Online Adaptive MR-Guided Ultrahypofractionated Radiotherapy of Prostate Cancer on a 1.5 T MR-Linac: Clinical Experience and Prospective Evaluation.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06).

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.

Preoperative growth dynamics of untreated glioblastoma: Description of an exponential growth type, correlating factors, and association with postoperative survival.

Background: Little is known about the growth dynamics of untreated glioblastoma and its possible influence on postoperative survival. Our aim was to analyze a possible association of preoperative growth dynamics with postoperative survival. Methods: We performed a retrospective analysis of all adult patients surgically treated for newly diagnosed glioblastoma at our center between 2010 and 2020. By volumetric analysis of data of patients with availability of ≥3 preoperative sequential MRI, a growth pattern was aimed to be identified. Main inclusion criterion for further analysis was the availability of two preoperative MRI scans with a slice thickness of 1 mm, at least 7 days apart. Individual growth rates were calculated. Association with overall survival (OS) was examined by multivariable. Results: Out of 749 patients screened, 13 had ≥3 preoperative MRI, 70 had 2 MRI and met the inclusion criteria. A curve estimation regression model showed the best fit for exponential tumor growth. Median tumor volume doubling time (VDT) was 31 days, median specific growth rate (SGR) was 2.2% growth per day. SGR showed negative correlation with tumor size (rho = -0.59, P < .001). Growth rates were dichotomized according to the median SGR.OS was significantly longer in the group with slow growth (log-rank: P = .010). Slower preoperative growth was independently associated with longer overall survival in a multivariable Cox regression model for patients after tumor resection. Conclusions: Especially small lesions suggestive of glioblastoma showed exponential tumor growth with variable growth rates and a median VDT of 31 days. SGR was significantly associated with OS in patients with tumor resection in our sample.

Ulcerating skin lesions from blastic plasmacytoid dendritic cell neoplasm responding to low-dose radiotherapy-a case report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can manifest with skin nodules and erythematous plaques. In most cases BPDCN progresses rapidly, causing multiple skin lesions and also affecting internal organs and bone marrow, warranting initiation of systemic therapies or hematopoietic stem cell transplantation (HCT). Although not curative, radiotherapy for isolated lesions might be indicated in case of (imminent) ulceration and large or symptomatic lesions. To this end, doses of 27.0-51.0 Gy have been reported. Here, we present the case of an 80-year-old male with BPDCN with multiple large, nodular, and ulcerating lesions of the thorax, abdomen, and face. Low-dose radiotherapy of 2â€¯× 4.0 Gy was administered to several lesions, which resolved completely within 1 week with only light residual hyperpigmentation of the skin in affected areas and reliably prevented further ulceration. Radiotoxicity was not reported. Therefore, low-dose radiotherapy can be an effective and low-key treatment in selected cases of BPDCN, especially in a palliative setting, with a favorable toxicity profile.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12).

Background and purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. Results: Median NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCPex was a median of 1.77 (range 1.60-1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible. Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Potential of pre-operative MRI features in glioblastoma to predict for molecular stem cell subtype and patient overall survival.

AIM OF THE STUDY: A molecular signature based on 10 mRNA abundances that characterizes the mesenchymal-to-proneural phenotype of glioblastoma stem(like) cells (GSCs) enriched in primary culture has been previously established. As this phenotype has been proposed to be prognostic for disease outcome the present study aims to identify features of the preoperative MR imaging that may predict the GSC phenotype of individual tumors. MATERIAL/METHODS: Molecular mesenchymal-to-proneural mRNA signatures and intrinsic radioresistance (SF4, survival fraction at 4 Gy) of primary GSC-enriched cultures were associated with survival data and pre-operative MR imaging of the corresponding glioblastoma patients of a prospective cohort (n = 24). The analyzed imaging parameters comprised linear vectors derived from tumor volume, necrotic volume and edema as contoured manually. RESULTS: A necrosis/tumor vector ratio and to a weaker extent the product of this ratio and the edema vector were identified to correlate with the mesenchymal-to-proneural mRNA signature and the SF4 of the patient-derived GSC cultures. Importantly, both parameter combinations were predictive for overall survival of the whole patient cohort. Moreover, the combination of necrosis/tumor vector ratio and edema vector differed significantly between uni- and multifocally recurring tumors. CONCLUSION: Features of the preoperative MR images may reflect the molecular signature of the GSC population and might be used in the future as a prognostic factor and for treatment stratification especially in the MGMT promotor-unmethylated sub-cohort of glioblastoma patients.

Is consolidative thoracic radiotherapy of extensive-stage small cell lung cancer still beneficial in the era of immunotherapy? A retrospective analysis.

PURPOSE: Extensive-stage small cell lung cancer (ES-SCLC) carries a dismal prognosis. The benefit of consolidative thoracic radiotherapy (TR) after first-line chemoimmunotherapy with PD-L1 inhibitors in this setting remains unclear. As TR can improve overall survival (OS) after conventional chemotherapy, we retrospectively analyzed OS of an inhouse cohort treated either with TR or with chemoimmunotherapy alone. METHODS: A total of 41 patients treated with chemoimmunotherapy with PD-L1 inhibitors (atezolizumab or durvalumab) for ES-SCLC at our hospital since 2019 were analyzed. TR was administered in 10 fractions of 3 Gy. Patient characteristics, number of immunotherapy cycles received, brain irradiation, and presence of hepatic and cerebral metastasis at diagnosis were assessed. Primary endpoint was OS after first diagnosis. RESULTS: Consolidative TR was associated with a significantly longer OS than systemic therapy alone (1-year OS 78.6% and 2­year OS 37.1% vs. 1­year OS 39.7% and 2 years not reached, p = 0.019). With regard to radiotherapy indication, survival at 1 year was 88.9% (log-rank p = 0.016) for patients receiving consolidative TR. For patients receiving TR in case of progression, 1­year survival was 66.7%. Hepatic and cerebral metastasis at first diagnosis had no significant effect on OS. CONCLUSION: TR was significantly associated with longer OS. The survival benefit of TR was most pronounced for consolidative radiotherapy after initial chemoimmunotherapy compared to TR in case of progression. Although retrospective findings need to be interpreted with caution, in the absence of prospective data, our findings provide a basis for offering consolidative TR in the era of chemoimmunotherapy.

Clinical outcome of biomarker-guided therapies in adult patients with tumors of the nervous system.

Background: The clinical utility of molecular profiling and targeted therapies for neuro-oncology patients outside of clinical trials is not established. We aimed at investigating feasibility and clinical utility of molecular profiling and targeted therapy in adult patients with advanced tumors in the nervous system within a prospective observational study. Methods: molecular tumor board (MTB)@ZPM (NCT03503149) is a prospective observational precision medicine study for patients with advanced tumors. After inclusion of patients, we performed comprehensive molecular profiling, formulated ranked biomarker-guided therapy recommendations based on consensus by the MTB, and collected prospective clinical outcome data. Results: Here, we present initial data of 661 adult patients with tumors of the nervous system enrolled by December 31, 2021. Of these, 408 patients were presented at the MTB. Molecular-instructed therapy recommendations could be made in 380/408 (93.1%) cases and were prioritized by evidence levels. Therapies were initiated in 86/380 (22.6%) cases until data cutoff. We observed a progression-free survival ratio >1.3 in 31.3% of patients. Conclusions: Our study supports the clinical utility of biomarker-guided therapies for neuro-oncology patients and indicates clinical benefit in a subset of patients. Our data might inform future clinical trials, translational studies, and even clinical care.

Neurobiological correlates and attenuated positive social intention attribution during laughter perception associated with degree of autistic traits.

Laughter plays an important role in group formation, signaling social belongingness by indicating a positive or negative social intention towards the receiver. In adults without autism, the intention of laughter can be correctly differentiated without further contextual information. In autism spectrum disorder (ASD), however, differences in the perception and interpretation of social cues represent a key characteristic of the disorder. Studies suggest that these differences are associated with hypoactivation and altered connectivity among key nodes of the social perception network. How laughter, as a multimodal nonverbal social cue, is perceived and processed neurobiologically in association with autistic traits has not been assessed previously. We investigated differences in social intention attribution, neurobiological activation, and connectivity during audiovisual laughter perception in association with the degree of autistic traits in adults [N = 31, Mage (SD) = 30.7 (10.0) years, nfemale = 14]. An attenuated tendency to attribute positive social intention to laughter was found with increasing autistic traits. Neurobiologically, autistic trait scores were associated with decreased activation in the right inferior frontal cortex during laughter perception and with attenuated connectivity between the bilateral fusiform face area with bilateral inferior and lateral frontal, superior temporal, mid-cingulate and inferior parietal cortices. Results support hypoactivity and hypoconnectivity during social cue processing with increasing ASD symptoms between socioemotional face processing nodes and higher-order multimodal processing regions related to emotion identification and attribution of social intention. Furthermore, results reflect the importance of specifically including signals of positive social intention in future studies in ASD.

The immunohistochemical expression of SSTR2A is an independent prognostic factor in meningioma.

The expression of somatostatin receptors in meningioma is well established. First, suggestions of a prognostic impact of SSTRs in meningioma have been made. However, the knowledge is based on few investigations in small cohorts. We recently analyzed the expression of all five known SSTRs in a large cohort of over 700 meningiomas and demonstrated significant correlations with WHO tumor grade and other clinical characteristics. We therefore expanded our dataset and additionally collected information about radiographic tumor recurrence and progression as well as clinically relevant factors (gender, age, extent of resection, WHO grade, tumor location, adjuvant radiotherapy, neurofibromatosis type 2, primary/recurrent tumor) for a comprehensive prognostic multivariate analysis (n = 666). The immunohistochemical expression scores of SSTR1, 2A, 3, 4, and 5 were scored using an intensity distribution score ranging from 0 to 12. For recurrence-free progression analysis, a cutoff at an intensity distribution score of 6 was used. Univariate analysis demonstrated a higher rate of tumor recurrence for increased expression scores for SSTR2A, SSTR3, and SSTR4 (p = 0.0312, p = 0.0351, and p = 0.0390, respectively), while high expression levels of SSTR1 showed less frequent tumor recurrences (p = 0.0012). In the Kaplan-Meier analysis, a higher intensity distribution score showed a favorable prognosis for SSTR1 (p = 0.0158) and an unfavorable prognosis for SSTR2A (0.0143). The negative prognostic impact of higher SSTR2A expression remained a significant factor in the multivariate analysis (RR 1.69, p = 0.0060). We conclude that the expression of SSTR2A has an independent prognostic value regarding meningioma recurrence.

Radiotherapy planning parameters correlate with changes in the peripheral immune status of patients undergoing curative radiotherapy for localized prostate cancer.

PURPOSE: The influence of radiotherapy on patient immune cell subsets has been established by several groups. Following a previously published analysis of immune changes during and after curative radiotherapy for prostate cancer, this analysis focused on describing correlations of changes of immune cell subsets with radiation treatment parameters. PATIENTS AND METHODS: For 13 patients treated in a prospective trial with radiotherapy to the prostate region (primary analysis) and five patients treated with radiotherapy to prostate and pelvic nodal regions (exploratory analysis), already published immune monitoring data were correlated with clinical data as well as radiation planning parameters such as clinical target volume (CTV) and volumes receiving 20 Gy (V20) for newly contoured volumes of pelvic blood vessels and bone marrow. RESULTS: Most significant changes among immune cell subsets were observed at the end of radiotherapy. In contrast, correlations of age and CD8+ subsets (effector and memory cells) were observed early during and 3 months after radiotherapy. Ratios of T cells and T cell proliferation compared to baseline correlated with CTV. Early changes in regulatory T cells (Treg cells) and CD8+ effector T cells correlated with V20 of blood vessels and bone volumes. CONCLUSIONS: Patient age as well as radiotherapy planning parameters correlated with immune changes during radiotherapy. Larger irradiated volumes seem to correlate with early suppression of anti-cancer immunity. For immune cell analysis during normofractionated radiotherapy and correlations with treatment planning parameters, different time points should be looked at in future projects. TRIAL REGISTRATION NUMBER: NCT01376674, 20.06.2011.

Increased proliferation is associated with CNS invasion in meningiomas.

INTRODUCTION: Meningiomas are the most common benign intracranial neoplasms. CNS invasion in meningiomas has been integrated into the 2016 WHO classification of CNS tumors as a stand-alone criterion for atypia. Since then, its prognostic impact has been debated based on contradictory results from retrospective analyses. The aim of the study was to elucidate whether histopathological evidence of CNS invasion is associated with increased proliferative potential. METHODS: We have conducted a quantified measurement of the proliferation marker Ki67 and analyzed its association with CNS invasion determined by histology together with other established prognostic markers of progression. Routine, immunohistochemical staining for Ki67 were digitalized and automatic quantification was done using Image J software. RESULTS: Overall, 1718 meningiomas were assessed. Histopathological CNS invasion was seen in 108 cases (6.7%). Uni- and multivariate analysis revealed a significantly higher Ki67 proliferation rate in meningiomas with CNS invasion (p < 0.0001 and p = 0.0098, respectively). CONCLUSIONS: Meningiomas with histopathological CNS invasion show a higher proliferative activity.

Retrospective analysis of recurrence patterns and clinical outcome of grade II meningiomas following postoperative radiotherapy.

BACKGROUND: Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated. METHODS: The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions. RESULTS: Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth. CONCLUSIONS: The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

The role of Simpson grading in meningiomas after integration of the updated WHO classification and adjuvant radiotherapy.

Since the introduction of the Simpson grading for the extent of resection in meningiomas in 1957, its usefulness in modern neurosurgery has been challenged. Especially, the updated WHO classification regarding brain invasion and the efficacy of radiation therapy has not been taken into account when evaluating the prognostic role of the Simpson grading in this era. We analyzed the clinical and histopathological data of 1571 meningiomas that were surgically resected in the authors' institution between July 2003 and March 2017. Operative reports were reviewed regarding the extent of resection according to Simpson grading. Meningioma subtype according to the updated WHO classification of 2016 and clinical characteristics and time to tumor progression were analyzed. The mean follow-up was 38.4 months (range 1.2 to 195.6). A higher rate of tumor recurrence was observed for male gender, younger age, recurrent tumors, non-spinal tumor localization, higher WHO, and Simpson grades in the univariate analysis. In the multivariate analysis older age, recurrent tumors and higher WHO grades remained negative prognostic factors. Among the different Simpson grades, the relative risk for recurrence was highest for grade IV compared to all other grades (each p < 0.0001), while there was no difference between Simpson grades I and II. Adjuvant radiotherapy showed lower rates of tumor recurrence. Subtotal microsurgical resection remains an independent prognostic factor with a higher rate of tumor recurrence. The prognostic benefit of radical treatment of the dural attachment is questionable and needs to be considered when weighing the intraoperative risks of radicality.

Neuro-Sweet syndrome - a rare differential diagnosis in aseptic meningoencephalitis.

Acute febrile neutrophilic dermatosis (Sweet's syndrome) is a dermatological entity, which may be associated with malignancies, drugs, and infections and which is characterized by high fever, elevated neutrophils, and tender erythematous skin lesions. Involvement of the nervous system - Neuro-Sweet syndrome (NSS) - is rare, manifesting most commonly with an encephalitic syndrome in addition to fever and dermal lesions. Here, we report an unusual case of NSS in a Caucasian male patient in the setting of B-cell-lymphocytosis, with encephalitis preceding dermal lesions. Symptoms resolved completely in response to corticoids. NSS is a rare, but important differential diagnosis in the work-up of febrile aseptic meningoencephalitis unresponsive to anti-infectious treatment. Due to its rarity and clinical variability, diagnosis of NSS might be challenging. Knowledge of this entity may facilitate proper diagnosis and differentiation from conditions with similar clinical presentation, especially Neuro-Behçet's disease. It may further lead to early detection of a potentially underlying malignancy and help in initiating adequate therapy.

Reduced functional connectivity to the frontal cortex during processing of social cues in autism spectrum disorder.

People diagnosed with autism spectrum disorder (ASD) characteristically present with severe difficulties in interpreting every-day social signals. Currently it is assumed that these difficulties might have neurobiological correlates in alterations in activation as well as in connectivity in and between regions of the social perception network suggested to govern the processing of social cues. In this study, we conducted functional magnetic resonance imaging (fMRI)-based activation and connectivity analyses focusing on face-, voice-, and audiovisual-processing brain regions as the most important subareas of the social perception network. Results revealed alterations in connectivity among regions involved in the processing of social stimuli in ASD subjects compared to typically developed (TD) controls-specifically, a reduced connectivity between the left temporal voice area (TVA) and the superior and medial frontal gyrus. Alterations in connectivity, moreover, were correlated with the severity of autistic traits: correlation analysis indicated that the connectivity between the left TVA and the limbic lobe, anterior cingulate and the medial frontal gyrus as well as between the right TVA and the frontal lobe, anterior cingulate, limbic lobe and the caudate decreased with increasing symptom severity. As these frontal regions are understood to play an important role in interpreting and mentalizing social signals, the observed underconnectivity might be construed as playing a role in social impairments in ASD.