithms, Augmented Likelihood Image Reconstruction and linear interpolation, in improving dose calculation in the presence of metal artifacts. MATERIALS AND METHODS: In order to simulate a pelvis with a double-sided total endoprosthesis, a polymethylmethacrylate phantom was equipped with two steel bars. Artifacts were reduced by applying the Augmented Likelihood Image Reconstruction, a linear interpolation, and a manual correction approach. Using the treatment planning system Eclipse™, identical planning target volumes for an idealized prostate as well as structures for bladder and rectum were defined in corrected and noncorrected images. Volumetric modulated arc therapy plans have been created with double arc rotations with and without avoidance sectors that mask out the prosthesis. The irradiation plans were analyzed for variations in the dose distribution and their homogeneity. Dosimetric measurements were performed using isocentric positioned ionization chambers. RESULTS: Irradiation plans based on images containing artifacts lead to a dose error in the isocenter of up to 8.4%. Corrections with the Augmented Likelihood Image Reconstruction reduce this dose error to 2.7%, corrections with linear interpolation to 3.2%, and manual artifact correction to 4.1%. When applying artifact correction, the dose homogeneity was slightly improved for all investigated methods. Furthermore, the calculated mean doses are higher for rectum and bladder if avoidance sectors are applied. CONCLUSION: Streaking artifacts cause an imprecise dose calculation within irradiation plans. Using a metal artifact correction algorithm, the planning accuracy can be significantly improved. Best results were accomplished using the Augmented Likelihood Image Reconstruction algorithm.

Portal branch ligation does not counteract the inhibiting effect of temsirolimus on extrahepatic colorectal metastatic growth.

The mTor-inhibitor temsirolimus (TEM) has potent anti-tumor activities on extrahepatic colorectal metastases. Treatment of patients with advanced disease may require portal branch ligation (PBL). While PBL can induce intrahepatic tumor growth, the effect of PBL on extrahepatic metastases under TEM treatment is unknown. Therefore, we analyzed the effects of TEM treatment on extrahepatic metastases during PBL-associated liver regeneration. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of BALB/c-mice. Mice were randomized to four groups (n = 8). One was treated daily with TEM (1.5 mg/kg), PBS-treated animals served as controls. Another group underwent PBL of the left liver lobe and received daily TEM treatment. Animals with PBL and PBS treatment served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied over 14 days. In non-PBL animals TEM treatment inhibited tumor cell proliferation as well as vascularization and growth of the extrahepatic metastases. PBL did not influence tumor cell engraftment, vascularization and metastatic growth. Of interest, TEM treatment significantly reduced tumor cell engraftment, neovascularization and metastatic groth also after PBL. PBL does not counteract the inhibiting effect of TEM on extrahepatic colorectal metastatic growth.

The effects of metal artifact reduction on the retrieval of attenuation values.

BACKGROUND: The quality of CT slices can be drastically reduced in the presence of high-density objects such as metal implants within the patients' body due to the occurrence of streaking artifacts. Consequently, a delineation of anatomical structures might not be possible, which strongly influences clinical examination. PURPOSE: The aim of the study is to clinically evaluate the retrieval of attenuation values and structures by the recently proposed Augmented Likelihood Image Reconstruction (ALIR) and linear interpolation in the presence of metal artifacts. MATERIAL AND METHODS: A commercially available phantom was equipped with two steel inserts. At a position between the metal rods, which shows severe streaking artifacts, different human tissue-equivalent inserts are alternately mounted. Using a single-source computer tomograph, raw data with and without metal rods are acquired for each insert. Images are reconstructed using the ALIR algorithm and a filtered back projection with and without linear interpolation. Mean and standard deviation are compared for a region of interest in the ALIR reconstructions, linear interpolation results, uncorrected images with metal rods, and the images without metal rods, which are used as a reference. Furthermore, the reconstructed shape of the inserts is analyzed by comparing different profiles of the image. RESULTS: The measured mean and standard deviation values show that for all tissue classes, the metal artifacts could be reduced using the ALIR algorithm and the linear interpolation. Furthermore, the HU values for the different classes could be retrieved with errors below the standard deviation in the reference image. An evaluation of the shape of the inserts shows that the reconstructed object fits the shape of the insert accurately after metal artifact correction. Moreover, the evaluation shows a drop in the standard deviation for the ALIR reconstructed images compared to the reference images while reducing artifacts and keeping the shape of the inserts, which indicates a noise reduction ability of the ALIR algorithm. CONCLUSION: HU values, which are distorted by metal artifacts, can be retrieved accurately with the ALIR algorithm and the linear interpolation approach. After metal artifact correction, structures, which are not perceptible in the original images due to streaking artifacts, are reconstructed correctly within the image using the ALIR algorithm. Furthermore, the ALIR produced images with a reduced noise level compared to reference images and artifact images. Linear interpolation results in a distortion of the investigated shapes and features remaining streaking artifacts.

Tumour growth of colorectal rat liver metastases is inhibited by hepatic arterial infusion of the mTOR-inhibitor temsirolimus after portal branch ligation.

Portal branch ligation (PBL) can be performed before major hepatic resection of colorectal liver metastases (mCRC) to increase the remnant liver mass. However, PBL may also stimulate mCRC growth through hepatic arterial hyperperfusion and growth factor release. Herein, we studied whether hepatic arterial infusion (HAI) of the mTOR-inhibitor temsirolimus (Tem) is capable of inhibiting the growth of colorectal liver metastases after PBL. WAG/Rij rats were randomized to four groups (n=6 each) and underwent subcapsular implantation of 5×10(5) CC531 cells into the left liver lobe. The animals of two groups underwent simultaneous PBL of the tumour bearing liver lobe. Ten days later animals underwent a HAI either of temsirolimus (Tem and PBL Tem) or saline solution (Sham and PBL Sham). Tumour size was analyzed at days 10 and 13 using three-dimensional ultrasound. In Sham controls tumour volume increased by 43%. After PBL Sham tumour volume increased by 52%. In contrast, in animals undergoing HAI of temsirolimus the tumour growth was not only completely inhibited, but tumour volume was found decreased, irrespective of PBL. After HAI of temsirolimus immunohistochemistry revealed an increased cleaved caspase-3 activity, indicating stimulation of apoptotic cell death. In parallel temsirolimus treatment was associated with a significant reduction of PECAM-1 positive cells within the tumour tissue, implying a reduced tumour vascularisation. HAI of temsirolimus is capable of inhibiting the growth of CC531 colorectal rat liver metastases also after PBL.

Intrahepatic cholangiocarcinoma in a transplant liver--selective internal radiation therapy followed by right hemihepatectomy: report of a case.

Intra- or extrahepatic cholangiocarcinomas are the second most common primary liver malignancies behind hepatocellular carcinoma. Whereas the incidence for intrahepatic cholangiocarcinoma is rising, the occurrence of extrahepatic cholangiocarcinoma is trending downwards. The treatment of choice for intrahepatic cholangiocarcinoma remains liver resection. However, a case of liver resection after selective internal radiation therapy in order to treat a recurrent intrahepatic cholangiocarcinoma in a transplant liver is unknown in the literature so far. Herein, we present a case of a patient undergoing liver transplantation for Wilson's disease with an accidental finding of an intrahepatic cholangiocarcinoma within the explanted liver. Due to a recurrent intrahepatic cholangiocarcinoma after liver transplantation, a selective internal radiation therapy with yttrium-90 microspheres was performed followed by right hemihepatectomy. Four years later, the patient is tumor-free and in a healthy condition.

Successful management of postoperative necrotizing pancreatitis after infrarenal abdominal aortic aneurysm repair.

We present a case of severe necrotizing pancreatitis that developed after elective repair of an abdominal aortic aneurysm. Surgeons are confronted in cases of postoperative acute pancreatitis with the dilemma of potential intraabdominal infection and the high risk of a subsequent infection of the retroperitoneal synthetic material. The therapeutic options range from a restrictive regime to radical necrosectomy and multivisceral resection.

Hepatic arterial infusion of temsirolimus inhibits tumor growth of colorectal rat liver metastases even after a growth stimulating procedure like liver resection.

BACKGROUND: Hepatic arterial infusion (HAI) of specific anti-tumor drugs can be more effective compared with systemic drug application. Herein, we studied whether HAI of temsirolimus is effective to inhibit tumor growth of colorectal liver metastases after liver resection. MATERIALS AND METHODS: Twenty-four Wistar Albino Glaxo from Rijswijk (WAG/Rij) rats were randomized to four groups and underwent subcapsular implantation of CC531 colorectal cancer cells in the left liver lobe. In two groups, a 70% liver resection (Phx) was performed simultaneously. After 10 d, animals received either a HAI of temsirolimus (CCI-779) or saline solution (controls). Tumor growth was determined on d 10 and 13 using three-dimensional ultrasound. On d 13, tumor tissue was removed for histologic and immunohistochemical analysis. RESULTS: Sham controls revealed a tumor growth of ∼40% from d 10 to d 13. HAI of temsirolimus completely inhibited this tumor growth. Controls with Phx showed a tumor growth of >60%. In contrast, HAI of temsirolimus in Phx animals did not only inhibit tumor growth but was even capable of decreasing the tumor size by ∼8%. Immunohistochemical analysis of the tumors showed a decreased proliferation rate and an increased cleaved caspase-3 activity, which was associated with a significant reduction of platelet endothelial cell adhesion molecule (PECAM)-1-positive cells after HAI of temsirolimus. CONCLUSIONS: HAI of temsirolimus inhibits tumor growth of CC531 colorectal liver metastases even if a growth-stimulating procedure like Phx is performed. Inhibition of tumor growth is provided by a decrease of tumor vascularization associated with an inhibition of tumor cell proliferation and an induction of tumor cell apoptosis.

Hepatic arterial infusion but not systemic application of cetuximab in combination with oxaliplatin significantly reduces growth of CC531 colorectal rat liver metastases.

PURPOSE: Systemic chemotherapy still represents the gold standard in the treatment of irresectable colorectal liver metastases. Modern anticancer agents like the monoclonal antibody cetuximab have improved the outcome of patients in clinical studies. As hepatic arterial infusion (HAI) is capable to potentially increase the anticancer effect of cytostatics, we herein studied whether HAI of cetuximab (CE) as a single agent or in combination with oxaliplatin (OX) exerts increased anticancer effects compared to the systemic application (SYS) of the drugs. METHODS: WAG/Rij rats were randomized to eight groups and underwent 10 days after subcapsular hepatic tumor implantation either HAI or SYS of CE, OX, or the combination of both agents (CE + OX). Saline-treated animals served as controls. Tumor volume was measured at days 10 and 13 using three-dimensional ultrasound. On day 13, liver and tumor tissue was sampled for histological and immunohistochemical analysis. RESULTS: In controls, the tumor volume significantly increased from day 10 to 13. Application of OX alone via HAI or SYS did not inhibit tumor growth compared to controls. SYS of CE or CE + OX did also not reduce tumor growth. In contrast, HAI of CE and CE + OX significantly inhibited tumor growth. HAI of CE significantly reduced tumor vascularization as measured by the number of platelet endothelial cell adhesion molecule-1-positive cells and significantly increased the number of apoptotic tumor cells as measured by the cellular caspase-3 expression. CONCLUSION: HAI of CE and CE + OX reduces tumor growth of colorectal rat liver metastases involving the inhibition of angiogenesis and induction of tumor cell apoptosis.

Liver-directed chemotherapy of cetuximab and bevacizumab in combination with oxaliplatin is more effective to inhibit tumor growth of CC531 colorectal rat liver metastases than systemic chemotherapy.

Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Saline-treated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p < 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.

Hepatic arterial infusion of bevacizumab in combination with oxaliplatin reduces tumor growth in a rat model of colorectal liver metastases.

Unresectable colorectal liver metastases are commonly treated with systemic chemotherapy (SCT). Clinical studies on the effect of additional systemic application of bevacizumab (BE), a monoclonal antibody directed against vascular endothelial growth factor, to SCT showed a slight increase of patient survival. Herein, we studied in a rat model of colorectal liver metastasis whether a locoregional application of oxaliplatin (OX) and BE via hepatic arterial infusion (HAI) is more effective to inhibit metastatic growth compared to systemic drug application. Ten days after implantation of CC531 colorectal cancer cells into the left liver lobe of WAG/Rij rats, animals underwent either HAI or systemic intravenous application of BE (5 mg/kg body weight), OX (85 mg/m(2) body surface) or a combination of both. Sham-treated animals received saline and served as controls. Tumor volume was measured at days 10 and 13 using three dimensional ultrasound. At day 13 tumor tissue was analyzed histologically and immunohistochemically. Systemic application of OX, BE or their combination did not affect tumor volume when compared to controls. In contrast, HAI of BE and particularly the combination of BE and OX significantly reduced tumor volume. In the tumor tissue this was associated with a decrease of vascularization and cell proliferation as well as an increase of cell apoptosis, as indicated by a decreased number of PECAM-1- and PCNA-positive cells and an increased number of cleaved caspase-3-positive cells. Locoregional administration of BE, particularly in combination with OX, enhances the inhibitory effect on hepatic metastatic growth compared to systemic application of the drugs.

Beta-lactam antibiotic-induced release of lipoteichoic acid from Staphylococcus aureus leads to activation of neutrophil granulocytes.

BACKGROUND: Polymorphonuclear neutrophil granulocytes (PMN) are phagocytes of the first line of antimicrobial defense. Previously we demonstrated that lipoteichoic acid (LTA) from Staphylococcus aureus (S. aureus) directly activates neutrophil granulocytes. Others have reported that exposure of S. aureus to beta-lactam antibiotics leads to LTA release. In the present study we addressed the question whether exposure of S. aureus to beta-lactam antibiotics or antibiotics of other groups results in the generation of PMN-stimulating activity and whether this activity can be attributed to LTA. METHODS: S. aureus were exposed to flucloxacillin, a beta-lactam antibiotic or to the protein synthesis-inhibitors erythromycin and gentamicin, or to ciprofloxacin, a gyrase inhibitor. Supernatants of the antibiotic-treated bacteria were assayed for their LTA content and for their effect on PMN functions. RESULTS: We observed that exposure of S. aureus to flucloxacillin and, to a lesser degree to ciprofloxacin, but not to erythromycin or gentamicin led to LTA release. Co-incubation of neutrophil granulocytes with LTA-containing supernatants led to PMN activation as assed by morphological changes, release of IL-8, delay of spontaneous apoptosis and enhanced phagocytic activity. Depletion of LTA from the supernatants markedly reduced their PMN-activating capacity. CONCLUSION: The findings suggest that, via the activation of PMN, antibiotic-induced LTA release from S. aureus leads to enhanced antimicrobial activity of the innate immune defense mechanisms.