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Background: This study aimed to develop and validate a survival scoring system for patients with metastatic spinal cord compression (MSCC) from prostate cancer.Patients and Methods: Of 436 patients, 218 patients were assigned to the test group and 218 patients to the validation group. Eight potential prognostic factors (age, performance status, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time developing motor deficits) plus the fractionation regimen were retrospectively investigated for associations with survival. Factors significant in the multivariate analysis were included in the survival score. The score for each significant prognostic factor was determined by dividing the 6-month survival rate (%) by 10. The total score represented the sum of the scores for each factor. The prognostic groups of the test group were compared to the validation group.Results: In the multivariate analysis of the test group, performance status, ambulatory status, other bone metastases, visceral metastases, and interval from cancer diagnosis to radiotherapy were significantly associated with survival. Total scores including these factors were 20, 21, 22, 24, 26, 28, 29, 30, 31, 32, 33, 35, 37, or 39 points. In the test group, the 6-month survival rates were 6.5% for 20-24 points, 44.6% for 26-33 points, and 95.8% for 35-39 points (p < 0.0001). In the validation group, the 6-month survival rates were 7.4%, 45.4%, and 94.7%, respectively (p < 0.0001).Conclusions: Because the survival rates of the validation group were almost identical to the test group, this score can be considered valid and reproducible. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic spinal cord compression (MSCC) from non-small cell lung cancer (NSCLC) have an unfavorable prognosis compared to most other MSCC patients. This study was performed to identify prognostic factors for functional outcome and survival in these patients after radiotherapy (RT) alone.Patients and Methods: Data of 356 patients irradiated for MSCC from NSCLC were retrospectively analyzed. Ten potential prognostic factors were investigated including age, gender, Eastern cooperative Oncology Group performance score (ECOG-PS), number of involved vertebrae, pre-RT ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to RT of MSCC, time developing motor deficits before RT, and the radiation schedule.Results: On multivariate analysis, better functional outcome was associated with pre-RT ambulatory status (estimate: - 0.84, p = 0.022), no visceral metastases (estimate: - 1.15, p < 0.001), interval from cancer diagnosis to RT of > 15 months (estimate:  + 0.48, p = 0.019), and slower (> 7 days) development of motor deficits (estimate:  + 1.56, p < 0.001). On multivariate analysis, improved survival was significantly associated with female gender (risk ratio (RR) 1.32, p = 0.043), ECOG-PS 1-2 (RR 1.45, p = 0.034), pre-RT ambulatory status (RR 0.58, p < 0.001), no other bone metastases (RR 1.38, p = 0.010), no visceral metastases (RR 2.87, p < 0.001), interval from cancer diagnosis to RT of > 15 months (RR 0.84, p = 0.035), and slower (> 7 days) development of motor deficits (RR 0.78, p < 0.001).Conclusion: This study identified additional independent prognostic factors for outcomes after radiotherapy of MSCC from NSCLC. These prognostic factors can be used for stratification in future trials and can help develop prognostic scores for MSCC from NSCLC. [ABSTRACT FROM AUTHOR]

Background: The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect.Discussion: GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients.Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function.Summary: Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We investigated whether the content of information provided by radiation oncologists and their information giving performance increase patients' trust in them. METHODS: Questionnaires were used to assess radiotherapy patients (n=111) characteristics before their first consultation, perception of information giving after the first consultation and trust before the follow-up consultation. Videotaped consultations were scored for the content of the information provided and information giving performance. RESULTS: Patients mean trust score was 4.5 (sd=0.77). The more anxious patients were, the less they tended to fully trust their radiation oncologist (p=0.03). Patients' age, gender, educational attainment and anxious disposition together explained 7%; radiation oncologists' information giving (content and performance) explained 3%, and patients' perception of radiation oncologists' information-giving explained an additional 4% of the variance in trust scores. CONCLUSION: It can be questioned whether trust is a sensitive patient reported outcome of quality of communication in highly vulnerable patients. PRACTICE IMPLICATIONS: It is important to note that trust may not be a good patient reported outcome of quality of care. Concerning radiation oncologists' information giving performance, our data suggest that they can particularly improve their assessments of patients' understanding. [ABSTRACT FROM AUTHOR]

Background: In patients with advanced stage cancer of the uterine cervix who undergo irradiation with curative intent, there is the necessity to treat all suspicious nodes on imaging. Our hypothesis was that adding fluorodeoxyglucose positron emission computer tomography/computer tomography (FDG-PET/CT) to the imaging workup would alter the external beam radiotherapy (EBRT) treatment plan, either resulting in an extended external beam radiotherapy (EBRT) field to the para-aortal region or an additional boost to suspicious nodes. Since extended field radiotherapy or additional boost can cause toxicity, our secondary aim was to assess the incidence of severe late bowel toxicity in patients treated with extended para-aortal EBRT-field and boost compared to elective pelvic radiotherapy., Methods: Eighty-eight patients were enrolled. First, the optimal radiation treatment plan (EBRT and boost) was retrospectively determined based on magnetic resonance imaging (MRI) or FDG-PET/CT. Second, the severe bowel toxicity caused by the extended para-aortal field was assessed, based on the executed radiotherapy., Results: Based on MRI 8/88 patients would receive EBRT with para-aortic extension, this was 21/88 for FDG-PET/CT. Based on MRI 47/704 lymph node regions would receive additional boost, while based on PET/CT 91/704. Late severe bowel toxicity was seen in 12/84 patients, 6/65 in the group who received elective pelvic irradiation and 6/19 with para-aortal EBRT and boost at common iliac and/or para-aortal lymph nodes. Significant worse overall survival was seen of patients who needed para-aortal irradiation., Conclusions: Addition of FDG-PET/CT leads to an extension of the elective EBRT volume and more suspicious lymph nodes receive a boost. However, when deciding to intensify radiation therapy, late severe bowel toxicity has to be taken into account.

Background: Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro., Methods: The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot., Results: A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM)., Conclusions: The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.

Severe late damage to normal tissue is a major limitation of cancer radiotherapy in prostate cancer patients. In a recent retrospective study, late radiation toxicity was found to relate to a decreased decay of γ-H2AX foci and reduced induction of DNA double-strand break repair genes. Here, we report evidence of prognostic utility in prostate cancer for γ-H2AX foci decay ratios and gene expression profiles derived from ex vivo -irradiated patient lymphocytes. Patients were followed ≥2 years after radiotherapy. Clinical characteristics were assembled, and toxicity was recorded using the Common Terminology Criteria (CTCAE) v4.0. No clinical factor was correlated with late radiation toxicity. The γ-H2AX foci decay ratio correlated negatively with toxicity grade, with a significant difference between grade ≥3 and grade 0 patients ( P = 0.02). A threshold foci decay ratio, determined in our retrospective study, correctly classified 23 of 28 patients with grade ≥3 toxicity (sensitivity 82%) and 9 of 14 patients with grade 0 toxicity (specificity 64%). Induction of homologous recombination (HR) repair genes was reduced with increasing toxicity grade. The difference in fold induction of the HR gene set was most pronounced between grade 0 and grade ≥3 toxicity ( P = 0.008). Notably, reduced responsiveness of HR repair genes to irradiation and inefficient double-strand break repair correlated with severe late radiation toxicity. Using a decay ratio classifier, we correctly classified 82% of patients with grade ≥3 toxicity, suggesting a prognostic biomarker for cancer patients with a genetically enhanced risk for late radiation toxicity to normal tissues after radiotherapy. Cancer Res; 77(6); 1485-91. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects.

Purpose: Patients with keloids complain of the cosmetic aspect, pain, and pruritus. Many different therapies are being used for keloids. The aim of this study was to evaluate the recurrence rate and outcome after resection followed by a single-dose brachytherapy., Methods and Materials: Patients treated by resection of the keloid plus a single dose of 13 Gy high-dose-rate brachytherapy were evaluated at least 1 year after treatment. Clinical response and cosmesis were assessed by a plastic surgeon and by the patients using the Patient and Observer Scar Assessment Scale., Results: Only 24 of the 61 invited patients responded to participate with the study; 29 keloids were evaluated. The recurrence rate was 24.1% after a median followup of 53 months (19-95 months). Patients scored on average 24.3 for their total Patient and Observer Scar Assessment Scale score (range 6-52), whereas the observer scored on average 14.6 (range 6-42)., Conclusions: This treatment has a higher recurrence rate than that reported in most other studies. This may be explained by differences in recurrence definition, differences in followup time among studies, and selection bias because of not contributing to the study. The cosmetic outcome for evaluated patients is relatively good. This treatment policy has the advantage that patients are treated in a single day., (Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Specific absorption rate (SAR) assessment is essential for safety purposes during MR acquisition. Online SAR assessment is not trivial and requires, in addition, knowledge of the electric tissue properties and the electric fields in the human anatomy. In this study, the potential of the recently developed CSI-EPT method to reconstruct SAR distributions is investigated. This method is based on integral representations for the electromagnetic field and attempts to reconstruct the tissue parameters and the electric field strength based on [Formula: see text] field data only. Full three-dimensional FDTD simulations using a female pelvis model are used to validate two-dimensional CSI reconstruction results in the central transverse plane of a 3T body coil. Numerical experiments demonstrate that the reconstructed SAR distributions are in good agreement with the SAR distributions as determined via 3D FDTD simulations and show that these distributions can be computed very efficiently in the central transverse plane of a body coil with the two-dimensional approach of CSI-EPT.

Purpose: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAF V600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway., Experimental Design: We used human glioma lines containing BRAF V600E (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAF V600E -expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAF V600E ), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model., Results: In BRAF V600E cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAF WT cells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAF V600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01)., Conclusions: In BRAF V600E tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAF WT pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312-21. ©2016 AACR., Competing Interests: of potential conflicts of interest None of the authors have any conflict of interest to report., (©2016 American Association for Cancer Research.)

Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT-based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with ΔT90 = -1.37 °C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients ΔT90 was less than 0.6 °C; for one patient it was 1.5 °C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures.

Background Image-guided adaptive proton therapy (IGAPT) can potentially be applied to take into account interfraction motion while limiting organ at risk (OAR) dose in cervical cancer radiation therapy (RT). In this study, the potential dosimetric advantages of IGAPT compared with photon-based image-guided adaptive RT (IGART) were investigated. Material and methods For 13 cervical cancer patients, full and empty bladder planning computed tomography (CT) images and weekly CTs were acquired. Based on both primary clinical target volumes (pCTVs) [i.e. gross tumor volume (GTV), cervix, corpus-uterus and upper part of the vagina] on planning CTs, the pretreatment observed full range primary internal target volume (pITV) was interpolated to derive pITV subranges. Given corresponding ITVs (i.e. pITVs including lymph nodes), patient-specific photon and proton plan libraries were generated. Using all weekly CTs, IGART and IGAPT treatments were simulated by selecting library plans and recalculating the dose. For each recalculated IGART and IGAPT fraction, CTV (i.e. pCTV including lymph nodes) coverage was assessed and differences in fractionated substitutes of dose-volume histogram (DVH) parameters (V15Gy, V30Gy, V45Gy, Dmean, D2cc) for bladder, bowel and rectum were tested for significance (Wilcoxon signed-rank test). Also, differences in toxicity-related DVH parameters (rectum V30Gy, bowel V45Gy) were approximated based on accumulated dose distributions. Results In 92% (96%) of all recalculated IGAPT (IGART) fractions adequate CTV coverage (V95% >98%) was obtained. All dose parameters for bladder, bowel and rectum, except the fractionated substitute for rectum V45Gy, were improved using IGAPT. Also, IGAPT reduced the mean dose to bowel, bladder and rectum significantly (p < 0.01). In addition, an average decrease of rectum V30Gy and bowel V45Gy indicated reductions in toxicity probabilities when using IGAPT. Conclusion This study demonstrates the feasibility of IGAPT in cervical cancer using a plan-library based plan-of-the-day approach. Compared to photon-based IGART, IGAPT maintains target coverage while significant dose reductions for the bladder, bowel and rectum can be achieved.

Hyperthermia can transiently degrade BRCA2 and thereby inhibit the homologous recombination pathway. Induced DNA-double strand breaks (DSB) then have to be repaired via the error prone non-homologous end-joining pathway. In the present study, to investigate the role of hyperthermia in genotoxicity and radiosensitization, the induction of chromosomal aberrations was examined by premature chromosome condensation and fluorescence in situ hybridisation (PCC-FISH), and cell survival was determined by clonogenic assay shortly (0-1 h) and 24 h following exposure to hyperthermia in combination with ionizing radiation. Prior to exposure to 4 Gy γ-irradiation, confluent cultures of SW‑1573 (human lung carcinoma) and RKO (human colorectal carcinoma) cells were exposed to mild hyperthermia (1 h, 41˚C). At 1 h, the frequency of chromosomal translocations was higher following combined exposure than following exposure to irradiation alone. At 24 h, the number of translocations following combined exposure was lower than following exposure to irradiation only, and was also lower than at 1 h following combined exposure. These dynamics in translocation frequency can be explained by the hyperthermia-induced transient reduction of BRCA2 observed in both cell lines. In both cell lines exposed to radiation only, potentially lethal damage repair (PLDR) correlated with a decreased number of chromosomal fragments at 24 h compared to 1 h. With combined exposure, PLDR did not correlate with a decrease in fragments, as in the RKO cells at 24 h following combined exposure, the frequency of fragments remained at the level found after 1 h of exposure and was also significantly higher than that found following exposure to radiation alone. This was not observed in the SW‑1573 cells. Cell survival experiments demonstrated that exposure to hyperthermia radiosensitized the RKO cells, but not the SW‑1573 cells. This radiosensitization was at least partly due to the induction of apoptosis, which was only observed in the RKO cells and which may have been induced by BRCA2 degradation or different types of chromosomal aberrations. An important observation of this study is that the genotoxic effect of hyperthermia shortly after combined epxosure (to hyperthermia and radiation) is not observed at 24 h after treatment.

The in vivo electric conductivity (σ) values of tissue are essential for accurate electromagnetic simulations and specific absorption rate (SAR) assessment for applications such as thermal dose computations in hyperthermia. Currently used σ-values are mostly based on ex vivo measurements. In this study the conductivity of human muscle, bladder content and cervical tumors is acquired non-invasively in vivo using MRI. The conductivity of 20 cervical cancer patients was measured with the MR-based electric properties tomography method on a standard 3T MRI system. The average in vivo σ-value of muscle is 14% higher than currently used in human simulation models. The σ-value of bladder content is an order of magnitude higher than the value for bladder wall tissue that is used for the complete bladder in many models. Our findings are confirmed by various in vivo animal studies from the literature. In cervical tumors, the observed average conductivity was 13% higher than the literature value reported for cervical tissue. Considerable deviations were found for the electrical conductivity observed in this study and the commonly used values for SAR assessment, emphasizing the importance of acquiring in vivo conductivity for more accurate SAR assessment in various applications.

Background: Locoregional hyperthermia combined with radiotherapy significantly improves locoregional control and overall survival for cervical tumors compared to radiotherapy alone. In this study biological modelling is applied to quantify the effect of radiosensitization for three cervical cancer patients to evaluate the improvement in equivalent dose for the combination treatment with radiotherapy and hyperthermia., Methods: The Linear-Quadratic (LQ) model extended with temperature-dependent LQ-parameters α and β was used to model radiosensitization by hyperthermia and to calculate the conventional radiation dose that is equivalent in biological effect to the combined radiotherapy and hyperthermia treatment. External beam radiotherapy planning was performed based on a prescription dose of 46Gy in 23 fractions of 2Gy. Hyperthermia treatment using the AMC-4 system was simulated based on the actual optimized system settings used during treatment., Results: The simulated hyperthermia treatments for the 3 patients yielded a T50 of 40.1 °C, 40.5 °C, 41.1 °C and a T90 of 39.2 °C, 39.7 °C, 40.4 °C, respectively. The combined radiotherapy and hyperthermia treatment resulted in a D95 of 52.5Gy, 55.5Gy, 56.9Gy in the GTV, a dose escalation of 7.3-11.9Gy compared to radiotherapy alone (D95 = 45.0-45.5Gy)., Conclusions: This study applied biological modelling to evaluate radiosensitization by hyperthermia as a radiation-dose escalation for cervical cancer patients. This model is very useful to compare the effectiveness of different treatment schedules for combined radiotherapy and hyperthermia treatments and to guide the design of clinical studies on dose escalation using hyperthermia in a multi-modality setting.

Gamma-H2AX foci detection is the standard method to quantify DNA double-strand break (DSB) induction and repair. In this study, we investigated the induction and decay of γ-H2AX foci of different tumor cell lines and fibroblasts with known mutations in DNA damage repair genes, including ATM, LigIV, DNA-PKcs, Rad51 and Rad54. A radiation dose of 2.4 Gy was used for either an acute single high-dose-rate (sHDR) exposure or a pulsed dose-rate (pDR) exposure over 24 h. The number of γ-H2AX foci was determined at 30 min and 24 h after sHDR irradiation and directly after pDR irradiation. In a similar manner, γ-H2AX foci were also examined in lymphocytes of patients with differences in normal tissue toxicity after a total radiation dose of 1 Gy. In an initial count of the number of foci 30 min after sHDR irradiation, repair-proficient cell types could not be distinguished from repair-deficient cell types. However at 24 h postirradiation, while we observed a large decrease in foci numbers in NHEJ-proficient cells, the amount of γ-H2AX foci in cell types with mutated NHEJ repair remained at high levels. Except for IRS-1SF cells, HR-deficient cell types eventually did show a moderate decrease in foci number over time, albeit to a lesser extent than their corresponding parentals or repair-proficient control cells. In addition, analysis of γ-H2AX foci after sHDR exposure of patients with different sensitivity status clearly showed individual differences in radiation response. Radiosensitive patients could be distinguished from the more radioresistant patients with γ-H2AX foci decay ratios (initial number of foci divided by residual number of foci). Significantly higher decay ratios were observed in patients without toxicities, indicating more proficient repair compared to patients with radiation-induced side effects. After pDR irradiation, no consistent correlation could be found between foci number and radiosensitivity. In conclusion, γ-H2AX formation is a rapid and sensitive cellular response to DNA DSBs. Decay ratios after sHDR exposure elucidated large differences in γ-H2AX foci kinetics between the repair-proficient or -deficient cell types and patients. This assay may be useful for measuring cellular radiosensitivity and could serve as a clinically useful test for predicting radiosensitivity ex vivo before treatment.

Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

Introduction: There is ongoing discussion about the primary treatment of women with bulky early-stage cervical cancer. Because of the high number of patients who need adjuvant (chemo)radiotherapy after initial surgical treatment, some state that primary (chemo)radiotherapy should be the treatment of choice to prevent morbidity. The aim of our study is to assess the results of radical surgery for women with bulky early-stage cervical cancer in terms of recurrence patterns and survival., Materials and Methods: We conducted a retrospective cohort study. We included 129 women who underwent a radical hysterectomy with pelvic lymphadenectomy for stage IB2/IIA2 cervical cancer between 1984 and June 2010. Disease-specific survival was measured using a Kaplan-Meier method and univariate and multivariate regression analyses were performed to determine prognostic factors associated with survival. A literature search was performed to analyze our data in the context of findings from the literature., Results: Five-year disease-specific survival was 84%. Fifty percent of the women received adjuvant treatment. The pelvic recurrence rate was 8%. With our multivariate analysis we found that histology, tumor diameter, and parametrial involvement were independently associated with disease-specific survival. Our literature search showed wide diversity in rates of adjuvant treatment after initial surgery as well as for survival and recurrence rates., Conclusions: In the context of current knowledge about survival and side effects of various treatments for bulky early-stage cervical cancer, radical surgery is a good treatment option in these patients. Depending on the type of surgery used, adjuvant radiotherapy can be minimized., (© 2015 Nordic Federation of Societies of Obstetrics and Gynecology.)

Planning of combined radiotherapy and hyperthermia treatments should be performed taking the synergistic action between the two modalities into account. This work evaluates the available experimental data on cytotoxicity of combined radiotherapy and hyperthermia treatment and the requirements for integration of hyperthermia and radiotherapy treatment planning into a single planning platform. The underlying synergistic mechanisms of hyperthermia include inhibiting DNA repair, selective killing of radioresistant hypoxic tumour tissue and increased radiosensitivity by enhanced tissue perfusion. Each of these mechanisms displays different dose-effect relations, different optimal time intervals and different optimal sequences between radiotherapy and hyperthermia. Radiosensitisation can be modelled using the linear-quadratic (LQ) model to account for DNA repair inhibition by hyperthermia. In a recent study, an LQ model-based thermoradiotherapy planning (TRTP) system was used to demonstrate that dose escalation by hyperthermia is equivalent to ∼10 Gy for prostate cancer patients treated with radiotherapy. The first step for more reliable TRTP is further expansion of the data set of LQ parameters for normally oxygenated normal and tumour tissue valid over the temperature range used clinically and for the relevant time intervals between radiotherapy and hyperthermia. The next step is to model the effect of hyperthermia in hypoxic tumour cells including the physiological response to hyperthermia and the resulting reoxygenation. Thermoradiotherapy planning is feasible and a necessity for an optimal clinical application of hyperthermia combined with radiotherapy in individual patients.

Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 °C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell-cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes., (©2015 American Association for Cancer Research.)

Objectives: Test performance is conventionally expressed by gain in diagnostic certainty. We propose net diagnostic gain and indication area as more appropriate measures of test performance; then, the loss in certainty due to misclassification and the information of "no test" would be performed are taken into account., Study Design and Setting: A decision analytical model was developed in which two alternative strategies were compared: testing and no testing. Correct diagnostic test results received a positive value; undesired test results received a negative value. Within the "no test" scenario, it was assumed that physicians are more prone to treat as the probability of disease is higher., Results: Discounting gain and loss in diagnostic certainty results in a concave function of the prior. The indication area is the range of priors with a net diagnostic gain; testing is deleterious beyond this range. The net diagnostic gain reaches a maximum at a specific prior. A freely available Web site-based calculator was developed for easy calculation of the indication area and the maximum diagnostic gain for each combination of sensitivity and specificity., Conclusion: Medical testing is not indicated when the prior disease probabilities are low (as to screening for a condition) or high (for diagnostic confirmation)., (Published by Elsevier Inc.)

Objectives: Any diagnostic test has an indication area of prior probabilities wherein the gain in diagnostic certainty outweighs its loss. Here, we investigate whether indication area and the maximum diagnostic gain are robust measures if we assume test dependence, alternative physician's heuristics, and varying patient's utilities., Study Design and Setting: Three mathematical functions for the dependence of test sensitivity (Se) and specificity (Sp) on the prior disease probability were studied. In addition, three different decision heuristics for further management were explored for the case that "no test" would be done. Finally, the valuation of test outcomes was varied. A sensitivity analysis was performed to determine the impact of the alternative assumptions on the indication area and maximum diagnostic gain., Results: By assuming test dependence, the indication area shifts to higher priors and increases the maximum diagnostic gain. Decision strategies assuming a "threshold before treat" can inadvertently widen the indication area and increase the maximum diagnostic gain. Varying patient utilities will usually reduce the net diagnostic gain. A sensitivity analysis revealed the robustness of the model., Conclusion: The indication area and the maximum diagnostic gain are robust measures of test performance and are easier to interpret than the classical performance measures., (Published by Elsevier Inc.)

Purpose: This study compared single-fraction to multi-fraction short-course radiation therapy (RT) for symptomatic metastatic epidural spinal cord compression (MESCC) in patients with limited survival prognosis., Methods and Materials: A total of 121 patients who received 8 Gy × 1 fraction were matched (1:1) to 121 patients treated with 4 Gy × 5 fractions for 10 factors including age, sex, performance status, primary tumor type, number of involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, pre-RT ambulatory status, and time developing motor deficits prior to RT. Endpoints included in-field repeated RT (reRT) for MESCC, overall survival (OS), and impact of RT on motor function. Univariate analyses were performed with the Kaplan-Meier method and log-rank test for in-field reRT for MESCC and OS and with the ordered-logit model for effect of RT on motor function., Results: Doses of 8 Gy × 1 fraction and 4 Gy × 5 fractions were not significantly different with respect to the need for in-field reRT for MESCC (P=.11) at 6 months (18% vs 9%, respectively) and 12 months (30% vs 22%, respectively). The RT regimen also had no significant impact on OS (P=.65) and post-RT motor function (P=.21). OS rates at 6 and 12 months were 24% and 9%, respectively, after 8 Gy × 1 fraction versus 25% and 13%, respectively, after 4 Gy × 5 fractions. Improvement of motor function was observed in 17% of patients after 8 Gy × 1 fraction and 23% after 4 Gy × 5 fractions, respectively., Conclusions: There were no significant differences with respect to need for in-field reRT for MESCC, OS, and motor function by dose fractionation regimen. Thus, 8 Gy × 1 fraction may be a reasonable option for patients with survival prognosis of a few months., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Electric properties tomography (EPT) is an imaging modality to reconstruct the electric conductivity and permittivity inside the human body based on B1(+) maps acquired by a magnetic resonance imaging (MRI) system. Current implementations of EPT are based on the local Maxwell equations and assume piecewise constant media. The accuracy of the reconstructed maps may therefore be sensitive to noise and reconstruction errors occur near tissue boundaries. In this paper, we introduce a multiplicative regularized CSI-EPT method (contrast source inversion-electric properties tomography) where the electric tissue properties are retrieved in an iterative fashion based on a contrast source inversion approach. The method takes the integral representations for the electromagnetic field as a starting point and the tissue parameters are obtained by iteratively minimizing an objective function which measures the discrepancy between measured and modeled data and the discrepancy in satisfying a consistency equation known as the object equation. Furthermore, the objective function consists of a multiplicative Total Variation factor for noise suppression during the reconstruction process. Finally, the presented implementation is able to simultaneously include more than one B1(+) data set acquired by complementary RF excitation settings. We have performed in vivo simulations using a female pelvis model to compute the B1(+) fields. Three different RF excitation settings were used to acquire complementary B1(+) fields for an improved overall reconstruction. Numerical results illustrate the improved reconstruction near tissue boundaries and the ability of CSI-EPT to reconstruct small tissue structures.

Purpose: To assess the reliability of magnetic resonance imaging (MRI) for evaluation of craniocaudal tumour extension by comparing the craniocaudal tumour extension on the pre-operative MRI and post-operative hysterectomy specimen in patients with early stage uterine cervical cancer., Materials and Methods: After approval of the institutional review board was acquired, pre-operative MRI and hysterectomy specimen of 21 women with early stage cervical cancer were re-evaluated. The craniocaudal extension on MRI was measured separately by two experienced radiologists and compared with corresponding measurements from the hysterectomy specimen, which were re-evaluated by an experienced pathologist., Results: Median craniocaudal extension of uterine cervical cancer on MRI was slightly smaller compared to histopathology (2.1 cm vs. 2.5 cm). The median underestimation was 0.4 cm (range -0.6 cm to 2.2 cm, mean 0.4 cm, standard deviation (SD) ±0.7 cm); Pearson's correlation was 0.83 (p < 0.001). In two patients (9%) MRI underestimated tumour craniocaudal extension by more than 1.8 cm., Conclusion: MRI represents the histopathological craniocaudal tumour extension in the majority of patients with early stage uterine cervical cancer, but with a systematic small underestimation of the real craniocaudal tumour extension.

Purpose: Investigation of the validity of the "transceive phase assumption" for Electric Property Tomography of pelvic tumors at 3T. The acquired electric conductivities of pelvic tumors are beneficial for improved specific absorption rate determination in hyperthermia treatment planning., Methods: Electromagnetic simulations and magnetic resonance imaging measurements of a pelvic-sized phantom and the human pelvis of a volunteer and a cervix cancer patient., Results: The reconstructed conductivity values of the phantom tumor model are in good quantitative agreement (mean deviation: 1-10%) with the probe measurements. Furthermore, the average reconstructed conductivity of a pelvic tumor model was in close agreement with the input conductivity (0.86 S/m vs. 0.90 S/m). The reconstructed tumor conductivity of the presented patient (cervical carcinoma, Stage: IVA) was 1.16 ± 0.40 S/m., Conclusion: This study demonstrates the feasibility of electric property tomography to measure quantitatively the conductivity of centrally located tumors in a pelvic-sized phantom and human pelvis with a standard magnetic resonance (MR) system and MR sequences. A good quantitative agreement was found between the reconstructed σ-values and probe measurements for a wide range of σ-values and for off-axis located spherical compartment. As most pelvic tumors are located in the central region of the pelvis, these results can be exploited in hyperthermia treatment planning systems., (© 2014 Wiley Periodicals, Inc.)

Background: To evaluate the rate of vaginal, pelvic, and distant failures and acute toxicity after postoperative vaginal vault brachytherapy (VBT) delivered by a ring applicator in women with high intermediate-risk endometrial cancer., Methods and Materials: A total of 100 patients were treated with VBT after a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a Stage IA or IB (International Federation of Gynecology and Obstetrics 2009) intermediate-risk endometrial cancer; 26 patients received 30-Gy low-dose-rate, 74 patients received 28-Gy pulsed-dose-rate brachytherapy., Results: At a median followup of 37 months (range, 1-107), 6 (6%) patients showed failures. Three patients developed an in-field recurrence in the vaginal vault: 1 was isolate, whereas the other 2 showed simultaneous pelvic and/or distant failure. A fourth patient developed an out-of-field recurrence in the posterior vaginal wall of the proximal half of the vagina, including pelvic and distant failure. Two other patients showed only distant failure. The estimated 3-year actuarial rate of any vaginal recurrence was 2.6% (95% confidence interval, 0-6.3%). The 5-year overall survival was 84%, similar to that in the female Dutch population matched for age and date of diagnosis. The acute side effects were low, consisting mainly of the occurrence of temporary diarrhea (2%)., Conclusion: Postoperative VBT by a ring applicator results in a low recurrence risk, survival rates comparable with the normal female population, and a very low risk of acute morbidity., (Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: To safely optimize target volumes using magnetic resonance imaging (MRI) for uterine cervical cancer radiation therapy, MRI findings need to be validated. The aim of this study was to correlate pre-operatively acquired MRI and surgical specimen imaging for uterine cervical cancer patients using deformable image registration and quantify gross tumor volume (GTV) delineation discrepancies., Material and Methods: For 16 retrospectively selected early-stage uterine cervical cancer patients, the cervix-uterus structure, uterine cavity and the GTV were delineated on 2D pathology photos after macroscopic intersection and corresponding pre-operatively acquired T2-weighted 2D sagittal MR images. Segmentations of pathology photos and MR images were simultaneously registered using a three-step multi-image registration strategy. The registration outcome was evaluated by the Dice similarity coefficient (DSC) and the surface distance error (SDE). In addition, GTV expansions within the cervix-uterus structure needed to obtain 95% GTV coverage were determined., Results: After three-step multi-image registration, the median DSC and median SDE were 0.98 and 0.4 mm (cervix-uterus) and 0.90 and 0.4 mm (uterine cavity), respectively. The average SDE around the GTV was 0.7 mm (range, 0.1 mm - 2.6 mm). An underestimation of MRI-based GTV delineations was found when no margin was applied, indicated by a mean GTV coverage of 61%. To obtain 95% GTV coverage for 90% of the patients, a minimum 12.0 mm margin around MRI-based GTVs was needed., Conclusion: The presented three-step multi-image registration strategy was suitable and accurate to correlate MRI and pathology data for uterine cervical cancer patients. To cover the pathology-based GTV, a margin of at least 12.0 mm around GTV delineations on T2-weighted MRI is needed.

Background: Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM., Methods: After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m(2) and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150-200 mg/m(2) on days 1-5., Results: The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3-4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3-14.4 months). The median overall survival was 16 months (95% CI: 8.1-26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution., Conclusion: Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

Purpose: Hyperthermia is the clinical application of heat, in which tumor temperatures are raised to 40°C to 45°C. This proven radiation and chemosensitizer significantly improves clinical outcome for several tumor sites. Earlier studies of the use of pre-treatment planning for hyperthermia showed good qualitative but disappointing quantitative reliability. The purpose of this study was to investigate whether hyperthermia treatment planning (HTP) can be used more reliably for online adaptive treatment planning during locoregional hyperthermia treatments., Methods and Materials: This study included 78 treatment sessions for 15 patients with non-muscle-invasive bladder cancer. At the start of treatments, temperature rise measurements were performed with 3 different antenna settings optimized for each patient, from which the absorbed power (specific absorption rate [SAR]) was derived. HTP was performed based on a computed tomography (CT) scan in treatment position with the bladder catheter in situ. The SAR along the thermocouple tracks was extracted from the simulated SAR distributions. Correlations between measured and simulated (average) SAR values were determined. To evaluate phase steering, correlations between the changes in simulated and measured SAR values averaged over the thermocouple probe were determined for all 3 combinations of antenna settings., Results: For 42% of the individual treatment sessions, the correlation coefficient between measured and simulated SAR profiles was higher than 0.5, whereas 58% showed a weak correlation (R of <0.5). The overall correlation coefficient between measured and simulated average SAR was weak (R=0.31; P<.001). The measured and simulated changes in average SAR after adapting antenna settings correlated much better (R=0.70; P<.001). The ratio between the measured and simulated quotients of maximum and average SARs was 1.03 ± 0.26 (mean ± SD), indicating that HTP can also correctly predict the relative amplitude of SAR peaks., Conclusions: HTP can correctly predict SAR changes after adapting antenna settings during hyperthermia treatments. This allows online adaptive treatment planning, assisting the operator in determining antenna settings resulting in increased tumor temperatures., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy., Methods: Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000., Results: The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR=-0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR=-0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR=-0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%., Conclusion: Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer., Methods and Materials: Clinical parameters of 61 prostate cancer patients, 34 with (overresponding, OR) and 27 without (non-responding, NR) severe late radiation toxicity were assembled. In addition, for a matched subset the DNA damage repair kinetics (γ-H2AX assay) and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes., Results: Examination of clinical data indicated none of the considered clinical parameters to be correlated with the susceptibility of patients to develop late radiation toxicity. Although frequencies of γ-H2AX foci induced immediately after irradiation were similar (P=.32), significantly higher numbers of γ-H2AX foci were found 24 hours after irradiation in OR compared with NR patients (P=.03). Patient-specific γ-H2AX foci decay ratios were significantly higher in NR patients than in OR patients (P<.0001). Consequently, NR patients seem to repair DNA double-strand breaks (DSBs) more efficiently than OR patients. Moreover, gene expression analysis indicated several genes of the homologous recombination pathway to be stronger induced in NR compared with OR patients (P<.05). A similar trend was observed in genes of the nonhomologous end-joining repair pathway (P=.09). This is congruent with more proficient repair of DNA DSBs in patients without late radiation toxicity., Conclusions: Both gene expression profiling and DNA DSB repair kinetics data imply that less-efficient repair of radiation-induced DSBs may contribute to the development of late normal tissue damage. Induction levels of DSB repair genes (eg, RAD51) may potentially be used to assess the risk for late radiation toxicity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study is to develop and validate a generic method for automatic bladder segmentation on cone beam computed tomography (CBCT), independent of gender and treatment position (prone or supine), using only pretreatment imaging data., Methods: Data of 20 patients, treated for tumors in the pelvic region with the entire bladder visible on CT and CBCT, were divided into four equally sized groups based on gender and treatment position. The full and empty bladder contour, that can be acquired with pretreatment CT imaging, were used to generate a patient-specific bladder shape model. This model was used to guide the segmentation process on CBCT. To obtain the bladder segmentation, the reference bladder contour was deformed iteratively by maximizing the cross-correlation between directional grey value gradients over the reference and CBCT bladder edge. To overcome incorrect segmentations caused by CBCT image artifacts, automatic adaptations were implemented. Moreover, locally incorrect segmentations could be adapted manually. After each adapted segmentation, the bladder shape model was expanded and new shape patterns were calculated for following segmentations. All available CBCTs were used to validate the segmentation algorithm. The bladder segmentations were validated by comparison with the manual delineations and the segmentation performance was quantified using the Dice similarity coefficient (DSC), surface distance error (SDE) and SD of contour-to-contour distances. Also, bladder volumes obtained by manual delineations and segmentations were compared using a Bland-Altman error analysis., Results: The mean DSC, mean SDE, and mean SD of contour-to-contour distances between segmentations and manual delineations were 0.87, 0.27 cm and 0.22 cm (female, prone), 0.85, 0.28 cm and 0.22 cm (female, supine), 0.89, 0.21 cm and 0.17 cm (male, supine) and 0.88, 0.23 cm and 0.17 cm (male, prone), respectively. Manual local adaptations improved the segmentation results significantly (p < 0.01) based on DSC (6.72%) and SD of contour-to-contour distances (0.08 cm) and decreased the 95% confidence intervals of the bladder volume differences. Moreover, expanding the shape model improved the segmentation results significantly (p < 0.01) based on DSC and SD of contour-to-contour distances., Conclusions: This patient-specific shape model based automatic bladder segmentation method on CBCT is accurate and generic. Our segmentation method only needs two pretreatment imaging data sets as prior knowledge, is independent of patient gender and patient treatment position and has the possibility to manually adapt the segmentation locally.

Objective: Cancer patients need to trust their oncologist. How the oncologist communicates probably contributes to patients' trust. Yet, patient characteristics such as their attachment style and health locus of control may influence how such communication is perceived. We examined how these personality characteristics influence trust as well as moderate the relation between oncologist communication and trust., Methods: Eight videotaped scenarios of an oncologic consultation were created. Oncologist communication was systematically varied regarding their expressed competence, honesty and caring. Cancer patients (n = 345) were randomly assigned to view the videos and report their trust in the observed oncologist. Patients' self-reported attachment style, health locus of control and trust in their own oncologist were assessed., Results: Patients with a stronger external health locus of control trusted the observed oncologist more (p < .001). Neither attachment avoidance nor attachment anxiety was related to trust in the observed oncologist. However, attachment avoidance moderated the positive effect of the oncologists' communication of caring and honesty on trust: avoidant attachment significantly diminished the effect (p < .011 and p < .044, respectively). High attachment avoidance (p = .003) and attachment anxiety (p < .001) were related to weaker trust in patients' own oncologist., Discussion: Patients' attachment avoidance may hamper their trust in their own, but not necessarily in a newly observed, oncologist. As expected, patients' attachment style influences how oncologist communication influences trust, underscoring the importance of oncologists tailoring their communication to individual patients. We confirmed observational findings that patients convinced that others control their health trust their oncologist more than others., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The influence of p53 status on potentially lethal damage repair (PLDR) and DNA double-strand break (DSB) repair was studied in two isogenic human colorectal carcinoma cell lines: RKO (p53 wild-type) and RC10.1 (p53 null). They were treated with different doses of ionizing radiation, and survival and the induction of DNA-DSB were studied. PLDR was determined by using clonogenic assays and then comparing the survival of cells plated immediately with the survival of cells plated 24 h after irradiation. Doses varied from 0 to 8 Gy. Survival curves were analyzed using the linear-quadratic formula: S(D)/S(0) = exp-(αD+βD(2)). The γ-H2AX foci assay was used to study DNA DSB kinetics. Cells were irradiated with single doses of 0, 0.5, 1 and 2 Gy. Foci levels were studied in non-irradiated control cells and 30 min and 24 h after irradiation. Irradiation was performed with gamma rays from a (137)Cs source, with a dose rate of 0.5 Gy/min. The RKO cells show higher survival rates after delayed plating than after immediate plating, while no such difference was found for the RC10.1 cells. Functional p53 seems to be a relevant characteristic regarding PLDR for cell survival. Decay of γ-H2AX foci after exposure to ionizing radiation is associated with DSB repair. More residual foci are observed in RC10.1 than in RKO, indicating that decay of γ-H2AX foci correlates with p53 functionality and PLDR in RKO cells.

Purpose: To develop a method to quantify the therapeutic effect of radiosensitization by hyperthermia; to this end, a numerical method was proposed to convert radiation therapy dose distributions with hyperthermia to equivalent dose distributions without hyperthermia., Methods and Materials: Clinical intensity modulated radiation therapy plans were created for 15 prostate cancer cases. To simulate a clinically relevant heterogeneous temperature distribution, hyperthermia treatment planning was performed for heating with the AMC-8 system. The temperature-dependent parameters α (Gy(-1)) and β (Gy(-2)) of the linear-quadratic model for prostate cancer were estimated from the literature. No thermal enhancement was assumed for normal tissue. The intensity modulated radiation therapy plans and temperature distributions were exported to our in-house-developed radiation therapy treatment planning system, APlan, and equivalent dose distributions without hyperthermia were calculated voxel by voxel using the linear-quadratic model., Results: The planned average tumor temperatures T90, T50, and T10 in the planning target volume were 40.5°C, 41.6°C, and 42.4°C, respectively. The planned minimum, mean, and maximum radiation therapy doses were 62.9 Gy, 76.0 Gy, and 81.0 Gy, respectively. Adding hyperthermia yielded an equivalent dose distribution with an extended 95% isodose level. The equivalent minimum, mean, and maximum doses reflecting the radiosensitization by hyperthermia were 70.3 Gy, 86.3 Gy, and 93.6 Gy, respectively, for a linear increase of α with temperature. This can be considered similar to a dose escalation with a substantial increase in tumor control probability for high-risk prostate carcinoma., Conclusion: A model to quantify the effect of combined radiation therapy and hyperthermia in terms of equivalent dose distributions was presented. This model is particularly instructive to estimate the potential effects of interaction from different treatment modalities., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation., Objective: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin., Methods: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant., Results: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27-74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3-4 haematological complications did not exceed 10%., Conclusion: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.

Purpose: In patients with uterine cervical cancer, pretreatment recognition of uterine extension is crucial in treatment decision-making for fertility-sparing surgery and for target delineation in radiotherapy. Although MRI is generally considered the most reliable method, its value for detecting involvement of the uterine internal os is unclear., Methods: Medline, Embase and Cochrane databases were systematically searched (January 1997-December 2012) for MRI studies that measured the accuracy of involvement of the uterine internal os compared to histopathology as reference standard in patients with uterine cervical cancer. Data were assessed using the QUADAS tool. Accuracy concerned either involvement (yes/no) of the uterine internal os, or measuring invasion distance toward the uterine corpus., Results: Two retrospective and two prospective studies described 366 patients diagnosed with uterine cervical cancer FIGO stage IIB or below, in whom 64 (17%) had uterine internal os involvement. For three studies the summary estimates of specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and accuracy were 91%, 97%, 99%, 79% and 95%, respectively; one study had an area under the curve (AUC) of 0.8., Conclusion: MRI has a high level of accuracy; however, data are limited and for validation a large prospective study is needed that compares actual measurements on MRI with histopathological examination., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

To determine the relationship between ionizing radiation-induced levels of γ-H2AX foci and cell survival in cultured prostate cancer cell lines, three prostate cancer cell lines: LNCaP (wt TP53), DU145 (mut TP53) and PC3 (TP53 null), were studied. For γ-H2AX foci induction, cells were irradiated with a single dose of 2 Gy and foci levels were studied at 30 min and 24 h after irradiation. Cell survival was determined by clonogenic assay, directly and 24 h after irradiation with doses ranging from 0 to 8 Gy. Irradiation was performed with a Siemens Stabilipan 250 KeV X-ray machine at a dose rate of approximately 3 Gy/min. Survival curves were analyzed using the linear-quadratic model S(D)/S(0)=exp-(αD+βD2). LNCaP cells clearly demonstrated potentially lethal damage repair (PLDR) which was assessed as increased survival levels after delayed plating as compared to cells plated immediately after irradiation. DU145 cells demonstrated only a slight PLDR and PC3 cells did not show PLDR at all. Levels of γ-H2AX foci were significantly decreased in all cell lines at 24 h after irradiation, compared to levels after 30 min. The LNCaP cells which demonstrated a clear PLDR also showed the largest decay in the number of γ-H2AX foci. In addition, the PC cells which did not show PLDR had the lowest decay of γ-H2AX foci. A clear correlation was demonstrated between the degree of decay of γ-H2AX foci and PLDR.

The linear-quadratic model (LQ model) provides a biologically plausible and experimentally established method to quantitatively describe the dose-response to irradiation in terms of clonogenic survival. In the basic LQ formula, the clonogenic surviving fraction Sd/S₀ following a radiation dose d (Gy) is described by an inverse exponential approximation: Sd/S₀ = e-(αd+βd²), wherein α and β are experimentally derived parameters for the linear and quadratic terms, respectively. Radiation is often combined with other agents to achieve radiosensitisation. In this study, we reviewed radiation enhancement ratios of hyperthermia (HT), halogenated pyrimidines (HPs), various cytostatic drugs and poly(ADP-ribose) polymerase‑1 (PARP1) inhibitors expressed in the parameters α and β derived from cell survival curves of various mammalian cell cultures. A significant change in the α/β ratio is of direct clinical interest for the selection of optimal fractionation schedules in radiation oncology, influencing the dose per fraction, dose fractionation and dose rate in combined treatments. The α/β ratio may increase by a mutually independent increase of α or decrease of β. The results demonstrated that the different agents increased the values of both α and β. However, depending on culture conditions, both parameters can also be separately influenced. Moreover, it appeared that radiosensitisation was more effective in radioresistant cell lines than in radiosensitive cell lines. Furthermore, radiosensitisation is also dependent on the cell cycle stage, such as the plateau or exponentially growing phase, as well as on post-treatment plating conditions. The LQ model provides a useful tool in the quantification of the effects of radiosensitising agents. These insights will help optimize fractionation schedules in multimodality treatments.

Background: In HIV-negative patients, radiotherapy (RT) decreases CD4 T-cell counts. We studied the effects of RT in HIV-1 positive patients., Methods: HIV-1 positive patients with a subsequent diagnosis of a solid tumor were selected from the Dutch national observational HIV cohort, Aids Therapy Evaluation in the Netherlands (ATHENA). The patients were grouped according to whether they had received RT or not. Primary endpoint of the study was the time from baseline to reaching CD4 cell counts higher than those at baseline. Kaplan-Meier estimates of the percentage of patients reaching the endpoint were calculated., Results: Ninety patients were included of whom 36 received RT and 54 did not. Median duration of RT was 46 [interquartile range (IQR) 30-63] days. Median first CD4 cell count after stopping RT was 150 (IQR 30-270) × 10/L lower compared with baseline. In 13 of the 36 patients receiving RT, CD4 cell counts recovered to baseline, after a median of 469 (IQR 345-595) days. In 35 of the 54 patients without RT, the CD4 cell count recovered to baseline or higher, after a median of 112 (IQR 42-182) days. After 3 years, in 39% of patients who had RT compared with 71% of patients without RT, CD4 cell counts recovered to baseline or higher (P < 0.0001). In a Cox regression adjusted for potential confounders, RT was associated with a longer (hazard ratio 0.29; 95% confidence interval 0.13 to 0.63) and combination antiretroviral therapy use with a shorter time to return to baseline [hazard ratio 2.46 (95% confidence interval 1.11 to 5.48)]., Conclusions: RT resulted in a significant and prolonged decrease in CD4 cell counts.

Background: Patient decision aids facilitate treatment decisions. They are often evaluated in terms of their effect on decisional conflict, as measured by the Decisional Conflict Scale (DCS). It is unclear to what extent lower DCS scores are accompanied by observable patient behavior or emotions., Objective: To help interpret DCS scores., Design: In a Dutch university hospital, statements on behaviors or emotions during decision making were collected from asymptomatic aneurysm patients and healthy employees. Subsequently, they rated the intensity of decisional conflict that each statement expresses on a 1 to 10 scale. Selected statements were prospectively tested in aneurysm patients and cancer patients facing treatment dilemmas., Measurements: Associations between patients' DCS scores and reported behavior and emotions were analyzed using logistic regression analysis., Results: Participants provided 363 statements on behaviors and emotions during decision making, of which 28 were mentioned more than 4 times. Nine forms of behavior and emotions were selected as they were graded with the least variable median ratings of intensity of decisional conflict. Among 100 patients facing a treatment dilemma, each point increase in DCS lowered their odds for "immediately making the decision" (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.93-0.98), whereas the odds of "fretting regularly" (OR, 1.05; 95% CI, 1.02-1.08) and "feeling nervous when thinking of the decision" (OR, 1.04; 95% CI, 1.01-1.06) where higher., Conclusions: A decrease in decisional conflict scores leads to less decision postponing behavior, fretting, and nervousness. Research should focus on which DCS scores are needed to make deliberate decisions and which scores hinder patients in decision making.

In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). Results of several studies suggest that these two mechanistically distinct repair pathways can compete for DNA ends. Because HR and NHEJ differ with respect to error susceptibility, generation of chromosome rearrangements, which are potentially carcinogenic products of DSB repair, may depend on the pathway choice. To investigate this hypothesis, the influence of HR and NHEJ inhibition on the frequencies of chromosome aberrations in G2 phase cells was investigated. SW-1573 and RKO cells were treated with mild (41 °C) hyperthermia in order to disable HR and/or NU7441/cisplatin to inactivate NHEJ and frequencies of chromosomal fragments (resulting from unrepaired DSBs) and translocations (products of erroneous DSB rejoining) were studied using premature chromosome condensation (PCC) combined with fluorescence in situ hybridization (FISH). It is shown here that temporary inhibition of HR by hyperthermia results in increased frequency of ionizing-radiation (IR)-induced chromosomal translocations and that this effect is abrogated by NU7441- or cisplatin-mediated inhibition of NHEJ. The results suggest that in the absence of HR, DSB repair is shifted to the error-prone NHEJ pathway resulting in increased frequencies of chromosomal rearrangements. These results might be of consequence for clinical cancer treatment approaches that aim at inhibition of one or more DSB repair pathways., (Copyright © 2012 Elsevier B.V. All rights reserved.)