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Background/Aim: To determine the interaction of gemcitabine in chemoradiotherapy with heavy carbon ions in vitro in a mucoepidermoid carcinoma (MEC) cell line. Materials and Methods: The human lymphatic MEC metastasis cell line NCI-H292 was used. The cells were treated with photons, carbon ions, and gemcitabine. Survival fractions (SF), apoptosis, and cell cycle progression were analyzed. A paired two-sided t-test was used. Significance was defined as p<0.05. Results: Cell proliferation assays showed a significant reduction in SF for combined photon chemoradiation versus photons only. The linear-quadratic fits of combined therapy with carbon ion dose of 0 to 2.5 Gy led to reductions of mean 15% in SF. The LD50 (lethal radiation dose required to reduce cell survival by 50%) for carbon ions only was 0.7 Gy and for carbon ions with gemcitabine 0.6 Gy. The LD50 for photons (with gemcitabine) was 2.8 Gy (2.0 Gy) and for carbon ions (with gemcitabine) 0.7 Gy (0.6 Gy), resulting in a relative biological effectiveness at 10% cell survival (RBE10) of 3.0 (2.7). Carbon ions and photons reduced S phase and increased G2/M phase cell distribution. Isolated treatment with gemcitabine as well as combination with photons led to prolonged S phase transit, whereas combined treatment with carbon ions led to early accumulation in G2/M phase. A significant increase in the sub-G1 population as a hint of relevant number of apoptotic cells was not observed. Conclusion: Gemcitabine showed radiosensitizing effects in combination with photons. The combination of gemcitabine and carbon ions had independent additive effects. Carbon ions only had a RBE10 of 3.0, compared to photons only. The combination of gemcitabine, photon, and carbon ions in patients with MEC seems promising and warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background To retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia. Patients and methods Treatment results of 25 patients (median age 63 years; 5 female, 20 male) with cutaneous manifestations of advanced and therapy-refractory CL (n = 21; T-cell lymphomas n = 18, B-cell lymphomas n = 3) stage IIB-IV or leukemia (n = 4; AML n = 2, CLL n = 1, PDC n = 1) treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each. Results The median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1–18 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1–46 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%). Conclusion For palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option.

Abstract Background Different radiation-techniques in treating local staged prostate cancer differ in their dose- distribution. Physical phantom measurements indicate that for 3D, less healthy tissue is exposed to a relatively higher dose compared to SSIMRT. The purpose is to substantiate a dose distribution in lymphocytes in-vivo and to discuss the possibility of comparing it to the physical model of total body dose distribution. Methods For each technique (3D and SSIMRT), blood was taken from 20 patients before and 10 min after their first fraction of radiotherapy. The isolated leukocytes were fixed 2 hours after radiation. DNA double-strand breaks (DSB) in lymphocytes' nuclei were stained immunocytochemically using the gamma-H2AX protein. Gamma-H2AX foci inside each nucleus were counted in 300 irradiated as well as 50 non-irradiated lymphocytes per patient. In addition, lymphocytes of 5 volunteer subjects were irradiated externally at different doses and processed under same conditions as the patients' lymphocytes in order to generate a calibration-line. This calibration-line assigns dose-value to mean number of gamma-H2AX foci/ nucleus. So the dose distributions in patients' lymphocytes were determined regarding to the gamma-H2AX foci distribution. With this information a cumulative dose-lymphocyte-histogram (DLH) was generated. Visualized distribution of gamma-H2AX foci, correspondingly dose per nucleus, was compared to the technical dose-volume-histogram (DVH), related to the whole body-volume. Results Measured in-vivo (DLH) and according to the physical treatment-planning (DVH), more lymphocytes resulted with low-dose exposure (< 20% of the applied dose) and significantly fewer lymphocytes with middle-dose exposure (30%-60%) during Step-and-Shoot-IMRT, compared to conventional 3D conformal radiotherapy. The high-dose exposure (> 80%) was equal in both radiation techniques. The mean number of gamma-H2AX foci per lymphocyte was 0.49 (3D) and 0.47 (SSIMRT) without significant difference. Conclusions In-vivo measurement of the dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci. In case of 3D and SSIMRT, the results of this method correlate with the physical calculated total body dose-distribution, but cannot be interpreted unrestrictedly due to the blood circulation. One possible application of the present method could be in radiation-protection for in-vivo dose estimation after accidental exposure to radiation.

Abstract Purpose To report our experience with intensity-modulated or stereotactic reirradiation in patients suffering from recurrent nasopharyngeal carcinoma Patients and Methods The records of 17 patients with recurrent nasopharygeal carcinoma treated by intensity-modulated (n = 14) or stereotactic (n = 3) reirradiation in our institution were reviewed. Median age was 53 years and most patients (n = 14) were male. The majority of tumors showed undifferentiated histology (n = 14) and infiltration of intracranial structures (n = 12). Simultaneous systemic therapy was applied in 8 patients. Initial treatment covered the gross tumor volume with a median dose of 66 Gy (50-72 Gy) and the cervical nodal regions with a median dose of 56 Gy (50-60 Gy). Reirradiation was confined to the local relapse region with a median dose of 50.4 Gy (36-64Gy), resulting in a median cumulative dose of 112 Gy (91-134 Gy). The median time interval between initial and subsequent treatment was 52 months (6-132). Results The median follow up for the entire cohort was 20 months and 31 months for survivors (10-84). Five patients (29%) developed isolated local recurrences and three patients (18%) suffered from isolated nodal recurrences. The actuarial 1- and 2-year rates of local/locoregional control were 76%/59% and 69%/52%, respectively. Six patients developed distant metastasis during the follow up period. The median actuarial overall survival for the entire cohort was 23 months, transferring into 1-, 2-, and 3-year overall survival rates of 82%, 44% and 37%. Univariate subset analyses showed significantly increased overall survival and local control for patients with less advanced rT stage, retreatment doses > 50 Gy, concurrent systemic treatment and complete response. Severe late toxicity (Grad III) attributable to reirradiation occurred in five patients (29%), particularly as hearing loss, alterations of taste/smell, cranial neuropathy, trismus and xerostomia. Conclusion Reirradiation with intensity-modulated or stereotactic techniques in recurrent nasopharyngeal carcinoma is feasible and yields encouraging results in terms of local control and overall survival in patients with acceptable toxicity in patients with less advanced recurrences. However, the achievable outcome is limited in patients with involvement of intracranial structures, emphasising the need for close monitoring after primary therapy.

Abstract Background The protein kinase CK2 sustains multiple pro-survival functions in cellular DNA damage response and its level is tightly regulated in normal cells but elevated in cancers. Because CK2 is thus considered as potential therapeutic target, DNA double-strand break (DSB) formation and rejoining, apoptosis induction and clonogenic survival was assessed in irradiated mammalian cells upon chemical inhibition of CK2. Methods MRC5 human fibroblasts and WIDR human colon carcinoma cells were incubated with highly specific CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB), or mock-treated, 2 hours prior to irradiation. DSB was measured by pulsed-field electrophoresis (PFGE) as well as gamma-H2AX foci formation and removal. Apoptosis induction was tested by DAPI staining and sub-G1 flow cytometry, survival was quantified by clonogenic assay. Results TBB treatment did not affect initial DNA fragmention (PFGE; up to 80 Gy) or foci formation (1 Gy). While DNA fragment rejoining (PFGE) was not inhibited by the drug, TBB clearly delayed gamma-H2AX foci disappearence during postirradiation incubation. No apoptosis induction could be detected for up to 38 hours for both cell lines and exposure conditions (monotherapies or combination), but TBB treatment at this moderately toxic concentration of 20 μM (about 40% survival) enhanced radiation-induced cell killing in the clonogenic assay. Conclusions The data imply a role of CK2 in gamma-H2AX dephosporylation, most likely through its known ability to stimulate PP2A phosphatase, rather than DSB rejoining. The slight but definite clonogenic radiosensitization by TBB does apparently not result from interference with an apoptosis suppression function of CK2 in these cells but could reflect inhibitor-induced uncoupling of DNA damage response decay from break ligation.

Abstract Background Giant cell tumors are rare neoplasms, representing less than 5% of all bone tumors. The vast majority of giant cell tumors occurs in extremity sites and is treated by surgery alone. However, a small percentage occurs in pelvis, spine or skull bones, where complete resection is challenging. Radiation therapy seems to be an option in these patients, despite the lack of a generally accepted dose or fractionation concept. Here we present a series of five cases treated with high dose IMRT. Patients and Methods From 2000 and 2006 a total of five patients with histologically proven benign giant cell tumors have been treated with IMRT in our institution. Two patients were male, three female, and median age was 30 years (range 20 -- 60). The tumor was located in the sacral region in four and in the sphenoid sinus in one patient. All patients had measurable gross disease prior to radiotherapy with a median size of 9 cm. All patients were treated with IMRT to a median total dose of 64 Gy (range 57.6 Gy to 66 Gy) in conventional fractionation. Results Median follow up was 46 months ranging from 30 to 107 months. Overall survival was 100%. One patient developed local disease progression three months after radiotherapy and needed extensive surgical salvage. The remaining four patients have been locally controlled, resulting in a local control rate of 80%. We found no substantial tumor shrinkage after radiotherapy but in two patients morphological signs of extensive tumor necrosis were present on MRI scans. Decline of pain and/or neurological symptoms were seen in all four locally controlled patients. The patient who needed surgical salvage showed markedly reduced pain but developed functional deficits of bladder, rectum and lower extremity due to surgery. No severe acute or late toxicities attributable to radiation therapy were observed so far. Conclusion IMRT is a feasible option in giant cells tumors not amendable to complete surgical removal. In our case series local control was achieved in four out of five patients with marked symptom relief in the majority of cases. No severe toxicity was observed.

Background. Standard treatment is surgery with stage dependent postoperative radio(chemo)therapy, however, for organ preservation preoperative radio(chemo)therapy is used as an individual approach. The present analysis was performed to access outcome and toxicity of radiotherapeutical treatment of squamous cell carcinoma of the tongue. Patients and methods. Sixty-six patients (median age 55 years) with cancer of the mobile tongue (n30) or tongue margins (n36) treated between 1982 and 2006 were retrospectively analyzed. Treatment consisted of definitive- (n13, median dose 66 Gy), adjuvant- (n31, median dose 60 Gy) or neoadjuvant radiotherapy (n22, median dose 40 Gy) and chemotherapy (n34) or immunotherapy (n1). Results. After a median follow-up of 29 months the three- and five-year overall survival (OS) rates were 59% and 46%, respectively. The median OS was 54 months. Forty-two patients achieved complete remission whereas 14 patients showed partial remission. The one- and two-year loco-regional progression-free survival (LRPFS) rates were 76% and 58%, respectively. The median LRPFS time was 36 months. In χ2-test, T-stage showed a trend towards impact on local recurrence (Pearson, p0.082). In multivariate analysis, alcohol consumption (p0.003) and gender (p0.031) were prognostic. Grade III/IV acute toxicity was seen in 52% of patients. None of the locally controlled patients reported grade IV or higher late toxicity. Conclusion. No statistically significant differences between treatment modalities were found, but one should keep in mind that organ preservation plays a major role for quality of life. None of the locally controlled patients reported grade IV or higher late toxicity. However, tumor recurrence is common, especially in advanced tumor stage. Interdisciplinary concepts, further increasing the chance of tumor control are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Telomerase activity represents a radiation-inducible function, which may be targeted by a double-strand break (DSB)-activated signal transduction pathway. Therefore, the effects of DNA-PK inhibitors (Wortmannin and LY294002) on telomerase upregulation after irradiation were studied. In addition, the role of trans-dominant inhibition of poly(ADP-ribosyl)ation, which strongly reduces DSB rejoining, was assessed in comparison with 3-aminobenzamide., Methods and Materials: COM3 rodent cells carry a construct for the dexamethasone-inducible overexpression of the DNA-binding domain of PARP1 and exhibit greatly impaired DSB rejoining after irradiation. Telomerase activity was measured using polymerase chain reaction ELISA 1 h after irradiation with doses up to 10 Gy. Phosphorylation status of PKB/Akt and of PKCalpha/beta(II) was assessed by western blotting., Results: No telomerase upregulation was detectable for irradiated cells with undisturbed DSB rejoining. In contrast, incubation with LY294002 or dexamethasone yielded pronounced radiation induction of telomerase activity that could be suppressed by Wortmannin. 3-Aminobenzamide not only was unable to induce telomerase activity but also suppressed telomerase upregulation upon incubation with LY294002 or dexamethasone. Phospho-PKB was detectable independent of irradiation or dexamethasone pretreatment, but was undetectable upon incubations with LY294002 or Wortmannin, whereas phospho-PKC rested detectable., Conclusions: Telomerase activation postirradiation was triggered by different treatments that interfere with DNA DSB processing. This telomerase upregulation, however, was not reflected by the phosporylation status of the putative mediators of TERT activation, PKB and PKC. Although an involvement of PKB in TERT activation is not supported by the present findings, a respective role of PKC isoforms other than alpha/beta(II) cannot be ruled out.