Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

[Biomarkers in cardio-oncology patients]. / Biomarker bei onkokardiologischen Patienten.

In recent decades, major advances in the treatment of malignant diseases have significantly improved long-term survival. However, this has increased the spectrum of side effects of these treatment methods, particularly for the cardiovascular system. Cardiotoxicity can be acute and chronic, including hypertension, heart failure, arrhythmias, acute myocardial infarction, venous thromboembolism, stroke, and valvular heart disease. While the occurrence of cardiotoxicity is known for many older cancer therapies, it needs to be largely evaluated for newer forms of therapy. Diagnosing possible cardiotoxic side effects is essential for optimal treatment, but remains a challenge. Troponin and the natriuretic peptides play an essential role as cardiac biomarkers in the diagnosis of conventional heart diseases. However, they also appear to play an important role in the detection of cardiotoxicity, as well as in the treatment of cardio-oncology patients. Elevated troponin or B-type natriuretic peptide (BNP)/N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are associated with increased overall mortality and were associated with the development of heart failure in selected cohorts. Troponin can also be used to identify myocarditis associated with immune checkpoint inhibitor therapy. This overview summarizes the current knowledge about biomarkers for the detection of cardiotoxicity due to tumor therapy. Possible clinical recommendations for the detection of cardiotoxic effects using biomarkers are also outlined.

Xenografting for disease modeling of intramedullary spinal cord tumors: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: The overall incidence of intramedullary spinal cord tumors (IMSCT) remains low and clinical trials or standardized treatment strategies are missing. Therefore, multiple animal-based xenograft models (AXM) have been developed to foster preclinical research efforts on IMSCT. We constructed a systematic literature review to summarize and compare all AXM for IMSCT, published until April 16, 2018. METHODS: The review was conducted using 4 independent research databases following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included, if they reported on surgical transplantation of tumor cells or tumor tissue to the spinal cord. Methodological study quality was assessed according to the SYRCLE (systematic review center for laboratory animal experimentation) risk of Bias tool. RESULTS: Systematic search yielded 20 publications dealing with AXM for IMSCT. In summary, 4 tumor entities were analyzed in 23 experiments using ~337 animals, mainly investigating glioblastoma or gliosarcoma biology. Studies varied regarding the use of engrafted animals, surgical techniques and tumor burden. Most commonly authors used heterotopic, transdural injection of immortalized brain tumor cell lines (1 × 105 in 5 µl) into the thoracic spinal cord of immunocompromised rats. Quality assessment demonstrated an unclear risk of bias in most cases. CONCLUSION: Although different AXM for IMSCT have been described so far, one rat model is technically feasible, enables robust experiments and demonstrates reproducible results. However, there is a need for new AXM using orthotopic engraftment of patient-derived tumor cells and for genetically engineered animal models.

11C-MET PET/MRI for detection of recurrent glioma.

INTRODUCTION: Radiological assessment of brain tumors is widely based on the Radiology Assessment of Neuro-Oncology (RANO) criteria that consider non-specific T1 and T2 weighted images. Limitation of the RANO criteria is that they do not include metabolic imaging techniques that have been reported to be helpful to differentiate treatment related changes from true tumor progression. In the current study, we assessed if the combined use of MRI and PET with hybrid 11C-MET PET/MRI can improve diagnostic accuracy and diagnostic confidence of the readers to differentiate treatment related changes from true progression in recurrent glioma. METHODS: Fifty consecutive patients with histopathologically proven glioma were prospectively enrolled for a hybrid 11C-MET PET/MRI to differentiate recurrent glioma from treatment induced changes. Sole MRI data were analyzed based on RANO. Sole PET data and in a third evaluation hybrid 11C-MET-PET/MRI data were assessed for metabolic respectively metabolic and morphologic glioma recurrence. Diagnostic performance and diagnostic confidence of the reader were calculated for the different modalities, and the McNemar test and Mann-Whitney U Test were applied for statistical analysis. RESULTS: Hybrid 11C-MET PET/MRI was successfully performed in all 50 patients. Glioma recurrence was diagnosed in 35 of the 50 patients (70%). Sensitivity and specificity were calculated for MRI (86.11% and 71.43%), for 11C-MET PET (96.77% and 73.68%), and for hybrid 11C-MET-PET/MRI (97.14% and 93.33%). For diagnostic accuracy hybrid 11C-MET-PET/MRI (96%) showed significantly higher values than MRI alone (82%), whereas no significant difference was found for 11C-MET PET (88%). Furthermore, by rating on a five-point Likert scale significantly higher scores were found for diagnostic confidence when comparing 11C-MET PET/MRI (4.26 ± 0,777) to either PET alone (3.44 ± 0.705) or MRI alone (3.56 ± 0.733). CONCLUSION: This feasibility study showed that hybrid PET/MRI might strengthen RANO classification by adding metabolic information to conventional MRI information. Future studies should evaluate the clinical utility of the combined use of 11C-MET PET/MRI in larger patient cohorts.

Assessment of the amount of tooth wear on dental casts and intra-oral photographs.

Tooth wear is a multifactorial condition, leading to the loss of dental hard tissues. Many grading scales are available to assess the amount of tooth wear, one of which is the tooth wear evaluation system (TWES). A grading scale can be used chairside, on casts and on photographs. The aim was to test whether the grading scales of the TWES, used on casts and on photographs, resulted in comparable scores. In addition, it was tested whether these scales can be used to assess tooth wear reliably on photographs. Of 75 tooth wear patients, sets of casts and series of photographs were obtained and graded. Comparison of the grading on casts and on photographs revealed equal median values and percentiles for both occlusal/incisal grading and non-occlusal/non-incisal grading. The grading on casts and on photographs showed a high correlation for the occlusal/incisal grading and a low correlation for the non-occlusal/non-incisal grading (Spearman's rho = 0·74 and rho = 0·47; P < 0·001). Concerning the grading on photographs, the interexaminer reliability was fair-to-good (ICC = 0·41 to ICC = 0·55) while the intra-examiner reliability was fair-to-good to excellent (ICC = 0·68 to ICC = 0·86) for the occlusal/incisal grading. For the non-occlusal/non-incisal grading, the interexaminer reliability was poor to fair-to-good (ICC = 0·22 to ICC = 0·59), while the intra-examiner reliability was fair-to-good to excellent (ICC = 0·64 to ICC = 0·82). It was concluded that the scores obtained with the grading scales of the TWES on casts and on photographs are comparable. The grading scales can be used in a reliable way on photographs, which is especially the case for occlusal/incisal grading.

Bevacizumab treatment in malignant meningioma with additional radiation necrosis. An MRI diffusion and perfusion case study.

BACKGROUND AND PURPOSE: Recently two retrospective cohort studies report efficacy of bevacizumab in patients with recurrent atypical and anaplastic meningioma. Another successful therapeutic option of bevacizumab seems to be treatment of cerebral radiation necrosis. However, the antiangiogenic effects in MRI diffusion and perfusion in meningiomas have not been previously described in detail. The objective of this research was to evaluate the clinical and MR imaging effects of bevacizumab in a malignant meningioma patient harboring additional cerebral radiation necrosis. CASE PRESENTATION: We report the case of an 80-year-old woman who underwent bevacizumab therapy (5 mg/kg every 2 weeks for 2 months) for treatment of a symptomatic radiation necrosis in malignant meningiomatosis of World Health Organization (WHO) grade III. The patient was closely monitored with MRI including diffusion and perfusion studies. Upon bevacizumab therapy, the clinical situation was well stabilized over a period of 4 months until the patient unfortunately died due to pneumonia/septicemia probably unrelated to bevacizumab therapy. Consecutive MRI demonstrated 4 important aspects: (1) considerable decrease of the contrast medium (CM)-enhanced radiation necrosis, (2) mixed response with respect to the meningiomatosis with stable and predominantly growing tumor lesions, (3) a new diffusion-weighted imaging (DWI) lesion in a CM-enhanced tumor as described in gliomas, which we did not interpret as a response to bevacizumab therapy, and (4) new thrombembolic infarcts, which are a known side-effect of bevacizumab treatment. CONCLUSION: Bevacizumab is effective in the treatment of radiation necrosis. We could not confirm the potential antitumor effect of bevacizumab in this patient. However, we could describe several new radiographic effects of bevacizumab therapy in malignant meningioma.

A novel device for target controlled administration and reflection of desflurane--the Mirus™.

The Anaconda™ system is used to deliver inhalational sedation in the intensive care unit in mainland Europe. The new Mirus™ system also uses a reflector like the Anaconda; however, it also identifies end-tidal concentrations from the gas flow, injects anaesthetics during early inspiration, controls anaesthetic concentrations automatically, and can be used with desflurane, which is not possible using the Anaconda. We tested the Mirus with desflurane in the laboratory. Compared with an external gas monitor, the bias (two standard deviations) of the end-tidal concentration was 0.11 (0.29)% volume. In addition, automatic control was reasonable and maximum concentration delivered was 10.2%, which was deemed to be sufficient for clinical use. Efficiency was > 80% and was also deemed to be acceptable, but only when delivering a low concentration of desflurane (≤ 1.8%). By modifying the reflector, we improved efficiency up to a concentration of 3.6%. The Mirus appears to be a promising new device for long-term sedation with desflurane on the intensive care unit, but efficiency must be improved before routine clinical use becomes affordable.

Ifosfamide, carboplatin and etoposide in recurrent malignant glioma.

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

[Severe odontalgic pain preceding migraine attacks]. / Ernstige odontogene pijn voorafgaand aan een migraineaanval.

A 30-year-old woman appeared at the gnathology department of a centre for special dentistry complaining of migraine attacks which were preceded each time by severe odontalgic pain. Furthermore, she suffered from an autoimmune disease as well as from tension headaches. The oral health care provider in charge suspected that the episodes of odontalgic pain, which lasted for several hours or even several days, were caused by bruxism. Treatment of the bruxism resulted in reduced pain as well as reduced severity of the migraine attacks.

Correlation of optic nerve and optic nerve sheath diameter with intracranial pressure in pigs.

OBJECTIVE: Several studies have shown an association between intracranial pressure and the diameter of the optic nerve sheath measured by transbulbar ultrasonography. To understand the pathophysiology of this phenomenon, we aimed to measure the changes of the optic nerve, optic nerve sheath and perineural space separately with increasing intracranial pressure in a porcine model. METHODS: An external ventricular drain was placed into the third ventricle through a right paramedian burrhole in eight anesthesized pigs. The diameters of the optic nerve and the optic nerve sheath were measured while the intracranial pressure (ICP) was increased in steps of 10mmHg from baseline up to 60 mmHg. RESULTS: The median diameters of the optic nerve (ON) increased from 0.36 cm (baseline- 95% confidence interval (CI) 0.33 cm to 0.45 cm) to 0.68 cm (95% CI 0.57 cm to 0.82 cm) at ICP of 60 mmHg (p<0.0001) and optic nerve sheath (ONS) from 0.88 cm (95% CI 0.79 cm to 0.98 cm) to 1.24 cm (95% CI 1.02 cm to 1.38 cm) (p< 0.002) while the median diameter of the perineural space (PNS) (baseline diameter 95% CI 0.40 cm to 0.59 cm to diameters at ICP 60 95% CI 0.38 cm to 0.62 cm) did not change significantly (p = 0.399). Multiple comparisons allowed differentiation between baseline and values ≥40 mmHg for ON (p = 0.017) and between baseline and values ≥ 50mmHg for ONS (p = 0.006). A linear correlation between ON (R2 = 0.513, p<0.0001) and ONS (R2 = 0.364, p<0.0001) with ICP was found. The median coefficient of variation for intra- and inter-investigator variability was 8% respectively 2.3%. CONCLUSION: Unexpectedly, the increase in ONS diameter with increasing ICP is exclusively related to the increase of the diameter of the ON. Further studies should explore the reasons for this behaviour.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Nimustine (ACNU) plus teniposide (VM26) in recurrent glioblastoma.

BACKGROUND: In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated glioblastoma (GBM). After establishing temozolomide as standard first-line therapy in GBM patients, the nimustine (ACNU)/teniposide (VM-26) combination has been employed as salvage chemotherapy for recurrent GBM. However, data on the toxicity and efficacy of this regimen in recurrent GBM are lacking. PATIENTS AND METHODS: In two neurooncological centers, all patients with recurrent GBM treated with nimustine (90 mg/m(2), day 1/42) and teniposide (45-70 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Thirty-five patients (median age 51 years, range 25-71 years) were identified. Six months after chemotherapy initiation, PFS was 29% and the median OS 6 months; 23% of patients were alive > or = 1 year after initiation of nimustine-teniposide chemotherapy. Grade 4 hematotoxicity was observed in 12 of 35 patients (34%) and in 14 of 83 evaluable chemotherapy courses (17%). CONCLUSIONS: The benefit of the nimustine-teniposide combination is moderate in patients with recurrent GBM. The data support the efficacy of the nimustine-teniposide chemotherapy, but the rate of high-grade hematotoxicity is increased.

The western corn rootworm (Diabrotica virgifera virgifera) and its first appearance in Germany 2007.

Diabrotica v. virgifera (WCR) is one of the most successful invasive insect species and owes this success to its close association with mankind, to worldwide trade and commerce connections, and to widely practiced, monoculturally oriented production patterns which are characteristic for contemporary agriculture in several parts of the world. Without a drastic change in attitudes and approaches of a globalizing agriculture, WCR will in the foreseeable future have invaded all maize growing areas. WCR is continuing its spreading within Europe with its first documented appearance in Germany 2007, where two major and three minor sites of invasion are identified. Unfortunately, WCR already has secondary hosts and, through accelerated microevolution, soon may acquire more of them. The beetle may be seen as a clever follower in the footsteps of Homo sapiens and may thrive on worldwide ecological imbalances. Without major new paradigms in control and management approaches, WCR will be one of the big winners of globalization and mercilessly occupy the niches opening up. Some biotechnical and cultural alternatives are discussed which, in combination with biocontrol, may assist in evironmentally compatible management of WCR.

Therapy of leptomeningeal metastasis in solid tumors.

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2.

Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.

Investigation of bax, bcl-2, bcl-x and p53 gene polymorphisms in multiple sclerosis.

Clinical course, outcome, radiological features, severity, and histopathology are heterogenous in multiple sclerosis (MS). Since MS is considered to be a polygenic disease, the genetic background may at least partly be responsible for this variability. Some MS cases are histopathologically characterized by a dramatic oligodendrocyte loss that is in part caused by apoptosis. A dysregulated apoptotic elimination of self-reactive T cells may also contribute to disease susceptibility. To analyze genetic differences in the apoptosis regulating factors bcl-2, bax, bcl-x and p53 we investigated polymorphisms of these genes in 105 patients with a relapsing remitting disease course and 99 controls by PCR-SSCP and direct sequencing. We identified so far unpublished sequence alterations in the promotor region of the bxl-x gene, in exon 7 of the p53 gene, and in exon 1 of the bax gene. No differences were observed between MS patients and controls. Additional known polymorphisms were found in intron 3 of the bax gene and in exon 6 of the p53 gene. No significant differences in the frequency of gene sequence variations were found between MS patients and controls. The apoptosis genes studied here therefore appear less likely to be important effector genes in MS.