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Amino acid PET is an established method to assist differential diagnosis of therapy-related changes vs. recurrence in gliomas. However, its diagnostic value in brain metastases is yet to be determined. The goal of this study was to summarize evidence on diagnostic utility of amino acid PET in reccurent brain metastases.

Background: Painful spinal bone metastases (PSBMs) patients regularly receive palliative radiation therapy (RT) with response rates in about 2 of 3 patients. In this exploratory study, we evaluated the value of machine learning (ML) models based on radiomic, semantic and clinical features to predict complete pain response. Methods: Gross tumour volumes (GTV) and clinical target volumes (CTV) of 261 PSBMs were segmented on planning computed tomography (CT) scans. Radiomic, semantic and clinical features were collected for all patients. Random forest (RFC) and support vector machine (SVM) classifiers were compared using repeated nested cross-validation.Results: The best radiomic classifier was trained on CTV with an area under the receiver-operator curve (AUROC) of 0.62 ± 0.01 (RFC; 95% confidence interval). The semantic model achieved a comparable AUROC of 0.63 ± 0.01 (RFC), significantly below the clinical model (SVM, AUROC: 0.80 ± 0.01); and slightly lower than the spinal instability neoplastic score (SINS; LR, AUROC: 0.65 ± 0.01). A combined model did not improve performance (AUROC: 0,74 ± 0,01).Conclusions: We could demonstrate that radiomic and semantic analyses of planning CTs allowed for limited prediction of therapy response to palliative RT. ML predictions based on established clinical parameters achieved the best results.

Evidence from a few small randomized trials and retrospective cohorts mostly including various tumor entities indicates a prolongation of disease free survival (DFS) and overall survival (OS) from local ablative therapies in oligometastatic disease (OMD). However, it is still unclear which patients benefit most from this approach. We give an overview of the several aspects of stereotactic body radiotherapy (SBRT) in extracranial OMD in breast cancer from a radiation oncology perspective. A PubMed search referring to this was conducted. An attempt was made to relate the therapeutic efficacy of SBRT to various prognostic factors. Data from approximately 500 breast cancer patients treated with SBRT for OMD in mostly in small cohort studies have been published, consistently indicating high local tumor control rates and favorable progression-free (PFS) and overall survival (OS). Predictors for a good prognosis after SBRT are favorable biological subtype (hormone receptor positive, HER2 negative), solitary metastasis, bone-only metastasis, and long metastasis-free interval. However, definitive proof that SBRT in OMD breast cancer prolongs DFS or OS is lacking, since, with the exception of one small randomized trial (n = 22 in the SBRT arm), none of the cohort studies had an adequate control group. Further studies are needed to prove the benefit of SBRT in OMD breast cancer and to define adequate selection criteria. Currently, the use of local ablative SBRT should always be discussed in a multidisciplinary tumor board.

BACKGROUND Resection of brain metastases (BM) close to the motor cortex and the corticospinal tract (CST) bears a significant risk for treatment-related morbidity. Navigated transcranial mapping (nTMS) combined with diffusion-tensor-imaging (DTI) based fiber tracking (DTI-FTTMS) is a valuable tool to guide the neurosurgeon along the CST to preserve motor function. This study aims to proof the practicability of DTI-FTTMS in local adjuvant stereotactic RT planning in the management of BM. Method: Pre-surgical generated DTI-FTTMS-based CST reconstructions of 24 patients with 25 resected BM were incorporated into the RT planning system and elastic fused with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Fractionated stereotactic intensity-modulated RT (IMRT) plans (7 x 5 Gy) were retrospectively calculated and then optimized to preserve PRV-FTTMS. Areas covered by the planning target volume (PTV) were not spared (overlap). RESULTS In regular plans mean dose (Dmean) of complete PRV-FTTMS was 5.4 ± 2.5 Gy. Regarding PRV-FTTMS portions within the 8.75 Gy (25% of prescription dose) isodose level Dmean was 18.2 ± 4.3 Gy and after plan optimization 13.1 ± 3.8Gy (-28.0%, p < 0.001). Within the 17.5 Gy (50%) isodose line PRV-FTTMS Dmean was reduced by 31.7% from 24.3 ± 3 Gy to 16.6 ± 4.8 Gy (p< 0.001). There was no decline of the effective treatment dose, PTV Dmean in regular plans was 36.9 ± 0.7 Gy vs. 37.7 ± 1.4Gy (p=0.013) after adaption. PTV coverage (V35Gy(%)*100) did not change with plan optimization: 0.99 vs. 0.99 (p=0.43). Dose constraints of organs at risk were all met both in regular and optimized plans. CONCLUSION DTI-FTTMS based motor tracts could be implemented in the adjuvant stereotactic RT planning of cavities after resection of BM. A significant dose reduction of motor structures within critical dose levels seems possible without reducing PTV treatment dose. However, the functional benefit needs to be investigated prospectively within clinical trials.

Damage of the central nervous system (CNS), manifested by cognitive impairment, occurs in 80% of women with breast cancer (BC) as a complication of surgical treatment and radiochemotherapy. In this study, the levels of ICAM-1, PECAM-1, NSE, and anti-NR-2 antibodies which are associated with the damage of the CNS and the endothelium were measured in the blood by ELISA as potential biomarkers that might reflect pathogenetic mechanisms in these patients. A total of 102 patients enrolled in this single-center trial were divided into four groups: (1) 26 patients after breast cancer treatment, (2) 21 patients with chronic brain ischemia (CBI) and asymptomatic carotid stenosis (ICA stenosis) (CBI + ICA stenosis), (3) 35 patients with CBI but without asymptomatic carotid stenosis, and (4) 20 healthy female volunteers (control group). Intergroup analysis demonstrated that in the group of patients following BC treatment there was a significant increase of ICAM-1 (mean difference: −368.56, 95% CI −450.30 to −286.69, p < 0.001) and PECAM-1 (mean difference: −47.75, 95% CI −68.73 to −26.77, p < 0.001) molecules, as compared to the group of healthy volunteers. Additionally, a decrease of anti-NR-2 antibodies (mean difference: 0.89, 95% CI 0.41 to 1.48, p < 0.001) was detected. The intergroup comparison revealed comparable levels of ICAM-1 (mean difference: −33.58, 95% CI −58.10 to 125.26, p = 0.76), PECAM-1 (mean difference: −5.03, 95% CI −29.93 to 19.87, p = 0.95), as well as anti-NR-2 antibodies (mean difference: −0.05, 95% CI −0.26 to 0.16, p = 0.93) in patients after BC treatment and in patients with CBI + ICA stenosis. The NSE level in the group CBI + ICA stenosis was significantly higher than in women following BC treatment (mean difference: −43.64, 95% CI 3.31 to −83.99, p = 0.03). Comparable levels of ICAM-1 were also detected in patients after BC treatment and in the group of CBI (mean difference: −21.28, 95% CI −111.03 to 68.48, p = 0.92). The level of PECAM-1 molecules in patients after BC treatment was also comparable to group of CBI (mean difference: −13.68, 95% CI −35.51 to 8.15, p = 0.35). In conclusion, among other mechanisms, endothelial dysfunction might play a role in the damage of the CNS in breast cancer survivors.

Different neurological and psychiatric disorders such as vertebrobasilar insufficiency, chronic pain syndrome, anxiety, and depression are observed in more than 90% of patients after treatment for breast cancer and may cause alterations in the functional connectivity of the default mode network. The purpose of the present study is to assess changes in the functional connectivity of the default mode network in patients after breast cancer treatment using resting state functional magnetic resonance imaging (rs-fMRI). Rs-fMRI was performed using a 3.0T MR-scanner on patients (N = 46, women) with neurological disorders (chronic pain, dizziness, headaches, and/or tinnitus) in the late postoperative period (>12 months) after Patey radical mastectomy for breast cancer. According to the intergroup statistical analysis, there were differences in the functional connectivity of the default mode network in all 46 patients after breast cancer treatment compared to the control group (p < 0.01). The use of rs-fMRI in in breast cancer survivors allowed us to identify changes in the functional connectivity in the brain caused by neurological disorders, which correlated with a decreased quality of life in these patients. The results indicate the necessity to improve treatment and rehabilitation methods in this group of patients.

OBJECTIVE In adult patients, an increasing group of neurosurgeons specialize entirely in the treatment of highly eloquent tumors, particularly gliomas. In contrast, extensive perioperative neurophysiological workup for pediatric cases has been limited essentially to epilepsy surgery. METHODS The authors discuss radio-oncological and general oncological considerations based on the current literature and their personal experience. RESULTS While several functional mapping modalities facilitate preoperative identification of cortically and subcortically located eloquent areas, not all are suited for children. Direct cortical intraoperative stimulation is impractical in many young patients due to the reduced excitability of the immature cortex. Behavioral requirements also limit the utility of functional MRI and magnetoencephalography in children. In contrast, MRI-derived tractography and navigated transcranial magnetic stimulation are available across ages. Herein, the authors review the oncological rationale of function-guided resection in pediatric gliomas including technical implications such as personalized perioperative neurophysiology, surgical strategies, and limitations. CONCLUSIONS Taken together, these techniques, despite the limitations of some, facilitate the identification of eloquent areas prior to tumor surgery and radiotherapy as well as during follow-up of residual tumors.

Meningiomas represent the most common primary brain tumor type, with a recurrence rate of approximately 20% following resection. Classification by molecular classes was demonstrated to be more accurate in identifying patients at high risk of disease progression in meningiomas, compared to WHO grading only. Novel radiotherapeutic modalities using protons or carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, enabling a higher local dose deposition while reducing the radiation dose for organs of risks. The prospective single-arm phase II - MARCIE trial investigated a bimodal radiotherapy using photons (50 Gy in 25 fractions) and a carbon-ions boost with 18 Gy (RBE) in 6 fractions. Local progression-free survival after 3 years was defined as primary endpoint. In total, 33 patients were recruited before termination of the trial. After 3 years, local progression free survival was estimated at 94.7% and overall survival at 89.8%. Serious adverse events in the form of radiation necrosis were observed in 3 cases, requiring a subsequent treatment with bevacizumab. Post-hoc DNA methylation profiling revealed that relapses occur more frequently in high-risk meningiomas following radiotherapy, compared to the intermediate risk-group, confirming the prognostic relevance of the methylation-based meningioma classifier.Subsequently, a retrospective matched-pair analysis was performed to compare irradiated (n > 100) and non-irradiated meningiomas, stratified into the molecular risk groups (ben, int, high). The clinical benefit of postoperative radiotherapy and dose escalation with regard to the local control are currently being assessed for the respective molecular meningioma classes. Postoperative, bimodal radiotherapy with carbon-ion boost represent an auspicious treatment modality with an excellent local tumor control following resection. Molecular risk stratification is crucial in identifying patients who might benefit from postoperative radiotherapy.

PURPOSE Satisfaction with work-life balance (WLB) is an essential factor for persistent motivation of early career researchers. However, WLB satisfaction in the neuro-oncological landscape is not well characterized. We present the results of an interdisciplinary survey focusing on WLB satisfaction among neuro-oncologists in Germany. METHODS The questionnaire was sent to 351 physicians, all of whom were members of the Neuro-oncology Working Group “Neuroonkologische Arbeitsgemeinschaft” (NOA) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG). The participants were asked for personal information, individual motivations, scientific interests, activities, individual workload, and job satisfaction. The questionnaire was accessible from 18 March 2021 to 1 April 2021. RESULTS Ninety-six physicians (36 female, 60 male) participated in this survey. Age, gender and relationship status were significantly different between participants who were satisfied and those not satisfied with their WLB. Female participants were less likely to be satisfied with their WLB than male participants (25% vs 75%, p = 0.005). In a logistic regression model, the finding that female participants were less likely to be satisfied with their WLB than male participants remained statistically significant (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.21–0.84, p = 0.023) after accounting for possible confounding variables such as age (OR 1.06; 95% CI 1.01–1.11, p = 0.025), childlessness (children available vs not available, OR 0.40; 95% CI 0.10–1.35, p = 0.156), and relationship status (unmarried vs single, OR 2.49; 95% CI 0.50–13.98, p = 0.275; married vs single, OR 6.18; 95% CI 1.29–35.46, p = 0.029). CONCLUSIONS This survey demonstrates that WLB satisfaction is significantly decreased among female neuro-oncologists in Germany. It highlights the importance of programs such as “Diversity in Neurooncology” (DivINe), founded by the NOA and aiming to address gender disparities.

The purpose of this study was to determine the absolute reliability and responsiveness of the Timed Up and Go (TUG) test, as measured using minimal detectable change (MDC) and minimal clinical important difference (MCID) values.Prospective observational study of children aged 3 to 10 years with cerebral palsy (CP) in Gross Motor Function Classification System levels I-III who completed the TUG test. Minimal detectable change estimates were calculated using baseline data. MCID estimates for each Gross Motor Function Classification System (GMFCS) level were calculated using distribution- and anchor-based methods.Minimal detectable change values ranged from 1.40 to 8.74 seconds and MCID estimates ranged from 0.22 to 5.31 seconds.The TUG test is a reliable and responsive measure of balance and mobility for children with CP between 3 and 10 years of age in GMFCS levels I-III. Study results support improved use of the TUG test in clinical and research settings by providing reliability values and estimates of meaningful change.For more insights from the authors, see Supplemental Digital Content 1, available at http://links.lww.com/PPT/A117.

BACKGROUND Breast cancer (BC) is the most common cancer among women and radiotherapy (RT) plays a major role in its treatment. However, BC RT can lead to incidental irradiation of the heart, resulting in an increased risk of a variety of heart diseases arising many years after radiotherapy. Therefore, identifying BC patients with the highest-risk of radiation-induced cardiac complications is crucial for developing strategies for primary and secondary prevention, which may contribute to healthy ageing. There is still a need of precise knowledge on the relationship between radiation dose to specific cardiac structures and early subclinical cardiac changes and their occurrence in time that could finally lead to cardiac complications. OBJECTIVE The MEDIRAD EARLY HEART study aims to identify and validate new cardiac imaging and circulating biomarkers of radiation-induced cardiovascular changes arising in the first 2 years after BC RT and to develop risk models integrating these biomarkers combined with precise dose metrics of cardiac structures based on 3D-dosimetry. METHODS EARLY HEART study is a multicenter prospective cohort study that will include 250 women treated for breast cancer and followed for 2 years after RT. Women treated with RT without chemotherapy, for a unilateral breast cancer and aged 40 to 75 years meet the inclusion criteria. Baseline and follow-up data include cardiac measurements based on 2D-speckle-tracking-echocardiography, on coronary computed tomography angiography, on cardiac magnetic resonance imaging and a wide panel of circulating biomarkers of cardiac injury. The absorbed dose is evaluated globally for the heart and different substructures. Dose-response relationship will allow modeling radiation-induced occurrence and evolution of subclinical cardiac lesions and biomarkers in order to develop prediction models. RESULTS The article details the protocol of the MEDIRAD EARLY HEART study, and presents main limits and advantages of this international project. Inclusion of patients began in 2017. Preliminary results are expected to be published in 2019, and complete analysis should be published in 2021. CONCLUSIONS The MEDIRAD EARLY HEART study will allow identifying the main cardiac imaging and blood-based determinants of radiation-induced cardiac injuries to better propose primary and secondary preventive measures in order to contribute to enhanced patients’ care and quality of life. CLINICALTRIAL Clinicaltrials.gov NCT03297346 - https://clinicaltrials.gov/ct2/show/NCT03297346

Aims and background Primary liver cancer is the fourth leading cause of cancer-related death worldwide and is still associated with a poor prognosis. Hepatocellular carcinoma and cholangiocarcinoma are known to cause bone metastasis resulting in pain, neurologic impairment and risk of fracture. Palliative radiotherapy is the treatment of choice in symptomatic bone lesions and is usually performed as percutaneous fractionated radiotherapy. Methods and study design From June 1987 to December 2009, 41 patients (median age, 64 years) with bone metastasis received radiotherapy in our department. The analyzed patients were treated for 67 sites of bone lesions. We analyzed the applied fractionation schedules and the preferred sites of metastasis and symptoms, evaluated the therapeutic outcome in terms of symptomatic improvement, and described the prognosis of these patients. Results Main indication for palliative radiotherapy was pain in 94% of all cases. Most frequent radiation protocols were 10 × 3 Gy (20 patients) and 20 × 2 Gy (19 patients). Median applied overall dose was 39 Gy (range, 4–48 Gy) and median single dose was 2.5 Gy (range, 1.8–4 Gy). The median duration of the radiotherapeutic treatment was 15 days (range, 2–24 days) and in 12 cases treatment was discontinuated. The overall response rate to palliative radiotherapy in bone metastasis was 77%. Median overall survival in both cholangiocarcinoma and hepatocellular carcinoma patients was 4.2 months after initiation of radiotherapy (range, 0.2–38.9). Conclusions Considering the poor prognosis of patients with bone metastasis in hepatocellular carcinoma and cholangiocarcinoma, with a poor median survival of 3.7–5.0 months according to our study and existing literature, shorter radiotherapy schedules or even single-fraction irradiation can be considered.

Aim To evaluate helical tomotherapy for the treatment of complex-shaped uni- or multifocal meningiomas. Methods and materials Between 2007 and 2009, 12 patients with complex-shaped meningiomas and/or multiple meningioma lesions were treated with helical tomotherapy. Histologic classification according to the most recent WHO classification for brain tumors was WHO grade I meningioma in 5 patients, atypical WHO grade II meningioma in 5 patients, and anaplastic WHO grade III meningioma in 2 patients. Eight patients were treated with primary radiotherapy, and in 4 patients tomotherapy was performed as re-irradiation for recurrent tumors. Results All patients were alive at the time of this analysis. Treatment was well tolerated by all patients. No severe side effects were observed. Four of 12 patients developed progression during follow-up at 2, 4, 17 and 29 months after radiotherapy. Of these, 2 patients were diagnosed with anaplastic meningiomas, and 2 patients suffered from atypical meningioma. Tumor progression developed after primary radiotherapy in 2 patients, and 2 recurrences developed after re-irradiation. Conclusions Helical tomotherapy can help meet the challenge of treating complex-shaped meningiomas in critical locations with one or multiple lesions due to the excellent dose distributions and the favorable clinical results.

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Chromaffin cells, the neuroendocrine cells of the adrenal medulla, play an important role in molecular, cellular, and developmental neurobiology. Unlike the closely related sympathetic neurons, chromaffin cells are able to proliferate throughout their whole life span. Proliferation of chromaffin cells in vivo is thought to be regulated by the interaction of neurogenic and hormonal signals. Previous studies have shown that chromaffin cells synthesize and release transforming growth factor-betas (TGF-betas). In the present study, effects of TGF-betas on proliferation and differentiation of chromaffin cells in mouse adrenal chromaffin cells were investigated in a genetic mouse model. We observed a significant increase in the total number of tyrosine hydroxylase-positive (TH(+)) cells in Tgfbeta2(-/-) knockout mouse embryos at embryonic day (E) 18.5 compared with wild-type animals (Tgfbeta2(+/+)), but no changes in the number of TH(+) cells were observed in Tgfbeta3(-/-) mouse mutants. At E15.5, but not at E18.5, there was a marked increase in the number of proliferative cell nuclear antigen-positive chromaffin cells in Tgfbeta2(-/-) knockout embryos compared with the wild-type group. On the other hand, there was a clear decrease in the ratio of total number of phenylethanolamine-N-methyltransferase-positive cells to the total TH(+) in Tgfbeta2(-/-) mice embryos at E18.5 compared with wild-type animals. This is the first documentation of the physiological significance of the TGF-beta2, an isoform that has been suggested to play a role in the regulation of chromaffin cells proliferation and differentiation based on in vitro experiments.

The developmental diversification of neural crest-derived sympathoadrenal (SA) progenitor cells into neuroendocrine adrenal chromaffin cells and sympathetic neurons has been thought to be largely understood. Based on two decades of in vitro studies with isolated SA progenitor and chromaffin cells, it was widely assumed that chromaffin cell development crucially depends on glucocorticoid hormones provided by adrenal cortical cells. However, analysis of mice lacking the glucocorticoid receptor has revealed that the chromaffin cell phenotype develops largely normally in these mice, except for the induction of the adrenaline synthesizing enzyme phenylethylamine N-methyl transferase. In a search for novel candidate genes that might be involved in triggering the sympathetic neuron/chromaffin cell decision, we have studied putative contributions of transforming growth factor (TGF)-alpha, BMP-4, and the transcription factor MASH-1, molecules with distinct expressions in SA progenitor cells, in their migratory pathways and final destinations. TGF-beta2 and -beta3 and BMP-4 are highly expressed in the wall of the dorsal aorta and in the adrenal anlagen during and after immigration of SA progenitors but expressed at much lower levels in sympathetic ganglia. We found that neutralizing antibodies against all three TGF-beta isoforms applied to the chorionic-allantoic membrane (CAM) of quail embryos interfere with proliferation of immigrated adrenal chromaffin cells but do not affect their specific neuroendocrine ultrastructural phenotype. Grafting of noggin-producing cells to the CAM, which scavenges BMPs, interferes with visceral arch and limb development but does not overtly affect the chromaffin phenotype. The transcription factor MASH-1 promotes early differentiation of SA progenitors. Mice deficient for MASH-1 lack sympathetic ganglia, whereas the adrenal medulla previously has been reported to be present. We show here that most adrenal medullary cells in MASH-1(-/-) mice identified by Phox2b immunoreactivity lack the catecholaminergic marker tyrosine hydroxylase. More surprisingly, most cells do not contain chromaffin granules and display a neuroblast-like ultrastructure and show strongly enhanced expression of c-RET comparable to that observed in sympathetic ganglia. Together, our data suggest that TGF-betas and BMP-4 do not seem to be essential for chromaffin cell differentiation. In contrast with previous reports, however, MASH-1 apparently plays a crucial role in chromaffin cell development.