Evaluation of a New Inverse, Globally Convex Treatment Planning System Algorithm for Gamma Knife Radiation Surgery Within a Prospective Trial: Advantages and Disadvantages in Practical Application.

Purpose: A new inverse planning software called IntuitivePlan (IP) based on a global convex optimization algorithm was adopted for the Gamma Knife radiation surgery. We investigated IP's suitability for daily clinical use and its applicability for different cerebral entities. Methods and Materials: For 230 target volumes, IP was tested in a prospective trial. The computed treatment plans were compared with conventional expert preplans, which included forward planning by the expert and local internal optimization. Based on the same dose constraints, we used the default settings for the inverse calculation of the treatment plans. Plan quality metrics such as the Paddick conformity index were compared for both planning techniques with additional subdivisions into the 3 selectable IP planning strategies and different entity groups. Results: IP calculated treatment plans of quality similar to that of preplans created by expert planners. Some plan quality metrics, especially those related to conformity and dose gradient, attained statistically significantly higher scores combined with high coverage for the inversely generated plans except for the selectivity optimizing strategy. Normal brain volume receiving 10 Gy or 12 Gy or higher (V 1 0 Gy or V 1 2 Gy ) did not show significant differences for the coverage optimizing strategies. The IP software demonstrated significantly shorter planning times versus manual planning as well as greater numbers of isocenters, often associated with longer treatment times. In terms of total time, these differences almost balanced out again. Conclusions: Our results suggest that IP is advantageous for complex tumors. We observed general clinical significance for conformity and superiority for the selectivity optimizing strategy. In addition, the high-quality calculation from IP enables novices in the profession to achieve pre-treatment plans of a quality similar to that of expert planners. IP allows for optimizing the sparing of surrounding tissue and conformity for benign tumors within a short time. Thus, IP forms a solid basis for further planning on the treatment day.

[Alternative treatment options for periorbital basal cell carcinoma]. / Alternative Behandlungsoptionen beim Basalzellkarzinom am Auge.

BACKGROUND: Latest developments as well as established procedures offer alternative treatment approaches to basal cell carcinoma (BCC) when micrographically controlled surgical removal is not a valid option. OBJECTIVE: Alternative treatment options for periorbital BCC are presented. METHODS: A literature search was carried out and a structured display and analysis of the results are given. RESULTS: Micrographically controlled surgical removal represents the gold standard in treatment of BCC. When for various reasons surgical removal is not a valid option, other procedures are required. The alternative treatment options can be divided into three main groups: treatment options for locally advanced or metastasized BCC, topical approaches for small and superficial BCC and prophylactic measures. While radiotherapy and systemic therapy are suitable for locally advanced BCC and are discussed in a tumor board, small and superficial BCC can be treated by topical medication. In cases of a previous BCC history, a prophylactic treatment can be considered. Combinations of systemic treatment and also neoadjuvant or adjuvant approaches before and after surgery are promising options for a successful outcome, which can further improve the standard treatment for locally advanced BCC. CONCLUSION: Alternative treatment options for periocular BCC are available; however, the use is only indicated when microscopically controlled excision with subsequent oculoplastic reconstruction is not possible. According to the national guidelines a prior presentation to a suitable tumor board is practically compulsory.

Ionizing radiation increases the endothelial permeability and the transendothelial migration of tumor cells through ADAM10-activation and subsequent degradation of VE-cadherin.

BACKGROUND: We analyzed the changes in permeability of endothelial cell layers after photon irradiation, with a focus on the metalloproteases ADAM10 and ADAM17, and on VE-cadherin, components crucial for the integrity of endothelial intercellular junctions, and their roles in the transmigration of cancer cells through endothelial cell monolayers. METHODS: Primary HUVEC were irradiated with 2 or 4 Gy photons at a dose rate of 5 Gy/min. The permeability of an irradiated endothelial monolayer for macromolecules and tumor cells was analyzed in the presence or absence of the ADAM10/17 inhibitors GI254023X and GW280264X. Expression of ADAM10, ADAM17 and VE-Cadherin in endothelial cells was quantified by immunoblotting and qRT. VE-Cadherin was additionally analyzed by immunofluorescence microscopy and ELISA. RESULTS: Ionizing radiation increased the permeability of endothelial monolayers and the transendothelial migration of tumor cells. This was effectively blocked by a selective inhibition (GI254023X) of ADAM10. Irradiation increased both, the expression and activity of ADAM10, which led to increased degradation of VE-cadherin, but also led to higher rates of VE-cadherin internalization. Increased degradation of VE-cadherin was also observed when endothelial monolayers were exposed to tumor-cell conditioned medium, similar to when exposed to recombinant VEGF. CONCLUSIONS: Our results suggest a mechanism of irradiation-induced increased permeability and transendothelial migration of tumor cells based on the activation of ADAM10 and the subsequent change of endothelial permeability through the degradation and internalization of VE-cadherin.

The increased adhesion of tumor cells to endothelial cells after irradiation can be reduced by FAK-inhibition.

BACKGROUND: Radiotherapy is administered in more than 60% of all solid tumors. Most patients are cured but a significant number develops local recurrences or distant metastases. The question arises if irradiation might influence the metastatic process. In the present study we examined whether the adhesion of glioblastoma or breast cancer cells to endothelial cells, an important step in metastasis, is affected by photon irradiation. METHODS: U-87 MG, U-373 MG and MDA-MB-231 cancer cells as well as primary human endothelial cells were irradiated with 0, 2, 4, or 8 Gy photons at a dose rate of 5 Gy/min. The adhesion of cancer cells to endothelial cells was tested either with the Vybrant based assay via fluorescent labelling or with an ibidi pump system able to mimic the physiological blood flow in vitro. In addition, the impact of FAK (focal adhesion kinase) inhibitor PF-573, 228 on the adhesion of non-irradiated and irradiated tumor cells was analyzed. Adhesion related and regulated proteins were analyzed by Western blotting. RESULTS: The cellular adhesion was increased after irradiation regardless of which cell type was irradiated. The FAK-inhibitor was able to reduce the adhesion of non-irradiated cells but also the irradiation-induced increase in adhesion of tumor cells to endothelium. Adhesion related proteins were enhanced after irradiation with 4 Gy or 8 Gy in both cells types. The increased adhesion after irradiation is accompanied by the phosphorylation of src (Y416), FAK (Y397) and increased expression of paxillin. CONCLUSION: Irradiation with photons in therapeutic doses is able to enhance the interaction between tumor cells and endothelial cells and by that might influence important steps of the metastatic process.

Functional recovery after surgical stabilization and postoperative radiotherapy due to metastases of long bones.

PURPOSE: To reinvestigate the functional recovery after combined treatment with surgery and postoperative irradiation of complete or impending pathologic fractures of long bones. METHODS: We retrospectively evaluated the results of external beam radiation therapy (EBRT) carried out after 68 orthopedic stabilization procedures (femur, n = 55, 80.8%; humerus, n = 13, 19.2%) for actual or impending pathological fracture of long bone in 61 patients with skeletal metastases. The mean normalized total dose was 34.7 ± 7.8 Gy. Endpoints were patient's functional status (FS; 1 = normal pain free status; 2 = normal use with pain; 3 = significantly limited used; 4 = nonfunctional status), a need for a secondary procedure to the same site and overall survival following surgery. RESULTS: Overall, 75% of patients achieved normal functional status (FS 1-2) within 12 weeks after surgery. Functional recovery in surviving patients reached 93%. Median survival was 17 months (95% confidence interval 13.7-20.2). Secondary surgical intervention at the same location was necessary in 3 patients (4.4%). On multivariate analysis, only general status (p = 0.011) and growing potential of primary tumor (p = 0.049) were associated with achieving normal functional status within 12 weeks after surgery and radiotherapy. The applied radiation schemes demonstrated a comparable impact on functional recovery. CONCLUSIONS: Our results confirm the effectiveness of stabilizing surgery and fractionated postoperative radiotherapy in terms of functional recovery, supporting prior results assessing postsurgical radiotherapy versus follow-up. The patient's general status is a strong prognostic factor for functional recovery. Rapidly growing tumors may hinder achievement of a normal functional status.

Robo1 and vimentin regulate radiation-induced motility of human glioblastoma cells.

Glioblastoma is a primary brain tumor with a poor prognosis despite of many treatment regimens. Radiotherapy significantly prolongs patient survival and remains the most common treatment. Slit2 and Robo1 are evolutionarily conserved proteins involved in axon guidance, migration, and branching of neuronal cells. New studies have shown that Slit2 and Robo1 could play important roles in leukocyte chemotaxis and glioblastoma cell migration. Therefore, we investigated whether the Slit2/Robo1 complex has an impact on the motility of glioblastoma cells and whether irradiation with therapeutic doses modulates this effect. Our results indicate that photon irradiation increases the migration of glioblastoma cells in vitro. qPCR and immunoblotting experiments in two different glioblastoma cell lines (U-373 MG and U-87 MG) with different malignancy revealed that both Slit2 and Robo1 are significantly lower expressed in the cell populations with the highest motility and that the expression was reduced after irradiation. Overexpression of Robo1 significantly decreased the motility of glioblastoma cells and inhibited the accelerated migration of wild-type cells after irradiation. Immunoblotting analysis of migration-associated proteins (fascin and focal adhesion kinase) and of the epithelial-mesenchymal-transition-related protein vimentin showed that irradiation affected the migration of glioblastoma cells by increasing vimentin expression, which can be reversed by the overexpression of Slit2 and Robo1. Our findings suggest that Robo1 expression might counteract migration and also radiation-induced migration of glioblastoma cells, a process that might be connected to mesenchymal-epithelial transition.

[Dosimetric verification of MammoSite treatment plans using Monte Carlo simulations and measurements with a 2D ionization chamber array]. / Dosimetrische Verifikation von MammoSite-Bestrahlungsplänen mit Monte-Carlo-Simulationen sowie Messungen mit einem 2D-Ionisationskammer-Array.

The surgical removal of a breast tumour is often followed by postoperative irradiation of the surrounding tissue with a radioactive source (brachytherapy). When performing the MammoSite procedure, a spherical silicone balloon is inserted and filled with a NaCl solution. In a period of about five days in several sessions an iridium-192 source with high activity travels through a catheter into the balloon (afterloading) to irradiate the tumour cells remaining in the cavity. In this study, dose distributions of a MammoSite applicator are investigated based on measurements with a 2D detector array, Monte Carlo simulations and calculations with BrachyVision. The focus is set on the 2D detector array and its possible application in the verification process in 3D brachytherapy treatment planning. The measured dose distributions conform well to the doses of BrachyVision with deviations of less than 5% within the clinically relevant field range. The deviations of the measured and calculated distributions from the simulation results are below 3%. The 2D detector array allows a new verification method for MammoSite treatment plans with sufficient accuracy. Future verifications can be performed without additional Monte Carlo simulations.

Automated Multichamber Time-lapse Videography for Long-term In Vivo Observation of Migrating Cells.

AIM: To observe and document the migration of living cells by time-lapse videography, we constructed a low-budget system based on a common inverted microscope. MATERIALS AND METHODS: Long-term observation of six-well plates is enabled through maintenance of cell culture conditions (5% CO2 in air at 37°C). Points of interest can be revisited in definable intervals with <1 µm repositioning error. Digital photographs from each programmed time point are paired with environmental data and combined into a record. RESULTS: We used this new chamber to observe the migration of various cell lines. The design represents a good compromise between low cost and good precision. Detailed analyses verified that the environmental conditions were appropriately maintained, enabling long-term observation of viable cells. The stimulating influence of irradiation with photons (radiotherapy) on cellular motility of glioblastoma cells is presented. CONCLUSION: This study demonstrates that useful videographic systems can be constructed at low cost.

Zoledronic Acid Inhibits the Motility of Cancer Stem-like Cells from the Human Breast Cancer Cell Line MDA-MB 231.

BACKGROUND/AIM: Various effects on tumor cells have been described for zoledronic acid (ZOL). However, only limited data exist regarding its influence on the motility of tumor cells. Since migration of tumor stem cells is a decisive step in metastasis, we examined whether ZOL reduces their motility. MATERIALS AND METHODS: We investigated the effects of ZOL on stem-like progenitor cells obtained via the formation of spheroids from the human breast cancer cell line MDA-MB 231. Stem cell properties were verified by measurement of high CD44 expression and absence of CD24 expression. Motility was explored by time-resolved videography, protein expression by western blotting. RESULTS: ZOL strongly reduced the migration of stem-like progenitor cells. Cellular velocity was reduced by 61% following exposure to 1 µM ZOL and by 82% after exposure to 10 µM ZOL. Accumulated distance traveled by the cells was reduced by 60% and 79% after exposure to 1 µM and 10 µM ZOL, respectively. The remaining cellular motility led to very little change in distance, with cellular activity appearing more as "stepping on the spot". The reduced motility might be due to reduced phosphorylation of focal adhesion kinase (FAK), an important enzyme in cellular migration. CONCLUSION: ZOL reduces the motility and cellular velocity of breast cancer cells in vitro. The reduced mobility might slow down or even stop metastasis, which is a known result of adjuvant ZOL therapy in breast cancer patients. In vivo studies are warranted to evaluate the impact of the reduced motility on the metastatic cascade.

Micronutrients in Oncological Intervention.

Nutritional supplements are widely used among patients with cancer who perceive them to be anticancer and antitoxicity agents. Depending on the type of malignancy and the gender 30%-90% of the cancer patients supplement their diets with antioxidant and immuno-stabilizing micronutrients, such as selenium, vitamin C, and vitamin D, often without the knowledge of the treating physician. From the oncological viewpoint, there are justifiable concerns that dietary supplements decrease the effectiveness of chemotherapy and radiotherapy. Recent studies, however, have provided increasing evidence that treatment is tolerated better-with an increase in patient compliance and a lower rate of treatment discontinuations-when micronutrients, such as selenium, are added as appropriate to the patient's medication. Nutritional supplementation tailored to an individual's background diet, genetics, tumor histology, and treatments may yield benefits in subsets of patients. Clinicians should have an open dialogue with patients about nutritional supplements. Supplement advice needs to be individualized and come from a credible source, and it is best communicated by the physician.

Survival and Symptom Relief after Palliative Radiotherapy for Esophageal Cancer.

PURPOSE: The aim of this study was to assess the 6-months dysphagia-free survival, improvement in swallowing function, complication rate, and overall survival in patients with incurable esophageal cancer treated with palliative radiotherapy. METHODS: We retrospectively reviewed data from 139 patients (median age 72 years) with advanced/recurrent incurable esophageal cancer, who were referred to 3 German radiation oncology centers for palliative radiotherapy between 1994 and 2014. Radiotherapy consisted of external beam radiotherapy (EBRT) with 30 - 40.5 Gy/2.5 - 3 Gy per fraction, brachytherapy alone (BT) with 15 - 25 Gy/5 - 7Gy per fraction/weekly and EBRT + BT (30 - 40.5 Gy plus 10 - 14 Gy with BT) in 65, 46, and 28 patients, respectively. Dysphagia-free survival (Dy-PFS) was defined as the time to worsening of dysphagia for at least one point, a new loco-regional failure or death of any cause. RESULTS: Median follow-up time was 6 months (range 1-6 months). Subjective symptom relief was achieved in 72 % of patients with median response duration of 5 months. The 1-year survival rate was 30%. The 6-months Dy-PFS time for the whole group was 73 ± 4%. The 6-months Dy-PFS was 90 ± 4% after EBRT, 92 ± 5% after EBRT + BT and 37 ± 7% after BT, respectively (p<0.001). Five patients lived for more than 2 years, all of them were treated with EBRT ± BT. Ulceration, fistula and stricture developed in 3, 6 and 7 patients, respectively. CONCLUSIONS: Radiotherapy leads to symptom improvement in the majority of patients with advanced incurable esophageal cancer. The present results favor EBRT ± BT over BT alone. Due to the retrospective nature of this study, imbalances in baseline characteristics might have contributed to this finding, and further trials appear necessary.

Radiotherapy, Bisphosphonates and Surgical Stabilization of Complete or Impending Pathologic Fractures in Patients with Metastatic Bone Disease.

PURPOSE: To report the treatment outcomes of patients with metastatic bone disease with complete or impending pathologic fractures, who were treated with postoperative radiotherapy (RT), bisphosphonates or both after orthopedic stabilization. MATERIAL AND METHODS: We retrospectively evaluated the results of RT, bisphosphonates or both after orthopedic stabilization for complete or impending pathologic fractures in 72 patients with skeletal metastases. After surgery, 32 patients (44%) were treated with RT alone (group 1), 31 patients (43%) were treated with RT and bisphosphonates (group 2) and 9 (13%) patients were treated with bisphosphonates (group 3), respectively. Patients were treated with a median dose of 30Gy (30-40 Gy/2-3Gy per fraction).The local tumor progression, pain progression and need for re-operation or re-radiotherapy were assessed from patients' medical records. Median follow-up time was 9 months. RESULTS: Median overall survival time was 14 months (95% CI: 12-17). Secondary surgical intervention at the same location was necessary in 1 patient of group 1 (2%), 2 patients of group 2(5%) and 2 patients of group 3 (15%), respectively (p=0.097). Local tumor progress was observed in 3 patients of group 1 (9%), 2 patients of group 2 (7%) and 4 patients in group 3 (44%), respectively (p=0.021). Local pain progress was observed in 19%, 16% and 67% of the same groups (p=0.011). CONCLUSION: Our data confirm the efficacy and necessity of postoperative RT after orthopedic stabilization for metastatic bone disease to control the local disease. Bisphosphonates do not obviate the need for RT in the management of bone metastases after surgical stabilization. The combined treatment might lead to a better local tumor and pain control.

The therapeutic effect of photon irradiation on viable glioblastoma cells is reinforced by hyperbaric oxygen.

BACKGROUND: Hyperbaric oxygen (HBO) seems to intensify the effect of ionising radiation. We investigated whether HBO combined with irradiation decreases the capability of U251 glioblastoma cells for relapse and metastasis. MATERIALS AND METHODS: Cells were treated with O2 at 1.3 bar and then irradiated with 2 Gy photons. Clonogenic survival was tested with colony formation. Motility is an important feature of metastasis and was measured with time-lapse videography. RESULTS: The clonogenic survival diminished by 22% through HBO, by 49% through irradiation, and by 70% through the combination of both. The accumulated distance travelled by cells fell by 3% with HBO, rose by 17% with irradiation, but was reduced by 11% with their combination. The respective values for the Euclidean distance travelled were +8%, +47% and -14%. Compared to normoxic irradiation, additional HBO lowered travel by 41%. CONCLUSION: HBO strengthens the effect of irradiation on clonogenic survival and reverses radiation-induced increase in the mobility of cells.

The prognostic value of irradiated lung volumes on the prediction of intra-/ post-operative mortality in patients after neoadjuvant radiochemotherapy for esophageal cancer. A retrospective multicenter study.

PURPOSE: To assess the association between dosimetric factors of the lung and incidence of intra- and postoperative mortality among esophageal cancer (EC) patients treated with neoadjuvant radiochemotherapy (N-RCT) followed by surgery (S). METHODS AND MATERIALS: Inclusion criteria were: age < 85 years, no distant metastases at the time of diagnosis, no induction chemotherapy, conformal radiotherapy, total dose ≤ 50.4 Gy, and available dose volume histogram (DVH) data. One-hundred thirty-five patients met our inclusion criteria. Median age was 62 years. N-RCT consisted of 36 - 50.4 Gy (median 45 Gy), 1.8 - 2 Gy per fraction. Concomitant chemotherapy consisted of 5-Fluoruracil (5-FU) and cisplatin in 113 patients and cisplatin and taxan-derivates in 15 patients. Seven patients received a single cytotoxic agent. In 130 patients an abdominothoracal and in 5 patients a transhiatal resection was performed. The following dosimetric parameters were generated from the total lung DVH: mean dose, V5, V10, V15, V20, V30, V40, V45 and V50. The primary endpoint was the rate of intra- and postoperative mortality (from the start of N-RCT to 60 days after surgical resection). RESULTS: A total of ten postoperative deaths (7%) were observed: 3 within 30 days (2%) and 7 between 30 and 60 days after surgical intervention (5%); no patient died during the operation. In the univariate analysis, weight loss (≥10% in 6 months prior to diagnosis, risk ratio: 1.60, 95%CI: 0.856-2.992, p=0.043), Eastern Cooperative Oncology Group-performance status (ECOG 2 vs. 1, risk ratio: 1.931, 95%CI: 0.898-4.150, p=0.018) and postoperative pulmonary plus non-pulmonary complications (risk ratio: 2.533, 95%CI: 0.978-6.563, p=0.004) were significantly associated with postoperative mortality. There was no significant association between postoperative mortality and irradiated lung volumes. Lung V45 was the only variable which was significantly associated with higher incidence of postoperative pulmonary plus non-pulmonary complications (Exp(B): 1.285, 95%CI 1.029-1.606, p=0.027), but not with the postoperative pulmonary complications (Exp(B): 1.249, 95%CI 0.999-1.561, p=0.051). CONCLUSIONS: Irradiated lung volumes did not show relevant associations with intra- and postoperative mortality of patients treated with moderate dose (36 - 50.4 Gy) conventionally fractionated conformal radiotherapy combined with widely used radiosensitizers. Postoperative mortality was significantly associated with greater weight loss, poor performance status and development of postoperative complications, but not with treatment-related factors. Limiting the volume of lung receiving higher radiation doses appears prudent because of the observed association with risk of postoperative complications.

[Vitamin D in oncology: Update 2015]. / Vitamin D in der Onkologie--Komplementäre Medizin: Update 2015.

Vitamin D deficiency is associated with increased incidence of breast and colon cancer as well as with an unfavourable course of non-Hodgkin lymphoma. Vitamin D deficiency is common in cancer patients and is associated with poor cancer prognosis and disease progression. In breast cancer patients under polychemotherapy with anthracycline and taxane, a significant drop in 25(OH)D levels was observed. Osteo-malacia represents a new and previously unreported risk factor for the development of bisphosphonate-related osteonecrosis of the jaw. In vitamin D deficiency (until it is corrected) oral and parenteral bisphosphonates should not be used. Vitamin D status should be monitored in all cancer patients and treated by adequate vitamin D3 supplementation. This applies in particular to cancer patients with poor nutritional status, treatment with aromatase inhibitors, bisphosphonates, and CTX containing anthracycline, taxane and monoclonal antibodies as well as in cases of muscular or mucocutaneous disorders, fatigue and tumor cachexia.